| Hao Watatu with Other Mamma

Home , Abetimus, Etaracizumab

|HAO WATATU WITHUS009840537B2 OTHER MAMMA MIT (12 ) United States Patent ( 10) Patent No. : US 9 ,840 , 537 B2 Gonzalez et al. ( 45 ) Date of Patent: Dec . 12 , 2017 (54 ) SELECTIVE DELIVERY MOLECULES AND ( 56 ) References Cited METHODS OF USE U . S . PATENT DOCUMENTS ( 71 ) Applicant: Avelas Biosciences , Inc. , La Jolla , CA 4 , 466 , 919 A 8 / 1984 Weingarten (US ) 4 ,507 , 389 A 3/ 1985 Weingarten 5 , 434 , 073 A 7 / 1995 Dawson et al . 5 ,674 , 980 A 10 / 1997 Frankel et al . (72 ) Inventors : Jesus Gonzalez , Carlsbad , CA (US ); 5 ,747 ,641 A 5 / 1998 Frankel et al. Junjie Liu , San Diego , CA (US ) 6 ,083 , 486 A 7 / 2000 Weissleder et al . 6 , 348, 185 B1 2 / 2002 Piwnica -Worms ( 73 ) Assignee: AVELAS BIOSCIENCES , INC . , La 6 , 592 , 847 B1 7 /2003 Weissleder et al. Jolla , CA (US ) 7, 431, 915 B2 10 / 2008 Jiang et al. 7 ,985 , 401 B2 7 / 2011 Jiang et al . 8 , 110 , 554 B2 2 / 2012 Jiang et al . ( * ) Notice: Subject to any disclaimer, the term of this 8 , 486 , 373 B2 7 /2013 Weissleder et al. patent is extended or adjusted under 35 8 , 642 ,561 B2 2 / 2014 Jiang et al. U . S .C . 154 (b ) by 0 days . 8 , 685, 372 B2 4 / 2014 Tsien et al . 9 , 072 , 773 B2 7 / 2015 Gonzalez et al . 9 , 072 , 792 B2 7 / 2015 Jiang et al . (21 ) Appl. No. : 15 /295 ,482 9 , 278, 144 B2 3 / 2016 Liu et al. 9 , 353 , 154 B2 5 / 2016 Gonzalez et al . (22 ) Filed : Oct . 17 , 2016 9 , 371 , 367 B1 6 / 2016 Gonzalez et al . 2002 / 0009786 A1 1 / 2002 Tang et al. (65 ) Prior Publication Data 2003 / 0176335 A1 9 /2003 Zhang et al. 2005 / 0069494 Al 3 / 2005 Li et al. US 2017/ 0044214 A1 Feb . 16 , 2017 2007 /0041904 A1 2 / 2007 Jiang et al . 2011 /0160147 Al 6 / 2011 Dal Pozzo et al. 2012 /0134922 A1 5 /2012 Tsien et al . 2012 /0134931 A1 5 / 2012 Tsien et al . Related U . S . Application Data 2012 /0148610 A1 6 / 2012 Doronina et al . 2013 / 0020537 A1 1 / 2013 Maruno et al . (63 ) Continuation of application No . 15 / 132 ,773 , filed on 2013 / 0078188 AL 3 / 2013 Tsien et al . Apr. 19 , 2016 , now Pat . No. 9, 504 ,763 , which is a 2015 /0359908 AL 12 / 2015 Gonzalez et al . continuation of application No . 15 /006 , 832 , filed on 2016 /0082119 Al 3/ 2016 Gonzalez et al. Jan . 26 , 2016 , now Pat. No. 9 ,371 ,367 , which is a ( Continued ) continuation of application No. 14 / 235 , 522 , filed as application No . PCT /US2012 /048732 on Jul. 27 , FOREIGN PATENT DOCUMENTS 2012 , now Pat . No. 9 , 278 , 144 . EP 2399939 A2 12 /2011 WO WO -0175067 A2 10 / 2001 WO W O -2005042034 AL 5 /2005 (60 ) Provisional application No . 61 /513 ,287 , filed on Jul. 29 , 2011. (Continued ) (51 ) Int . Cl. OTHER PUBLICATIONS A61K 38 /00 ( 2006 .01 ) Tomalia et al. Dendrimers as multi -purpose nanodevices for oncol COZK 7 / 08 ( 2006 .01 ) ogy drug delivery and diagnostic imaging. Cellular Delivery of A61K 49/ 00 ( 2006 .01 ) Therapeutic Macromolecules. 2007. vol. 35 , part 1 , pp . 61 -67 . * COZK 14 /435 ( 2006 .01 ) U . S . Appl. No. 13 / 384 ,581 Office Action dated Dec. 9 , 2016 . GOIN 21 / 64 ( 2006 .01 ) Yuan et al . Challenges associated with the targeted delivery of GOIN 33 /574 ( 2006 .01 ) gelonin to claudin -expressing cancer cells with the use of activat GOIN 33 / 58 ( 2006 .01 ) able cell penetrating peptides to enhance potency . BMC 11 ( 1 ): 61 (52 ) U . S . CI. ( 2011 ) . ??? ...... CO7K 7/ 08 (2013 .01 ); A61K 49 /0021 ( 2013 .01 ) ; A61K 49 /0032 (2013 . 01 ) ; A61K (Continued ) 49 /0034 (2013 .01 ) ; A61K 49 / 0054 (2013 . 01 ) ; A61K 49 / 0056 ( 2013 . 01 ) ; CO7K 14 /435 Primary Examiner — Marcela M Cordero Garcia (2013 .01 ); GOIN 21 /6428 ( 2013 .01 ); GOIN ( 74 ) Attorney, Agent, or Firm — Wilson Sonsini Goodrich 33 /574 (2013 .01 ) ; GOIN 33 /582 (2013 .01 ) ; & Rosati A61K 38 /00 (2013 .01 ) ; GOIN 2021/ 6432 ( 2013 .01 ) ; GOIN 2021 /6439 ( 2013. 01 ) (57 ) ABSTRACT ( 58 ) Field of Classification Search Disclosed herein is a selective delivery molecule compris ???CPC ...... A61K 38 /00 ; A61K 49 /0021 ; A61K ing : ( a) an acidic sequence (portion A ) which is effective to 49 /0032 , A61K 49 /0034 ; A61K 49 /0054 ; inhibit or prevent the uptake into cells or tissue retention , ( b ) A61K 49 /0056 ; CO7K 14 / 435 ; COOK a molecular transport or retention sequence (portion B ) , and 7 / 08 ; GOIN 2021/ 6432 ; GOIN ( c ) a linker between portion A and portion B , and ( d ) at least 2021/ 6439 ; GOIN 21 /6428 ; GOIN one cargo moiety . 33 /574 ; GOIN 33 / 582 See application file for complete search history . 20 Claims, 11 Drawing Sheets US 9, 840 ,537 B2 Page 2 ( 56 ) References Cited Olson et al. Activatable cell penetrating peptides for Imaging Protease Activity In Vivo . http :\ \escholarship .org /us / item / U . S . PATENT DOCUMENTS 3sc4h3n7 # page (2008 ) . Olson et al . Activatable cell penetrating peptides linked to 2016 /0220707 A1 8 /2016 Gonzalez et al. nanoparticles as dual probes for in vivo fluorescence and MR 2017 /0029466 AL 2 / 2017 Jiang et al. imaging of proteases . PNAS 107 ( 9 ) :4311 - 4316 (2010 ) . Olson et al . In vivo characterization of activatable cell penetrating FOREIGN PATENT DOCUMENTS peptides for targeting protease activity in cancer . Integr Biol ( Camb ) 1 ( 5 - 6 ): 382 - 393 (2009 ). WO WO - 2006125134 AL 11 / 2006 Olson et al. In vivo fluorescence imaging of atherosclerotic plaques WO WO - 2011008992 A2 1 / 2011 with activatable cell- penetrating peptides thrombin activity. Integr wo WO - 2011008996 A2 1 / 2011 Biol 4 :595 -605 ( 2012 ) . WO WO - 2014120837 A2 8 / 2014 WO WO - 2014120974 Al 8 / 2014 PCT/ US2010 /042184 International Search Report dated Apr. 26 , Wo 2011 . WO - 2014176284 Al 10 / 2014 PCT/ US2010 /042188 International Search Report dated Mar. 31 , 2011 . OTHER PUBLICATIONS PCT/ US2012 / 048732 International Search Report and Written Opinion dated Apr. 30 , 2013 . Aguilera et al . Systemic in vivo distribution of activatable cell PCT/ US2014 /013942 International Preliminary Report on Patent penetrating peptides is superior to that of cell penetrating peptides . ability dated Aug . 13 , 2015 . Integr Biol ( Camb ) . 1 ( 5 - 6 ) : 371- 381 ( 2009 ) . PCT /US2014 /013942 International Search Report and Written Arnold et al. Substrate specificity of cathepsins D and E determined Opinion dated May 28 , 2014 . by N - terminal and C - terminal sequencing of peptide pools . Eur J PCT/ US2014 /035043 International Preliminary Report on Patent Biochem 249: 171- 179 ( 1997 ) . ability dated Nov. 5 , 2015 . Bartles et al. Identification and characterization of espin , an actin PCT/ US2014 /035043 International Search Report and Written binding protein localized to the F - actin - rich junctional plaques of Opinion dated Aug . 26 , 2014 . 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References Cited Van Duijnhoven et al. Tumor Targeting of MMP- 2 / 9 Activatable ( 56 ) Cell -Penetrating Imaging Probes is Caused by Tumor - independent OTHER PUBLICATIONS Activation . J Nucl Med 52 :279 - 286 (2011 ) . Van Vlerken et al . Poly ( ethylene glycol) -modified nanocarriers for U . S . Appl. No . 13 / 384 ,581 Office Action dated Nov. 26 , 2014 . U . S . Appl. No. 13 / 384 ,591 Office Action dated Jul. 14 , 2015 . tumor- targeted and intracellular delivery. Pharma Res 24 ( 8 ): 1405 U . S . Appl . No. 13 /384 ,591 Office Action dated Jun . 24 , 2016 . 1414 ( 2007 ) . U . S . Appl. No. 13 / 384 , 591 Office Action dated Mar. 1, 2016 . Vartak et al. In vitro evaluation of functional interaction of integrin U . S . Appl. No. 13 / 384 ,591 Office Action dated Nov . 28 , 2014 . avß3 and matrix metalloprotease - 2 . Mol. Pharmaceutics 6 ( 6 ) : 1856 U . S . Appl. No. 13 / 566 , 913 Office Action dated Feb . 24 , 2015 . 1867 ( 2009 ) . U . S . Appl. No. 13 / 566 , 913 Office Action dated Jan . 29 , 2016 . Wang et al. Visualizing the mechanical activation of Src . Nature U . S . Appl. No. 13 / 566 , 913 Office Action dated Jun . 30 , 2015 . 434 : 1040 - 1045 ( Apr. 21 , 2005 ). U . S . Appl. No . 13 / 566 , 913 Office Action dated Sep . 12 , 2016 . U . S . Appl. No. 14 /235 ,522 Office Action dated Sep . 8 , 2015 . Whitney et al. Parallel in Vivo and in Vitro Selection Using Phage U . S . Appl. No. 15 /006 ,832 First Action Interview dated Mar. 21, Display Identifies Protease -dependent Tumor- targeting Peptides. 2016 . The Journal of Biological Chemistry 285 (29 ): 22532- 22541 ( 2010 ) . Van Berkel et al . Fluorogenic Peptide -Based Substrates for Moni Zhu et al. Dual- Functional , Receptor- Targeted Fluorogenic Probe toring Thrombin Activity . ChemMedChem 7: 606 -617 ( 2012 ). for in Vivo Imaging of Extracellular Protease Expressions . Van Dam et al. Intraoperative tumor - specific fluorescence imaging Bioconjugate Chemistry 22 (6 ): 1001 - 1005 ( 2011 ). in ovarian cancer by folate receptor- a targeting: first in -human results . Nature Medicine 17 : 1315 - 1319 ( 2011 ). * cited by examiner U . S . Patent Dec . 12, 2017 Sheet 1 of 11 US 9 ,840 ,537 B2

Contralateral tissue Tumor

X0 - 6 - 2016 $ 24. » vosdos85 11. . 679

Av & 0 - SAL w $ 235 Pouvoix * * * *

FIG . 1 U . S . Patent Dec . 12, 2017 Sheet 2 of 11 US 9 ,840 ,537 B2

9000 NO MMP2 ** 8000 * 7000 * MMP2 treatment

6000 ** . 8 . ** * * ** 5000 # * * ** ** AFU ** AFU 4000 * * 0 *2400 * . * 40 3000 . * ** ** * * ** * DANA 2000 *** * *** *

1000 * -. . .. . 0 .. . .. 640 660 680680 700700 720720 740 740 760 780 800 Wavelength (nm ) Wavelength (nm )

FIG . 2 U . S . Patent Dec . 12, 2017 Sheet 3 of 11 US 9 ,840 ,537 B2

6000

5000

* 4000 *** * *** * * * * * * ** * * *** * ** AFU *** * * * * * 3000

2000 1000 ...... e 20 40 60 80 100 120 140 OO Time after MMP cleavage (minutes )

FIG . 3 U . S . Patent Dec . 12, 2017 Sheet 4 of 11 US 9 ,840 ,537 B2

Cntri SDM - 10 /Buffer SDM - 10 / Tumor homogenates M9 TH2 GM TH3 GM Noncleaved SDM - 10 ( quenched )

women Cleaved SDM - 10 ( fluorescent)

FIG . 4 U . S . Patent Dec . 12, 2017 Sheet 5 of 11 US 9 ,840 ,537 B2

DUSUNUZUSUS.P * Serum COö * Tumor Liver .POSSIP & Kidney NAO | SDMSDM - 1 SDMSDM - 2 SDMSDM -6

LulFIG . 5 U . S . Patent Dec . 12, 2017 Sheet 6 of 11 US 9 ,840 ,537 B2

painti , - sex , Cyser uxlatz , y -sex , cy7e * * fpxinti / Exp1) / ( pxlnt2 / Exp2 )

FIG . 6 U . S . Patent Dec . 12, 2017 Sheet 7 of 11 US 9 ,840 ,537 B2

primary tumor

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0 como...... 0 100 200 300 400 500 600 Time (min ) ......

FIG . 7 U . S . Patent Dec . 12, 2017 Sheet 8 of 11 US 9 ,840 ,537 B2

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si Normal Breast Tissue Avg (with std deviation ) w WD2808 100000000 WD2821 w WD2815 wwwWD2817 yo 0 to u W WD2824 tongueurother Cy5/Cy7Ratio ** * 0 T TTTIIIII m el A wwwwwwwwww minimum numinini mimi en TUTTUUUUUTTITUUTTIAmint TUTTITUUT

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FIG , 8 U . S . Patent Dec . 12, 2017 Sheet 9 of 11 US 9 ,840 ,537 B2

YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY

- 0 .017 - SDM -25

- SDM - 32 0 .015

- PIPP-PP

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0 . 009 .

0 .007

0 . 005 WD2808 WD2815 WD2823

FIG . 9 U . S . Patent Dec . 12, 2017 Sheet 10 of 11 US 9 ,840 ,537 B2

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* positive ydus node wotheto onedvojssus & negative uduk

FIG . 10 U . S . Patent Dec . 12, 2017 Sheet 11 of 11 US 9 ,840 ,537 B2

Www

truepositiverate(sensitivity) -

+ -

+ 0 .0 * 0 . 0 0 . 2 0 .4 0 .6 0 .8 1. 0 false positive rate (1 -Specificity )

FIG . 11 US 9 , 840 , 537 B2 SELECTIVE DELIVERY MOLECULES AND Cm are each independently selected from any amino acid METHODS OF USE having a free thiol group , any amino acid having a N - ter minal amine group , and any amino acid with a side chain CROSS -REFERENCES capable of forming an oxime or hydrazone bond upon 5 reaction with a hydroxylamine or hydrazine group . In some This application is a continuation of U . S . application Ser . embodiments , C4, CB , and cy are each independently selected No . 15 / 132 , 773 , filed Apr. 19 , 2016 , which is a continuation from D - cysteine , D - glutamate , lysine, and para - 4 -acetyl of U .S . application Ser . No. 15/ 006 , 832 , filed Jan . 26 , 2016 , L -phenylalanine . In some embodiments , CB is any amino now issued as U . S . Pat. No . 9 ,371 , 367 on Jun . 21, 2016 , acid having a free thiol group . In some embodiments , CB is which is a continuation of U . S . application Ser. No . 14 / 235 , 10 D - cysteine. In some embodiments , CA is any amino acid 522 , filed on Sep . 18 , 2014 , now issued as U . S . Pat . No. having a N -terminal amine group . In some embodiments , CA 9 ,278 , 144 on Mar. 8 , 2016 , which is the National Stage entry is D - glutamate . In some embodiments , CA is lysine . In some of International Application No . PCT /US2012 / 048732 filed embodiments , cy is any amino acid with a side chain on Jul. 27 , 2012 , which claims priority to U . S . Provisional capable of forming an oxime or hydrazone bond upon Patent Application No .61 /513 ,287 , titled “ Selective Deliv - 15 reaction with a hydroxylamine or hydrazine group . In some ery Molecules and Methods of Use ” and filed Jul. 29 , 2011 , embodiments , cm is para - 4 - acetyl L - phenylalanine . In some the disclosures of which are incorporated herein by refer embodiments , X is cleavable by a protease . In some embodi ence in their entireties . ments , X is cleavable by a matrix metalloproteinase. In some embodiments , X comprises an amino acid sequence that is SEQUENCE LISTING 20 cleavable by MMP2, MMP7 , MMP9 , or MMP14 . In some embodiments , X comprises a peptide linkage . In some The instant application contains a Sequence Listing which embodiments , X comprises an amino acid sequence selected has been submitted electronically in ASCII format and is from : PLGLAG (SEQ ID NO : 2 ) , PLG - C (me ) - AG (SEQ ID hereby incorporated by reference in its entirety . Said ASCII NO : 1 ) , RPLALWRS (SEQ ID NO : 7 ), ESPAYYTA (SEQ copy , created on Aug . 8 , 2016 , is named “ 39088708303 . txt " 25 ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL ( SEQ ID and is 10, 795 bytes in size . NO : 10 ) , RLQLKL (SEQ ID NO : 11 ) , and RLQLK ( Ac ) ( SEQ ID NO : 12 ) . In some embodiments , X comprises the SUMMARY OF THE INVENTION amino acid sequence PLGLAG (SEQ ID NO : 2 ) . In some embodiments , X comprises the amino acid sequence PLG Disclosed herein , in certain embodiments , are selective 30 C (me ) - AG (SEO ID NO : 1 ). In some embodiments , X delivery molecule of Formula I , having the structure : comprises the amino acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodiments , X comprises the amino acid [DA - Ca ]- A -[ c -M ]- X -B -[ CB -Dp ] Formula I sequence DPRSFL (SEQ ID NO : 9 ) . In some embodiments , wherein , X comprises the amino acid sequence RLQLKL (SEQ ID X is a cleavable linker; 35 NO : 11) . In some embodiments , X comprises the amino acid A is a peptide with a sequence comprising 5 to 9 acidic sequence RLQLK (Ac ) (SEQ ID NO : 12 ) (SEQ ID NO : 12) . amino acids ; In some embodiments , M is selected from a protein , a B is a peptide with a sequence comprising 7 to 9 basic natural polymer , a synthetic polymer , or a dendrimer. In amino acids ; some embodiments, M is selected from dextran , a PEG CA, CB , and cm each independently comprise 0 -1 amino 40 polymer , albumin , or a combination thereof. In some acid ; embodiments , M is a PEG . In some embodiments , M is M is a macromolecule ; and selected from PEG 5 kDa , PEG 12 kDa , PEG 20 kDa , PEG DA and DB are each independently selected from an 30 kDa , and PEG40 kDa. In some embodiments , DA and DB imaging agent and a therapeutic ; and are a pair of acceptor and donor fluorescent moieties that are wherein [ cvM ] is bound to at any position on A or X , 45 capable of undergoing Försters/ fluorescence resonance [ D -CA ] is bound to any amino acid on A , and [ CR -DR ) is energy transfer with the other. In some embodiments, D , and bound to any amino acid on B . De are Cy5 and Cy7 . In some embodiments , D , and DR are In some embodiments , A and B do not have an equal Cy5 and IRDye750 . In some embodiments, DA and Do are number of acidic and basic amino acids. In some embodi- Cy5 and IRDye800 . In some embodiments, D , and Do are ments, the number of basic amino acids in B is greater than 50 Cy5 and ICG . In some embodiments , DA and Do are a the number of acidic amino acids in A . In some embodi- fluorescent moiety and a fluorescence - quenching moiety . In ments , A is a peptide comprising 5 or 9 consecutive gluta some embodiments , the molecule of Formula I is : SDM - 14 , mates (SEQ ID NO : 3 ) . In some embodiments , B is a peptide SDM -15 , SDM - 23, SDM -24 , SDM -25 , SDM -26 , SDM - 27 , comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In SDM -32 , or SDM - 35 . some embodiments , A is a peptide comprising 5 or 9 55 Disclosed herein , in certain embodiments , are selective consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide delivery molecules of Formula I , having the structure : comprising 8 or 9 consecutive arginines (SEQ ID NO : 4) . In some embodiments , A is a peptide comprising 5 consecutive DACA -A - levM ] -X - B - le -Del Formula I glutamates (SEQ ID NO : 5 ) and B is a peptide comprising wherein , 8 consecutive arginines (SEQ ID NO : 6 ) . In some embodi - 60 X is a cleavable linker; ments, CA , CB , and cy are each independently a 0 - 1 amino A is a peptide with a sequence comprising 5 to 9 acidic acid . In some embodiments, CA , CR , and Cy are each inde amino acids ; pendently selected from a naturally occurring amino acid or B is a peptide with a sequence comprising 7 to 9 basic a non -naturally - occurring amino acid . In some embodi ammoamino acids; ments , CA, CB , and cm are each independently selected from 65 CA, CB , and cm each independently comprise 0 - 1 amino a D amino acid , a L amino acid , an a - amino acid , a ß - amino acid ; acid , or a y -amino acid . In some embodiments , CA, CB , and Mis a polyethylene glycol (PEG ) polymer , and US 9 , 840 , 537 B2 DA and Do are each independently an imaging agent; and Cy5 and IRDye800. In some embodiments , DA and Do are wherein [ cy - M ] is bound to at any position on A or X , Cy5 and ICG . In some embodiments, DA and De are a [ D , - C ) is bound to any amino acid on A , and CR -DR ] is fluorescent moiety and a fluorescence - quenching moiety . In bound to any amino acid on B . some embodiments , the molecule of Formula I is : SDM - 14 , In some embodiments , A and B do not have an equal 5 SDM - 15 , SDM - 23 , SDM - 24 , SDM - 25 , SDM - 26 , SDM - 27 , number of acidic and basic amino acids. In some embodi- SDM - 32 ; or SDM - 35 . ments, the number of basic amino acids in B is greater than Disclosed herein , in certain embodiments , are molecules the number of acidic amino acids in A . In some embodi - of Formula II , having the structure : ments, A is a peptide comprising 5 or 9 consecutive gluta mates (SER ID NO : 3 ) . In some embodiments , B is a peptide 10 A1- X , -B1 ; Formula II comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In wherein , some embodiments , A is a peptide comprising 5 or 9 X , is a cleavable linker; consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide Aj is a peptide with a sequence comprising 5 to 9 acidic comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ). In amino acids and having a first reactive amino acid some embodiments, Ais a peptide comprising 5 consecutive 15 moiety ca ; glutamates (SEQ ID NO : 5 ) and B is a peptide comprising B , is a peptide with a sequence comprising 7 to 9 basic 8 consecutive arginines (SEQ ID NO : 6 ). In some embodi amino acids and having a second reactive amino acid ments , CA, CB, and cm are each independently a 0 - 1 amino moiety CB ; and acid . In some embodiments, CA, CB , and cm are each inde A1- X - B , has a third reactive amino acid moiety Cmon A , pendently selected from a naturally - occurring amino acid or 20 or X? ; and a non -naturally - occurring amino acid . In some embodi- wherein cx is capable of reacting with a first cargo moiety ments , CA, CB , and cm are each independently selected from comprising DA, CB is capable of reacting with a second cargo a D amino acid , a L amino acid , an a - amino acid , a ß - amino moiety comprising DB , and cm is capable of reacting with a acid , or a y -amino acid . In some embodiments , CA, CB , and macromolecular carrier comprising M to form a molecule of Cy are each independently selected from any amino acid 25 Formula I . having a free thiol group , any amino acid having a N -ter - In some embodiments , CA, CB , and cm are each indepen minal amine group, and any amino acid with a side chain dently a 0 - 1 amino acid . In some embodiments , the CA, CB , capable of forming an oxime or hydrazone bond upon and cyhave functional groups that are orthogonally reactive . reaction with a hydroxylamine or hydrazine group . In some In some embodiments , CA , CR , and cyare each independently embodiments , CA , CR , and cware each independently selected 30 selected from a naturally - occurring amino acid or a non from D - cysteine, D - glutamate , lysine, and para - 4 -acetyl naturally -occurring amino acid . In some embodiments , CA , L - phenylalanine. In some embodiments , Cg is any amino Cp , and Cy are each independently selected from a D amino acid having a free thiol group . In some embodiments , Cris acid , a L amino acid , an a - amino acid , a ß -amino acid , or a D - cysteine. In some embodiments , CA is any amino acid y - amino acid . In some embodiments , CA , CB, and cm are each having a N -terminal amine group . In some embodiments , c4 35 independently selected from any amino acid having a free is D - glutamate . In some embodiments , CA is lysine . In some thiol group , any amino acid having a N -terminal amine embodiments , cy is any amino acid with a side chain group , and any amino acid with a side chain capable of capable of forming an oxime or hydrazone bond upon forming an oxime or hydrazone bond upon reaction with a reaction with a hydroxylamine or hydrazine group . In some hydroxylamine or hydrazine group . In some embodiments , embodiments, Cy is para - 4 - acetyl L -phenylalanine . In some 40 CA , CR , and cw are each independently selected from D - cys embodiments , X is cleavable by a protease . In some embodi- teine , D - glutamate , lysine , and para - 4 -acetyl L -phenylala ments , X is cleavable by a matrix metalloproteinase . In some nine . In some embodiments , CB is any amino acid having a embodiments , X comprises an amino acid sequence that is free thiol group . In some embodiments , Cris D - cysteine . In cleavable by MMP2 , MMP7 , MMP9, or MMP14 . In some some embodiments , CA is any amino acid having a N - ter embodiments , X comprises a peptide linkage . In some 45 minal amine group . In some embodiments , CA is D - gluta embodiments , X comprises an amino acid sequence selected mate . In some embodiments , ca is lysine . In some embodi from : PLGLAG (SEQ ID NO : 2 ) , PLG - C (me ) - AG (SEQ ID ments , Cy is any amino acid with a side chain capable of NO : 1 ), RPLALWRS ( SEQ ID NO : 7 ) , ESPAYYTA (SEQ forming an oxime or hydrazone bond upon reaction with a ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID hydroxylamine or hydrazine group . In some embodiments , NO : 10 ) , RLOLKL (SEO ID NO : 11 ) , and RLQLK ( Ac ) 50 Cy is para - 4 -acetyl L -phenylalanine . ( SEQ ID NO : 12 ) . In some embodiments , X comprises the Disclosed herein , in certain embodiments , are tissue amino acid sequence PLGLAG (SEQ ID NO : 2 ). In some samples comprising a molecule of Formula I : embodiments , X comprises the amino acid sequence PLG C (me ) - AG (SEQ ID NO : 1 ) . In some embodiments , X [DA - Ca ]- A -[ cx -M ]- X -B -[ CB -De ]; Formula I comprises the amino acid sequence RPLALWRS ( SEO ID 55 wherein , NO : 7 ) . In some embodiments , X comprises the amino acid X is a cleavable linker ; sequence DPRSFL (SEO ID NO : 9 ) . In some embodiments , A is a peptide with a sequence comprising 5 to 9 acidic X comprises the amino acid sequence PPRSFL (SEQ ID amino acids; NO : 10 ) . In some embodiments , X comprises the amino acid B is a peptide with a sequence comprising 7 to 9 basic sequence RLQLKL ( SEQ ID NO : 11 ) . In some embodi- 60 amino acids ; ments , X comprises the amino acid sequence RLQLK ( Ac ) CA, CB , and cm each independently comprise 0 - 1 amino ( SEQ ID NO : 12 ). In some embodiments, D , and DR are a acid ; pair of acceptor and donor fluorescent moieties that are M is a polyethylene glycol (PEG ) polymer ; and capable of undergoing Försters/ fluorescence resonance DA and DR are each independently an imaging agent; and energy transfer with the other. In some embodiments , D? and 65 wherein [Cr - M ] is bound at any position on A or X , [DA -CA ] D , are Cy5 and Cy7 . In some embodiments , DA and Do are is bound to any amino acid on A , and [ CB -DB ) is bound to Cy5 and IRDye750 . In some embodiments, D? and DB are any amino acid on B . US 9 , 840 ,537 B2 In some embodiments , the tissue sample is a pathology rescence resonance energy transfer with the other. In some slide or section . In some embodiments, the tissue sample is embodiments , D , and D , are Cy5 and Cy7. In some embodi cancerous. In some embodiments , the cancerous tissue is : ments , D? and DB are Cy5 and IRDye750 . In some embodi breast cancer tissue, colon cancer tissue , squamous cell ments , D , and D , are Cy5 and IRDye800 . In some embodi carcinoma tissue , prostate cancer tissue , melanoma tissue , or 5 ments , D , and D , are Cy5 and ICG . In some embodiments , thyroid cancer tissue . In some embodiments , the cancerous D and De are a fluorescent moiety and a fluorescence tissue is breast cancer tissue . In some embodiments , the quenching moiety. In some embodiments , the molecule of cancerous tissue is colon cancer tissue . In some embodi- Formula I is : SDM - 14 , SDM - 15 , SDM - 23 , SDM - 24 , SDM ments, A and B do not have an equal number of acidic and 25 , SDM - 26 , SDM - 27 , SDM - 32 , and SDM - 35 . basic amino acids. In some embodiments , the number of 10 Disclosed herein , in certain embodiments , are methods of basic amino acids in B is greater than the number of acidic delivering a pair of imaging agents to a tissue of interest , amino acids in A . In some embodiments , A is a peptide comprising contacting the tissue of interest with a molecule comprising 5 or 9 consecutive glutamates (SEQ ID NO : 3 ) . of Formula I : In some embodiments, B is a peptide comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ). In some embodi - 15 [DA - CA ]- A -[ CAM ]- X -B -[ CB - DB ] ; Formula I ments, A is a peptide comprising 5 or 9 consecutive gluta - wherein , mates (SEQ ID NO : 3 ) and B is a peptide comprising 8 or X is a cleavable linker ; 9 consecutive arginines (SEQ ID NO : 4 ) . In some embodi A is a peptide with a sequence comprising 5 to 9 acidic ments, A is a peptide comprising 5 consecutive glutamates amino acids ; (SEQ ID NO : 5 ) and B is a peptide comprising 8 consecutive 20 B is a peptide with a sequence comprising 7 to 9 basic arginines (SEQ ID NO : 6 ) . In some embodiments , CA , CB; amino acids ; and cm are each independently a 0 - 1 amino acid . In some CA, CB , and cm each independently comprise 0 - 1 amino embodiments , CA , CB, and cm are each independently selected acid ; from a naturally -occurring amino acid or a non - naturally Mis a polyethylene glycol (PEG ) polymer; and occurring amino acid . In some embodiments , CA , CR, and cm 25 D , and DR are each independently an imaging agent; and are each independently selected from a D amino acid , a L wherein [cv - M ] is bound to at any position on A or X , amino acid , an a -amino acid , a ß -amino acid , or a y - amino [D4 -ca ] is bound to any amino acid on A , and [Co - DB ) is acid . In some embodiments , C4, Cp , and cy are each inde - bound to any amino acid on B . pendently selected from any amino acid having a free thiol In some embodiments , the tissue of interest is cancerous . group , any amino acid having a N -terminal amine group , 30 In some embodiments , the cancerous tissue is : breast cancer and any amino acid with a side chain capable of forming an tissue , colorectal cancer tissue, squamous cell carcinoma oxime or hydrazone bond upon reaction with a hydroxylam - tissue, prostate cancer tissue , melanoma tissue , and thyroid ine or hydrazine group . In some embodiments, CA , CB , and cancer tissue . In some embodiments , the cancerous tissue is Cy are each independently selected from D -cysteine , D - glu - breast cancer tissue. In some embodiments , the cancerous tamate , lysine , and para - 4 - acetyl L -phenylalanine . In some 35 tissue is colon cancer tissue . In some embodiments , A and B embodiments , CB is any amino acid having a free thiol group . do not have an equal number of acidic and basic amino In some embodiments , CB is D - cysteine . In some embodi - acids . In some embodiments , the number of basic amino ments , c , is any amino acid having a N -terminal amine acids in B is greater than the number of acidic amino acids group . In some embodiments , ca is D - glutamate . In some in A . In some embodiments, A is a peptide comprising 5 or embodiments , C , is lysine . In some embodiments , Cwis any 40 9 consecutive glutamates (SEQ ID NO : 3 ) . In some embodi amino acid with a side chain capable of forming an oxime ments , B is a peptide comprising 8 or 9 consecutive argin or hydrazone bond upon reaction with a hydroxylamine or ines (SEQ ID NO : 4 ) . In some embodiments , A is a peptide hydrazine group . In some embodiments , mis para - 4 -acetyl comprising 5 or 9 consecutive glutamates ( SEQ ID NO : 3 ) L -phenylalanine . In some embodiments , X is cleavable by a and B is a peptide comprising 8 or 9 consecutive arginines protease . In some embodiments , X is cleavable by a matrix 45 (SER ID NO : 4 ) . In some embodiments , A is a peptide metalloproteinase . In some embodiments , X comprises an comprising 5 consecutive glutamates ( SEQ ID NO : 5 ) and B amino acid sequence that is cleavable by MMP2, MMP7, is a peptide comprising 8 consecutive arginines (SEQ ID MMP9 , or MMP14 . In some embodiments , X comprises a NO : 6 ) . In some embodiments, CA , CB , and cm are each peptide linkage . In some embodiments , X comprises an independently a 0 - 1 amino acid . In some embodiments , CA , amino acid sequence selected from : PLGLAG (SEQ ID NO : 50 CB , and cw are each independently selected from a naturally 2 ), PLG - C (me ) - AG ( SEQ ID NO : 1 ) , RPLALWRS (SEQ ID occurring amino acid or a non -naturally - occurring amino NO : 7 ) , ESPAYYTA (SEQ ID NO : 8 ) , DPRSFL (SEQ ID acid . In some embodiments , CA , CR, and cw are each inde NO : 9 ), PPRSFL (SEQ ID NO : 10 ), RLQLKL ( SEQ ID NO : pendently selected from a D amino acid , a L amino acid , an 11) , and RLQLK ( Ac ) (SEQ ID NO : 12 ). In some embodi a -amino acid , a ß -amino acid , or a y -amino acid . In some ments , X comprises the amino acid sequence PLGLAG 55 embodiments , C4, CB , and cy are each independently selected (SEQ ID NO : 2 ) . In some embodiments , X comprises the from any amino acid having a free thiol group , any amino amino acid sequence PLG - C (me ) - AG (SEQ ID NO : 1 ) . In acid having a N - terminal amine group , and any amino acid some embodiments , X comprises the amino acid sequence with a side chain capable of forming an oxime or hydrazone RPLALWRS (SEQ ID NO : 7 ). In some embodiments , X bond upon reaction with a hydroxylamine or hydrazine comprises the amino acid sequence DPRSFL (SEQ ID NO : 60 group . In some embodiments , CA , CR , and cy are each 9 ) . In some embodiments , X comprises the amino acid independently selected from D - cysteine , D - glutamate , sequence PPRSFL ( SEQ ID NO : 10 ). In some embodiments, lysine, and para - 4 -acetyl L - phenylalanine . In some embodi X comprises the amino acid sequence RLQLKL (SEQ ID ments , CB is any amino acid having a free thiol group . In NO : 11 ) . In some embodiments, X comprises the amino acid some embodiments, Cris D - cysteine . In some embodiments , sequence RLQLK ( Ac ) ( SEQ ID NO : 12 ) . In some embodi - 65 CA is any amino acid having a N - terminal amine group . In ments , DA and DB are a pair of acceptor and donor fluores - some embodiments , CA is D - glutamate . In some embodi cent moieties that are capable of undergoing Försters / fluo ments , CA is lysine . In some embodiments , Cm is any amino US 9 ,840 ,537 B2 acid with a side chain capable of forming an oxime or decreased . In some embodiments , the method further com hydrazone bond upon reaction with a hydroxylamine or prises preparing a tissue sample from the removed cell or hydrazine group . In some embodiments , Cy is para - 4 -acetyl tissue of interest . In some embodiments, the method further L -phenylalanine . In some embodiments , X is cleavable by a comprises staging the cancerous tissue . In some embodi protease . In some embodiments , X is cleavable by a matrix 5 ments , A and B do not have an equal number of acidic and metalloproteinase . In some embodiments , X comprises an basic amino acids . In some embodiments, the number of amino acid sequence that is cleavable by MMP2 , MMP7, basic amino acids in B is greater than the number of acidic MMP9 , or MMP14 . In some embodiments , X comprises a amino acids in A . In some embodiments , A is a peptide peptide linkage . In some embodiments , X comprises an comprising 5 or 9 consecutive glutamates (SEQ ID NO : 3 ) . amino acid sequence selected from : PLGLAG (SEQ ID NO : 10 In some embodiments , B is a peptide comprising 8 or 9 2 ), PLG - C (me ) - AG ( SEQ ID NO : 1 ) , RPLALWRS (SEQ ID consecutive arginines (SEQ ID NO : 4 ) . In some embodi NO : 7 ) , ESPAYYTA ( SEQ ID NO : 8 ) , DPRSFL (SEQ ID ments , A is a peptide comprising 5 or 9 consecutive gluta NO : 9 ), PPRSFL ( SEQ ID NO : 10 ), RLQLKL ( SEQ ID NO : mates (SEQ ID NO : 3 ) and B is a peptide comprising 8 or 11) , and RLQLK (Ac ) (SEQ ID NO : 12 ) . In some embodi- 9 consecutive arginines ( SEQ ID NO : 4 ) . In some embodi ments , X comprises the amino acid sequence PLGLAG 15 ments , A is a peptide comprising 5 consecutive glutamates (SEQ ID NO : 2 ) . In some embodiments , X comprises the (SEQ ID NO : 5 ) and B is a peptide comprising 8 consecutive amino acid sequence PLG - C (me ) - AG (SEQ ID NO : 1 ). In arginines ( SEQ ID NO : 6 ). In some embodiments, CA , CB, some embodiments , X comprises the amino acid sequence and cm are each independently a 0 - 1 amino acid . In some RPLALWRS (SEQ ID NO : 7 ) . In some embodiments , X embodiments , C4, CB, and cm are each independently selected comprises the amino acid sequence DPRSFL (SEQ ID NO : 20 from a naturally occurring amino acid or a non - naturally 9 ) . In some embodiments , X comprises the amino acid occurring amino acid . In some embodiments , CA, CB , and cu sequence PPRSFL (SEQ ID NO : 10 ) . In some embodiments, are each independently selected from a D amino acid , a L X comprises the amino acid sequence RLQLKL (SEQ ID amino acid , an a -amino acid , a ß - amino acid , or a y -amino NO : 11 ) . In some embodiments, X comprises the amino acid acid . In some embodiments , CA, CR , and cy are each inde sequence RLQLK ( Ac ) ( SEQ ID NO : 12 ) . In some embodi- 25 pendently selected from any amino acid having a free thiol ments , D , and DR are a pair of acceptor and donor fluores - group, any amino acid having a N -terminal amine group , cent moieties that are capable of undergoing Försters/ fluo - and any amino acid with a side chain capable of forming an rescence resonance energy transfer with the other . In some oxime or hydrazone bond upon reaction with a hydroxylam embodiments , D , and DR are Cy5 and Cy7 . In some embodi- ine or hydrazine group . In some embodiments , CA , Cp , and ments, D , and DR are Cy5 and IRDye750 . In some embodi- 30 Cy are each independently selected from D -cysteine , D - glu ments , D , and DR are Cy5 and IRDye800 . In some embodi- tamate , lysine, and para - 4 - acetyl L - phenylalanine . In some ments, DA and D , are Cy5 and ICG . In some embodiments , embodiments , ce is any amino acid having a free thiol group . D , and D are a fluorescent moiety and a fluorescence - In some embodiments , Cris D - cysteine . In some embodi quenching moiety . In some embodiments , the molecule of ments , ca is any amino acid having a N - terminal amine Formula I is : SDM - 14 , SDM -15 , SDM -23 , SDM -24 , SDM - 35 group . In some embodiments, CA is D - glutamate . In some 25 , SDM -26 , SDM - 27 , SDM -32 , and SDM -35 . embodiments , C , is lysine . In some embodiments , cy is any Disclosed herein , in certain embodiments , are methods of amino acid with a side chain capable of forming an oxime visualizing a tissue of interest in an individual in need or hydrazone bond upon reaction with a hydroxylamine or thereof, comprising : hydrazine group . In some embodiments , Cm is para - 4 - acetyl ( a ) administering to the individual a molecule of Formula I 40 L - phenylalanine. In some embodiments , X is cleavable by a that localizes to the tissue of interest in the individual, protease . In some embodiments, X is cleavable by a matrix metalloproteinase . In some embodiments, X comprises an [DA - CA] - A - [CAM ]- X - B - [Co -D3 ] ; Formula I amino acid sequence that is cleavable by MMP2 , MMP7, wherein , MMP9 , or MMP14 . In some embodiments , X comprises a X is a cleavable linker ; 45 peptide linkage . In some embodiments , X comprises an A is a peptide with a sequence comprising 5 to 9 acidic amino acid sequence selected from : PLGLAG (SEQ ID NO : amino acids; 2 ) , PLG - C (me ) - AG (SEO ID NO : 1 ) , RPLALWRS ( SEO ID B is a peptide with a sequence comprising 7 to 9 basic NO : 7 ) , ESPAYYTA ( SEQ ID NO : 8 ) , DPRSFL ( SEQ ID amino acids ; NO : 9 ), PPRSFL (SEQ ID NO : 10 ), RLQLKL ( SEQ ID NO : CA , CR , and creach independently comprise 0 - 1 amino 50 11 ) , and RLQLK ( Ac ) (SEQ ID NO : 12 ) . In some embodi acid ; ments , X comprises the amino acid sequence PLGLAG M is a polyethylene glycol (PEG ) polymer ; and (SEQ ID NO : 2 ) . In some embodiments , X comprises the DA and DB are each independently an imaging agent; and amino acid sequence PLG - C (me ) - AG (SEQ ID NO : 1 ) . In wherein [Cm - M ] is bound to at any position on A or X , some embodiments , X comprises the amino acid sequence [DA - CA ] is bound to any amino acid on A , and [CB -DB ) 55 RPLALWRS (SEQ ID NO : 7) . In some embodiments , X is bound to any amino acid on B ; and comprises the amino acid sequence DPRSFL (SEQ ID NO : ( b ) visualizing at least one of the imaging agents. 9 ) . In some embodiments , X comprises the amino acid In some embodiments , the tissue is cancerous . In some sequence PPRSFL (SEQ ID NO : 10 ) . In some embodiments , embodiments , the cancerous tissue is : breast cancer tissue , X comprises the amino acid sequence RLQLKL (SEQ ID colorectal cancer tissue , squamous cell carcinoma tissue , 60 NO : 11 ) . In some embodiments , X comprises the amino acid prostate cancer tissue , melanoma tissue, or thyroid cancer sequence RLQLK (Ac ) ( SEQ ID NO : 12 ) . In some embodi tissue . In some embodiments , the cancerous cell or tissue is ments , D , and DB are a pair of acceptor and donor fluores breast cancer tissue . In some embodiments , the cancerous cent moieties that are capable of undergoing Försters/ fluo cell or tissue is colon cancer tissue . In some embodiments , rescence resonance energy transfer with the other. In some the method further comprises surgically removing the tissue 65 embodiments , DA and DR are Cy5 and Cy7. In some embodi of interest from the individual. In some embodiments , the ments , D , and DR are Cy5 and IRDye750 . In some embodi surgical margin surrounding the tissue of interest is ments , DA and DR are Cy5 and IRDye800 . In some embodi US 9 ,840 , 537 B2 10 ments, D? and DR are Cy5 and ICG . In some embodiments , CA , CB, and cm each independently comprise 0 - 1 amino the method further comprises visualizing Försters / fluores acid ; cence resonance energy transfer between D? and Do In some Mis a polyethylene glycol (PEG ) polymer; and embodiments , DA and DB are a fluorescent moiety and a DA and Do are a pair of acceptor and donor fluorescent fluorescence - quenching moiety . In some embodiments , the 5 moieties that are capable of undergoing Försters/ fluo molecule is chosen from : SDM - 14 , SDM - 15 , SDM - 23 , rescence resonance energy transfer with the other ; and SDM - 24 , SDM - 25 , SDM - 26 , SDM - 27 , SDM - 32 , and SDM - wherein [cv - M ] is bound to at any position on A or X , 35 . [DA - CA ] is bound to any amino acid on A , and [ CB -DB ] is Disclosed herein , in certain embodiments , are selective bound to any amino acid on B . delivery molecules of Formula I , having the structure : 10 In some embodiments , CA, CR , and cv are each indepen dently selected from any amino acid having a free thiol [DA - CA ]- A -[ oxrM ]- X -B -[ ch -Dp ] Formula I group , any amino acid having a N - terminal amine group , wherein , and any amino acid with a side chain capable of forming an X is a peptide linker cleavable by a matrix metallopro oxime or hydrazone bond upon reaction with a hydroxylam teinase ; 15 ine or hydrazine group . In some embodiments , CA , CR , and A is a peptide with a sequence comprising 5 or 9 con - Cw are each independently a 0 - 1 amino acid . In some secutive glutamates (SEQ ID NO : 3 ) ; embodiments , CA, CB , and cm are each independently selected B is a peptide with a sequence comprising 8 or 9 con - from D - cysteine , D - glutamate , lysine, and para - 4 - acetyl secutive arginines (SEQ ID NO : 4 ) ; L -phenylalanine . In some embodiments , CB is any amino CA , CB, and cm each independently comprise 0 - 1 amino 20 acid having a free thiol group . In some embodiments , Cg is acid ; D - cysteine . In some embodiments , CA is any amino acid M is a polyethylene glycol (PEG ) polymer; and having a N -terminal amine group . In some embodiments , CA DA and DR are a pair of acceptor and donor fluorescent is D - glutamate . In some embodiments , cm is any amino acid moieties that are capable of undergoing Försters / fluo - with a side chain capable of forming an oxime or hydrazone rescence resonance energy transfer with the other ; and 25 bond upon reaction with a hydroxylamine or hydrazine wherein [ cy - M ] is bound to at any position on A or X , group . In some embodiments, mis para - 4 - acetyl L -phenyl [DA - CA ] is bound to any amino acid on A , and [Co - DB ] is alanine . In some embodiments , X comprises the amino acid bound to any amino acid on B . sequence PLGLAG ( SEQ ID NO : 2 ). In some embodiments , In some embodiments , A and B do not have an equal X comprises the amino acid sequence PLG - C (me ) - AG (SEO number of acidic and basic amino acids. In some embodi- 30 ID NO : 1 ) . In some embodiments , X comprises the amino ments , CA , CB , and cm are each independently a 0 - 1 amino acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some acid . In some embodiments, CA, CR , and cy are each inde - embodiments , D , and D , are Cy5 and Cy7 . In some embodi pendently selected from any amino acid having a free thiol ments , D , and D , are Cy5 and IRDye750 . In some embodi group , any amino acid having a N -terminal amine group , ments , D and D , are Cy5 and IRDye800 . In some embodi and any amino acid with a side chain capable of forming an 35 ments , D , and D . are Cy5 and ICG . oxime or hydrazone bond upon reaction with a hydroxylam - Disclosed herein , in certain embodiments , are selective ine or hydrazine group . In some embodiments, CA , CB , and delivery molecules of Formula I , having the structure : Cy are each independently selected from D - cysteine , D - glu tamate , lysine , and para - 4 - acetyl L - phenylalanine. In some [DA - CA ]- A - [cxrM ]- X - B -[ CB -Dp ] Formula I embodiments , CR is any amino acid having a free thiol group . 40 wherein , In some embodiments , CB is D - cysteine . In some embodi X is a peptide linker cleavable by a matrix metallopro ments , CA is any amino acid having a N - terminal amine teinase ; group . In some embodiments , CA is D - glutamate . In some A is a peptide with a sequence comprising 9 consecutive embodiments , Cm is any amino acid with a side chain glutamates (SEQ ID NO : 13 ) ; capable of forming an oxime or hydrazone bond upon 45 B is a peptide with a sequence comprising 9 consecutive reaction with a hydroxylamine or hydrazine group . In some arginines (SEQ ID NO : 14 ) ; embodiments , Cm is para - 4 - acetyl L -phenylalanine . In some CA, CB , and cm each independently comprise 0 - 1 amino embodiments , X comprises the amino acid sequence acid ; PLGLAG (SEQ ID NO : 2 ). In some embodiments , X M is a polyethylene glycol (PEG ) polymer , and comprises the amino acid sequence PLG - C (me )- AG (SEQ 50 DA and Do are a pair of acceptor and donor fluorescent ID NO : 1 ) . In some embodiments , X comprises the amino moieties that are capable of undergoing Försters/ fluo acid sequence RPLALWRS (SEQ ID NO : 7) . In some rescence resonance energy transfer with the other ; and embodiments, D? and Do are Cy5 and Cy7 . In some embodi wherein [Cy - M ] is bound to at any position on A or X , ments , DA and DR are Cy5 and IRDye750 . In some embodi- [DA - CA ] is bound to any amino acid on A , and [ CB -DB ) is ments, D , and D , are Cy5 and IRDye800 . In some embodi- 55 bound to any amino acid on B . ments , DA and Do are Cy5 and ICG . In some embodiments , CA, CB, and cm are each indepen Disclosed herein , in certain embodiments , are selective dently selected from any amino acid having a free thiol delivery molecules of Formula I , having the structure : group , any amino acid having a N - terminal amine group , and any amino acid with a side chain capable of forming an [DA - CA ] - A - [CoM ]- X - B - [CB - DB ] Formula I 60 oxime or hydrazone bond upon reaction with a hydroxylam wherein , ine or hydrazine group . In some embodiments , CA , CR , and X is a peptide linker cleavable by a matrix metallopro - cm are each independently a 0 -1 amino acid . In some teinase ; embodiments , CA , CB, and cy are each independently selected A is a peptide with a sequence comprising 5 consecutive from D - cysteine , D - glutamate , lysine, and para - 4 - acetyl glutamates (SEQ ID NO : 5 ); 65 L -phenylalanine . In some embodiments , Ce is any amino B is a peptide with a sequence comprising 8 consecutive acid having a free thiol group . In some embodiments , CB is arginines (SEQ ID NO : 6 ) ; D -cysteine . In some embodiments , ca is any amino acid US 9 ,840 ,537 B2 11 12 having a N - terminal amine group . In some embodiments , ca age by MMP - 9 the fragment containing the fluorophore is is D - glutamate . In some embodiments , cy is any amino acid dequenched ( becoming highly fluorescent ) and runs near the with a side chain capable of forming an oxime or hydrazone bottom of the gel. As demonstrated in the gel, tumor bond upon reaction with a hydroxylamine or hydrazine homogenates also cleave SDM - 10 to generate the highly group . In some embodiments , Cmis para -4 - acetyl L -phenyl - 5 fluorescent product. This reaction is blocked by the MMP alanine . In some embodiments , X comprises the amino acid inhibitor indicating that the cleavage is due to tumor asso sequence PLGLAG (SEQ ID NO : 2 ) . In some embodiments , ciated MMPs . X comprises the amino acid sequence PLG - C (me ) - AG ( SEQ F IG . 5 exemplifies the bio - distribution of 3 fluorescent ID NO : 1 ) . In some embodiments , X comprises the amino compounds 6 hours after IV tail vein administration of 2 . 9 acid sequence RPLALWRS ( SEQ ID NO : 7 ) . In some 10 nmol of each compound . SDM -6 has 5 - fold higher tissue embodiments , D , and De are Cy5 and Cy7 . In some embodi - distribution into tumor compared to SDM - 1 and SDM - 2 . ments , D , and D , are Cy5 and IRDye750 . In some embodi DeSelective delivery molecules 1 and 2 have equal numbers of ments , D , and Deare Cy5 and IRDye800 . In some embodi- glutamates and arginines giving them a net neutral core ments , DA and Do are Cy5 and ICG . while SDM -6 has a net 3 + charge due to more positively Disclosed herein , in certain embodiments , are selective 15 charged arginines . delivery molecules according to SDM - 14 . FIG . 6 exemplifies application of emission ratio imaging Disclosed herein , in certain embodiments , are selective of FRET to determine the presence of cancer in mouse delivery molecules according to SDM - 15 . lymph nodes . An emission ratio image was generated using Disclosed herein , in certain embodiments , are selective equation 2 where Expl = 0 . 7 sec , Exp2 = 4 .1 sec and k = 20 . delivery molecules according to SDM - 23 . 20 The righthand panel show the ratio image which show high Disclosed herein , in certain embodiments , are selective contrast between the metastatic lymph node ( very large node delivery molecules according to SDM - 24 . indicated with lower left dark arrow ) and the non -metastatic Disclosed herein , in certain embodiments , are selective nodes (other arrows) . The higher ratio is shown as lighter delivery molecules according to SDM - 25 . pixels (metastatic ) compared to darker lower ratio pixels for Disclosed herein , in certain embodiments , are selective 25 the non -metastic nodes. delivery molecules according to SDM - 26 . FIG . 7 exemplifies results from an ex vivo mouse tissue Disclosed herein , in certain embodiments , are selective activity assay . SDM - 23 was incubated with activated tumor delivery molecules according to SDM - 27 . and normal thigh muscle tissue homogenates . Enzymatic Disclosed herein , in certain embodiments, are selective activity from the tissues resulted in SDM - 23 cleavage and delivery molecules according to SDM -32 . 30 generated a large FRET emission ratio increase ( labeled Disclosed herein , in certain embodiments , are selective primary tumor ) . The ratio increase was the result of SDM delivery molecules according to SDM -35 . cleavage .Normal muscle tissue showed no cleavage activity Disclosed herein , in certain embodiments , are peptides of SDM -- 23 .. according to Peptide P - 3 . FIG . 8 exemplifies FRET emission ratio data an ex vivo 35 human tissue assay . SDM - 25 was incubated with normal FIGURES human breast and cancerous human breast tissue ( WD2808 , WD2821 , WD2815 , WD2817 , WD2824 ) homogenates . FIG . 1 exemplifies the effects of a selective delivery Enzymatic activity and SDM -25 cleavage was found to be molecule (SDM ) by showing whole mouse fluorescence significantly greater in cancerous human breast tissue com images of 3 differentmice injected with SDM - 6 . The images 40 pared to normal human breast tissue ( data bar with errors ) . were taken 2 hours after injection . The tumor and contra - FIG . 9 exemplifies FRET emission ratio data from an ex lateral tissue used to calculate the contrast are indicated on vivo human tissue assay. SDM - 25 and SDM - 32 were incu the right hand mouse. The mean contrast for the three mice bated with normal healthy human breast (WD2823 ) and is 1 . 1 . cancerous human breast tissue (WD2808 , WD2815 ) . Enzy FIG . 2 exemplifies ratiometric fluorescence changes of 45 matic activity and SDM cleavage was found to be greater in selective delivery molecules . In this figure , SDM - 9 was cancerous human breast tissue compared to normal human cleaved with 1 nM MMP - 2 enzyme. The increase of donor breast tissue . ( left panel) and decrease in acceptor ( right panel) fluores FIG . 10 exemplifies a scatter plot of FRET emission ratio cence is indicative of decreased FRET after peptide cleav data of positive and negative lymph nodes from a mouse age . 50 metastatic lymph node model that have been treated with FIG . 3 exemplifies fluorescence enhancement of selective SDM - 24 . Nodes were assigned to be either positive or delivery molecules after protease cleavage . SDM - 10 was negative based on analysis of H & E staining by a pathologist. cleaved with 1 nM MMP - 9 enzyme in buffered saline . The FIG . 11 exemplifies a ROC curve generated by changing Cy5 fluorescence increases > 100 fold after peptide cleavage the threshold value used to assign either a positive or because the quencher dyes is no longer intramolecularly 55 negative metastatic prediction from emission ratio data attached to Cy5 and it can no longer efficiently quench Cy5 . using SDM - 24 in metastatic lymph node model. This data FIG . 4 exemplifies fluorescence enhancement of selective show high sensitivity and specificity for diagnosing cancer delivery molecule SDM - 10 upon cleavage by tumor homo- ous and non - cancerous lymph nodes . genates . Selective delivery molecule 10 (SDM - 10 ) was cleaved with HT- 1080 tumor homogenates . 1 nM MMP - 9 or 60 DETAILED DESCRIPTION OF THE 10 uL tumor tissue homogenates ( TH2 and TH3 ) were INVENTION mixed with 1 uM compound 13 in 100 uL buffer for 24 h at 37° C . GM6001 is a general broad spectrum inhibitor of Selective delivery molecules (SDMs ) allow the targeted MMPs. The control lane contains SDM -6 which is highly delivery of therapeutic agents and /or imaging agents to fluorescent in the intact, uncleaved form which runs at the 65 specific cells and /or tissues. In some embodiments , selective top of the gel . Uncleaved SDM - 10 is nonfluorescent due to delivery molecules comprise ( a ) a molecular transport or efficient quenching ( second column from left ). After cleav - retention sequence (portion B ), (b ) at least one cargo moiety US 9 ,840 ,537 B2 13 14 (portion D ) bound to portion A , B , or X , (c ) X a linker, and amino acids that are later modified , e . g ., hydroxyproline , ( d ) a macromolecular carrier and ( e ) an acidic sequence y - carboxyglutamate , and O -phosphoserine . Amino acid ana (portion A ) which is effective to inhibit or prevent the uptake logs refers to compounds that have the same basic chemical into cells or tissue retention . In some embodiments , cleavage structure as a naturally occurring amino acid , i. e ., an a of X linker, which allows the separation of portion A from 5 carbon that is bound to a hydrogen , a carboxyl group , an portion B , is effective to allow the uptake or retention of amino group , and an R group , e . g ., homoserine, norleucine , portion B and the attached cargo into cells and tissue . methionine sulfoxide . Such analogs have modified R groups However , selective delivery molecules may be subject to ( e . g . , norleucine ) or modified peptide backbones , but retain rapid pharmacokinetic clearance with short plasma half - life , the same basic chemical structure as a naturally occurring broad distribution , and slow wash out from multiple non - 10 amino acid . Amino acid mimetics refers to chemical com target tissues with non - specific uptake . Thus , there is a need pounds that have a structure that is different from the general for a selective delivery molecule with increased in vivo chemical structure of an amino acid , but that functions in a circulation , accumulation in target tissue relative to non - manner similar to a naturally occurring amino acid . Amino target tissue , modulated extravasation selectivity , and modu - acids are either D amino acids of L amino acids . lated bio -distribution . For imaging agents , there is a need for 15 Amino acids may be referred to herein by either their increased contrast in target tissue relative to background commonly known three letter symbols or by the one - letter tissue . symbols recommended by the IUPAC - IUB Biochemical Certain Definitions Nomenclature Commission . Nucleotides, likewise , may be As used herein , the following terms have the meanings referred to by their commonly accepted single -letter codes . ascribed to them unless specified otherwise . 20 One of skill will recognize that individual substitutions , As used herein , the term " targeting molecule ” refers to deletions or additions to a peptide , polypeptide , or protein any agent (e .g ., peptide, protein , nucleic acid polymer , sequence which alters , adds or deletes a single amino acid or aptamer , or smallmolecule ) that associates with ( e . g ., binds a small percentage of amino acids in the encoded sequence to ) a target of interest. The target of interestmay be a tissue , is a " conservatively modified variant” where the alteration a cell, a cellular structure ( e .g ., an organelle ), a protein , a 25 results in the substitution of an amino acid with a chemically peptide , a polysaccharide , or a nucleic acid polymer. In some similar amino acid . Conservative substitution tables provid embodiments , the targeting molecule is any agent that ing functionally similar amino acids are well known in the associates with ( e . g . , binds to one or more cancer cells of art . Such conservatively modified variants are in addition to a subject. and do not exclude polymorphic variants , interspecies The terms " polypeptide ,” “ peptide ” and “ protein ” are 30 homologs, and alleles of the invention . used interchangeably herein to refer to a polymer of amino As used herein , the term “ label” refers to a molecule that acid residues . The terms apply to naturally occurring amino facilitates the visualization and /or detection of a targeting acid polymers as well as amino acid polymers in which one molecule disclosed herein . In some embodiments , the label or more amino acid residues is a non -naturally occurring is a fluorescent moiety . amino acid ( e . g ., an amino acid analog ) . The terms encom - 35 The phrase " specifically binds” when referring to the pass amino acid chains of any length , including full length interaction between a targeting molecule disclosed herein proteins ( i . e ., antigens ) , wherein the amino acid residues are and a target ( e . g ., purified protein , cancer cells or cancerous linked by covalent peptide bonds. As used herein , the terms tissue , tumor, or metastatic lesion , metastases , or lymph " peptide ” refers to a polymer of amino acid residues typi- node or metastatic lymph node ) , refers to the formation of a cally ranging in length from 2 to about 50 residues. In certain 40 high affinity bond between the targeting molecule and the embodiments the peptide ranges in length from about 2 , 3 , target. Further , the term means that the targeting molecule 4 , 5 , 7 , 9 , 10 , or 11 residues to about 50 , 45 , 40 , 45, 30 , 25 , has low affinity for non - targets . 20 , or 15 residues . In certain embodiments the peptide “ Selective binding, " " selectivity ," and the like refers to ranges in length from about 8 , 9 , 10 , 11 , or 12 residues to the preference of an agent to interact with one molecule as about 15 , 20 or 25 residues . Where an amino acid sequence 45 compared to another . Preferably , interactions between a is provided herein , L -, D - , or beta amino acid versions of the targeting molecule disclosed herein and a target are both sequence are also contemplated as well as retro , inversion , specific and selective . Note that in some embodiments an and retro - inversion isoforms. Peptides also include amino agent is designed to “ specifically bind ” and “ selectively acid polymers in which one or more amino acid residues is bind ” two distinct , yet similar targets without binding to an artificial chemical analogue of a corresponding naturally 50 other undesirable targets occurring amino acid , as well as to naturally occurring The terms “ individual, " " patient, " or " subject” are used amino acid polymers . In addition , the term applies to amino interchangeably . As used herein , they mean any mammal acids joined by a peptide linkage or by other modified ( i . e . species of any orders , families , and genus within the linkages ( e . g . , where the peptide bond is replaced by an taxonomic classification animalia :chordata : vertebrata :mam a - ester , a B - ester, a thioamide , phosphonamide, carbamate , 55 malia ) . In some embodiments , the mammal is a human . hydroxylate , and the like (see , e . g ., Spatola , ( 1983 ) Chem . None of the terms require or are limited to situation char Biochem . Amino Acids and Proteins 7 : 267 -357 ) , where the acterized by the supervision ( e . g . constant or intermittent) of amide is replaced with a saturated amine (see , e . g . , Skiles et a health care worker ( e . g . a doctor , a registered nurse , a nurse al. , U . S . Pat . No . 4 ,496 , 542 , which is incorporated herein by practitioner , a physician ' s assistant , an orderly , or a hospice reference , and Kaltenbronn et al. , ( 1990 ) Pp . 969 - 970 in 60 worker ) . Proc . 11th American Peptide Symposium , ESCOM Science The terms “ administer, " " administering ” , " administra Publishers , The Netherlands , and the like ) ) . tion , ” and the like, as used herein , refer to the methods that The term " amino acid ” refers to naturally occurring and may be used to enable delivery of agents or compositions to synthetic amino acids , as well as amino acid analogs and the desired site of biological action . These methods include , amino acid mimetics that function in a manner similar to the 65 but are not limited to parenteral injection ( e . g . , intravenous, naturally occurring amino acids . Naturally occurring amino subcutaneous , intraperitoneal, intramuscular, intravascular, acids are those encoded by the genetic code , as well as those intrathecal, intravitreal , infusion , or local) . Administration US 9 ,840 ,537 B2 15 16 techniques that are optionally employed with the agents and some embodiments , A is a peptide comprising 5 consecutive methods described herein , include e . g . , as discussed in glutamates (SEQ ID NO : 5 ) and B is a peptide comprising Goodman and Gilman , The Pharmacological Basis of Thera 8 consecutive arginines (SEQ ID NO : 6 ) . In some embodi peutics, current ed .; Pergamon ; and Remington 's , Pharma ments , CA , CB , and cm are each independently a 0 - 1 amino ceutical Sciences ( current edition ) , Mack Publishing Co . , 5 acid . In some embodiments , CA , CB , and cw are each inde Easton , Pa . pendently selected from a naturally - occurring amino acid or The term " pharmaceutically acceptable " as used herein , a non - naturally -occurring amino acid . In some embodi refers to a material that does not abrogate the biological ments , CA , CR , and Cy are each independently selected from activity or properties of the agents described herein , and is a D amino acid , a L amino acid , an a -amino acid , a ß -amino relatively nontoxic (i . e . , the toxicity of the material signifi - 10 acid , or a y - amino acid . In some embodiments , CA , CB , and cantly outweighs the benefit of the material) . In some cy are each independently selected from any amino acid instances , a pharmaceutically acceptable material may be having a free thiol group , any amino acid having a N - ter administered to an individual without causing significant minal amine group , and any amino acid with a side chain undesirable biological effects or significantly interacting in capable of forming an oxime or hydrazone bond upon a deleterious manner with any of the components of the 15 reaction with a hydroxylamine or hydrazine group . In some composition in which it is contained . embodiments, CA, CB , and cy are each independently selected The term “ surgery ” as used herein , refers to any method from D - cysteine , D - glutamate , lysine , and para - 4 - acetyl thatmay be used to investigate ,manipulate , change, or cause L - phenylalanine . In some embodiments , CR is any amino an effect in a tissue by a physical intervention . These acid having a free thiol group . In some embodiments , Cg is methods include , but are not limited to open surgery, endo - 20 D - cysteine . In some embodiments , CA is any amino acid scopic surgery, laparoscopic surgery , minimally invasive having a N - terminal amine group . In some embodiments , ca surgery , robotic surgery, and any procedures that may affect is D -glutamate . In some embodiments , CA is lysine . In some a cancerous tissue such as tumor resection , cancer tissue embodiments , cm is any amino acid with a side chain ablation , cancer staging , cancer diagnosis , lymph node stag - capable of forming an oxime or hydrazone bond upon ing , sentinel lymph node detection , or cancer treatment. 25 reaction with a hydroxylamine or hydrazine group . In some The term “ guided surgery ” as used herein , refers to any embodiments , Cy is para - 4 -acetyl L - phenylalanine . In some surgical procedure where the surgeon employs an imaging embodiments , X is cleavable by a protease . In some embodi agent to guide the surgery . ments , X is cleavable by a matrix metalloproteinase . In some The term " cancer” as used herein , refers to any disease embodiments , X comprises an amino acid sequence that is involving uncontrolled growth or proliferation cells in the 30 cleavable by MMP2 , MMP7, MMP9, or MMP14 . In some human body . Cancers may further be characterized by the embodiments , X comprises a peptide linkage . In some ability of cells to migrate from the original site and spread embodiments, X comprises an amino acid sequence selected to distant sites ( i. e ., metastasize ) . Cancers may be sarcomas , from : PLGLAG (SEQ ID NO : 2 ), PLG - C (me ) - AG (SEQ ID carcinomas, lymphomas, leukemias, blastomas , or germ cell NO : 1 ) , RPLALWRS ( SEO ID NO : 7 ) , ESPAYYTA ( SEO tumors . Cancers may occur in a variety of tissues including 35 ID NO : 8 ), DPRSFL (SEQ ID NO : 9 ), PPRSFL (SEQ ID but not limited to lung , breast, ovaries, colon , esophagus , NO : 10 ) , RLQLKL ( SEQ ID NO : 11 ) , and RLQLK ( Ac ) rectum , bone , prostate , brain , pancreas , bladder , kidney, (SEQ ID NO : 12 ) . In some embodiments , X comprises the liver, blood cells , lymph nodes , and stomach . amino acid sequence PLGLAG (SEQ ID NO : 2 ) . In some Selective Delivery Molecules embodiments , X comprises the amino acid sequence PLG Disclosed herein , in certain embodiments , are selective 40 C (me ) - AG ( SEQ ID NO : 1 ) . In some embodiments , X delivery molecule of Formula I, having the structure: comprises the amino acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodiments , X comprises the amino acid [DA - Ca ]- A -[ CxM ]- X -B -[ C5 -De ] Formula I sequence DPRSFL (SEQ ID NO : 9 ) . In some embodiments , wherein , X comprises the amino acid sequence RLQLKL (SEQ ID X is a cleavable linker ; 45 NO : 11 ) . In some embodiments , X comprises the amino acid A is a peptide with a sequence comprising 5 to 9 acidic sequence RLQLK ( Ac ) (SEQ ID NO : 12 ) . In some embodi amino acids; ments, M is selected from a protein , a natural polymer, a B is a peptide with a sequence comprising 7 to 9 basic synthetic polymer, or a dendrimer. In some embodiments , M amino acids ; is selected from dextran , a PEG polymer, albumin , or a CA , CB , and cm each independently comprise 0 - 1 amino 50 combination thereof. In some embodiments , M is a PEG . In acid ; some embodiments , M is selected from PEG 5 kDa , PEG 12 M is a macromolecule ; and kDa, PEG 20 kDa , PEG 30 kDa, and PEG40 kDa. In some DA and Do are each independently selected from an embodiments , DA and DR are a pair of acceptor and donor imaging agent and a therapeutic ; and fluorescent moieties that are capable of undergoing Försters / wherein [CM - M ] is bound to at any position on A or X , 55 fluorescence resonance energy transfer with the other . In [DA - CA ] is bound to any amino acid on A , and [ CR- DB ] is some embodiments , DA and Do are Cy5 and Cy7. In some bound to any amino acid on B . embodiments , DA and DR are Cy5 and IRDye750 . In some In some embodiments , A and B do not have an equal embodiments , DA and DB are Cy5 and IRDye800 . In some number of acidic and basic amino acids . In some embodi- embodiments , D , and DR are Cy5 and ICG . In some embodi ments , the number of basic amino acids in B is greater than 60 ments , D , and De are a fluorescent moiety and a fluores the number of acidic amino acids in A . In some embodi - cence - quenching moiety . In some embodiments , the mol ments , A is a peptide comprising 5 or 9 consecutive gluta - ecule of Formula I is : SDM - 14 , SDM - 15 , SDM - 23 , SDM mates ( SEQ ID NO : 3 ) . In some embodiments , B is a peptide24 , SDM -25 , SDM - 26 , SDM - 27 , SDM -32 , or SDM -35 . comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In Disclosed herein , in certain embodiments , are selective some embodiments , A is a peptide comprising 5 or 9 65 delivery molecules of Formula I , having the structure : consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide comprising 8 or 9 consecutive arginines (SEQ ID NO : 4) . In [DA -CA ] - A - [ CrM ]- X - B - [ Co -De ] Formula I US 9 ,840 ,537 B2 17 18 wherein , NO : 10 ). In some embodiments , X comprises the amino acid X is a cleavable linker; sequence RLQLKL (SEQ ID NO : 11 ) . In some embodi A is a peptide with a sequence comprising 5 to 9 acidic ments, X comprises the amino acid sequence RLQLK ( Ac ) amino acids ; (SEQ ID NO : 12 ) . In some embodiments, DA and DB are a B is a peptide with a sequence comprising 7 to 9 basic 5 pair of acceptor and donor fluorescent moieties that are amino acids ; capable of undergoing Försters/ fluorescence resonance C4, C5 , and cm each independently comprise 0 - 1 amino energy transfer with the other. In some embodiments, D? and acid ; De are Cy5 and Cy7 . In some embodiments , D , and De are M is a polyethylene glycol (PEG ) polymer , and Cy5 and IRDye750 . In some embodiments , DA and DR are DA and DB are each independently an imaging agent; and 10 Cy5 and IRDye800 . In some embodiments , D , and D , are wherein [cv - M ] is bound to at any position on A or X , Cy5 and ICG . In some embodiments , DA and DB are a [DA - CA ] is bound to any amino acid on A , and [Co -DB ] fluorescentmoiety and a fluorescence - quenching moiety . In is bound to any amino acid on B . some embodiments , the molecule of Formula I is : SDM - 14 , In some embodiments , A and B do not have an equal SDM -15 , SDM - 23 , SDM -24 , SDM - 25, SDM - 26 , SDM - 27 , number of acidic and basic amino acids . In some embodi- 15 SDM - 32 : or SDM - 35 . ments, the number of basic amino acids in B is greater than Disclosed herein , in certain embodiments , are selective the number of acidic amino acids in A . In some embodi- delivery molecules of Formula I , having the structure : ments , A is a peptide comprising 5 or 9 consecutive gluta mates (SEQ ID NO : 3 ) . In some embodiments , B is a peptide [DA - CA] - A - [ CAM ]- X - B - [ CR- DB ] Formula I comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ). In 20 some embodiments , A is a peptide comprising 5 or 9 wherein , consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide X is a peptide linker cleavable by a matrix metallopro comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ). In teinase ; some embodiments , A is a peptide comprising 5 consecutive A is a peptide with a sequence comprising 5 or 9 con glutamates (SEQ ID NO : 5 ) and B is a peptide comprising 25 secutive glutamates (SEQ ID NO : 3 ); 8 consecutive arginines (SEQ ID NO : 6 ). In some embodi B is a peptide with a sequence comprising 8 or 9 con ments, C4, CB , and cm are each independently a 0 - 1 amino secutive arginines (SEQ ID NO : 4 ) ; acid . In some embodiments , CA , CR , and cw are each inde CA , Cb , and cm each independently comprise 0 - 1 amino pendently selected from a naturally occurring amino acid or acid ; a non -naturally - occurring amino acid . In some embodi - 30 M is a polyethylene glycol (PEG ) polymer, and ments , CA , CB , and cm are each independently selected from DA and Dg are a pair of acceptor and donor fluorescent a D amino acid , a L amino acid , an a -amino acid , a B - amino moieties that are capable of undergoing Försters / fluo acid , or a y - amino acid . In some embodiments , CA , CB , and rescence resonance energy transfer with the other; and cm are each independently selected from any amino acid wherein [ cvM ] is bound to at any position on A or X , having a free thiol group , any amino acid having a N - ter - 3535 [DA 44 -CA ] 15is bound to any amino acid on A , and [Co - DB ) is minal amine group , and any amino acid with a side chain bound to any amino acid on B . capable of forming an oxime or hydrazone bond upon In some embodiments , A and B do not have an equal reaction with a hydroxylamine or hydrazine group . In some number of acidic and basic amino acids . In some embodi embodiments , C4 , CB , and cm are each independently selected ments , CA, CB, and cu are each independently selected from from D - cysteine , D - glutamate, lysine, and para- 4 -acetyl 40 any amino acid having a free thiol group , any amino acid L -phenylalanine . In some embodiments , Cp is any amino having a N -terminal amine group , and any amino acid with acid having a free thiol group . In some embodiments , CB is a side chain capable of forming an oxime or hydrazone bond D - cysteine. In some embodiments , c is any amino acid upon reaction with a hydroxylamine or hydrazine group . In having a N - terminal amine group . In some embodiments , ca some embodiments , CA, CB , and cm are each independently a is D - glutamate . In some embodiments, C , is lysine . In some 45 0 - 1 amino acid . In some embodiments , CA , CB , and cm are embodiments , Cm is any amino acid with a side chain each independently selected from D - cysteine, D - glutamate , capable of forming an oxime or hydrazone bond upon lysine, and para - 4 - acetyl L - phenylalanine . In some embodi reaction with a hydroxylamine or hydrazine group . In some ments , CB is any amino acid having a free thiol group . In embodiments , Cyis para - 4 - acetyl L -phenylalanine . In some some embodiments , Cris D - cysteine . In some embodiments , embodiments , X is cleavable by a protease . In some embodi - 50 CAA is any amino acid having a N -terminal amine group . In ments , X is cleavable by a matrix metalloproteinase . In some some embodiments , CA is D - glutamate . In some embodi embodiments , X comprises an amino acid sequence that is ments , Cm is any amino acid with a side chain capable of cleavable by MMP2, MMP7 , MMP9 , or MMP14 . In some forming an oxime or hydrazone bond upon reaction with a embodiments , X comprises a peptide linkage . In some hydroxylamine or hydrazine group . In some embodiments , embodiments , X comprises an amino acid sequence selected 55 CmM isis parapar - 4 - acetyl L -phenylalanine . In some embodiments , from : PLGLAG (SEQ ID NO : 2 ), PLG - C (me ) - AG (SEQ ID X comprises the amino acid sequence PLGLAG (SEQ ID NO : 1 ) , RPLALWRS ( SEQ ID NO : 7 ) , ESPAYYTA (SEQ NO : 2 ) . In some embodiments , X comprises the amino acid ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID sequence PLG - C (me ) - AG (SEQ ID NO : 1 ) . In some NO : 10 ) , RLQLKL ( SEQ ID NO : 11 ) , and RLQLK (Ac ) embodiments , DA and DB are Cy5 and Cy7. In some embodi (SEO ID NO : 12 ) . In some embodiments . X comprises the 60 ments , Da and Do are Cy ) and Cy7 . amino acid sequence PLGLAG (SEQ ID NO : 2 ) . In some Disclosed herein , in certain embodiments , are selective embodiments , X comprises the amino acid sequence PLG delivery molecules of Formula I, having the structure : C (me ) - AG (SEQ ID NO : 1) . In some embodiments , X comprises the amino acid sequence RPLALWRS (SEQ ID [DA - Ca ]- A -[ cxc M ]- X -B - [ CB -De ] Formula I NO : 7 ) . In some embodiments , X comprises the amino acid 65 wherein , sequence DPRSFL (SEQ ID NO : 9 ) . In some embodiments , X is a peptide linker cleavable by a matrix metallopro X comprises the amino acid sequence PPRSFL (SEQ ID teinase ; US 9 , 840 , 537 B2 19 20 A is a peptide with a sequence comprising 5 consecutive embodiments , CA , CB , and cm are each independently selected glutamates (SEQ ID NO : 5 ) ; from D - cysteine , D - glutamate , lysine, and para -4 -acetyl B is a peptide with a sequence comprising 8 consecutive L -phenylalanine . In some embodiments , CB is any amino arginines (SEQ ID NO : 6 ) ; acid having a free thiol group . In some embodiments , CB is CA , CB , and cy each independently comprise 0 - 1 amino 5 D - cysteine . In some embodiments , CA is any amino acid acid ; having a N -terminal amine group . In some embodiments , CA M is a polyethylene glycol (PEG ) polymer, and is D - glutamate . In some embodiments, Cy is any amino acid DA and DB are a pair of acceptor and donor fluorescent with a side chain capable of forming an oxime or hydrazone moieties that are capable of bond upon reaction with a hydroxylamine or hydrazine undergoing Försters/ fluorescence resonance energy trans - 10 group. In some embodiments , cy is para - 4 - acetyl L -phenyl fer with the other; and alanine . In some embodiments , X comprises the amino acid wherein [ cy - M ] is bound to at any position on A or X , sequence PLGLAG (SEQ ID NO : 2 ). In some embodiments , [DA - CA ] is bound to any amino acid on A , and [ CR -DB ] is X comprises the amino acid sequence PLG - C (me ) - AG (SEQ bound to any amino acid on B . ID NO : 1 ) . In some embodiments , X comprises the amino In some embodiments , CA , CB , and cy are each indepen - 15 acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some dently a 0 - 1 amino acid . In some embodiments, CA , CB , and embodiments , DA and DR are Cy5 and Cy7 . In some embodi Cy are each independently selected from any amino acid ments , D , and DR are Cy5 and IRDye750 . In some embodi having a free thiol group , any amino acid having a N - ter - ments , DA and DR are Cy5 and IRDye800 . In some embodi minal amine group , and any amino acid with a side chain ments , D , and DR are Cy5 and ICG . capable of forming an oxime or hydrazone bond upon 20 Disclosed herein , in certain embodiments , are selective reaction with a hydroxylamine or hydrazine group . In some delivery molecules according to SDM - 14 . embodiments , CA , CR , and cy are each independently selected Disclosed herein , in certain embodiments , are selective from D - cysteine , D - glutamate , lysine, and para - 4 -acetyl delivery molecules according to SDM - 15 . L - phenylalanine . In some embodiments , Cg is any amino Disclosed herein , in certain embodiments , are selective acid having a free thiol group . In some embodiments , Cris 25 delivery molecules according to SDM - 23 . D - cysteine . In some embodiments , cx is any amino acid Disclosed herein , in certain embodiments , are selective having a N -terminal amine group . In some embodiments , delivery molecules according to SDM - 24 . is D - glutamate . In some embodiments , cv is any amino acid Disclosed herein , in certain embodiments, are selective with a side chain capable of forming an oxime orhydrazone delivery molecules according to SDM -25 . bond upon reaction with a hydroxylamine or hydrazine 30 Disclosed herein , in certain embodiments, are selective group . In some embodiments , Cyis para - 4 -acetyl L - phenyl- delivery molecules according to SDM - 26 . alanine . In some embodiments , X comprises the amino acid Disclosed herein , in certain embodiments , are selective sequence PLGLAG (SEQ ID NO : 2 ). In some embodiments , delivery molecules according to SDM -27 . X comprises the amino acid sequence PLG - C (me ) - AG ( SEQ D isclosed herein , in certain embodiments , are selective ID NO : 1 ) . In some embodiments , X comprises the amino 35 delivery molecules according to SDM - 32 . acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some Disclosed herein , in certain embodiments , are selective embodiments , DA and D , are Cy5 and Cy7 . In some embodi- delivery molecules according to SDM -35 . ments , DA and Do are Cy5 and IRDye750 . In some embodi- Disclosed herein , in certain embodiments , are peptides ments , D , and Do are Cy5 and IRDye800 . In some embodi- according to Peptide P - 3 . ments , DA and Do are Cy5 and ICG . 40 Disclosed herein , in certain embodiments , are selective Disclosed herein , in certain embodiments , are selective delivery molecules according to SDM - 14 . delivery molecules of Formula I , having the structure: Disclosed herein , in certain embodiments, are selective delivery molecules according to SDM - 15 . [DA - ca ] - A -[ Cr + M ]- X -B -[ CB- DB ] Formula I Disclosed herein , in certain embodiments , are selective wherein , 45 delivery molecules according to SDM -23 . X is a peptide linker cleavable by a matrix metallopro - Disclosed herein , in certain embodiments , are selective teinase ; delivery molecules according to SDM - 24 . A is a peptide with a sequence comprising 9 consecutive Disclosed herein , in certain embodiments , are selective glutamates (SEQ ID NO : 13 ); delivery molecules according to SDM - 25 . B is a peptide with a sequence comprising 9 consecutive 50 Disclosed herein , in certain embodiments , are selective arginines (SEQ ID NO : 14 ) ; delivery molecules according to SDM - 26 . CA , CB, and cm each independently comprise 0 - 1 amino Disclosed herein , in certain embodiments , are selective acid ; delivery molecules according to SDM -27 . M is a polyethylene glycol (PEG ) polymer , and Disclosed herein , in certain embodiments , are selective DA and Dg are a pair of acceptor and donor fluorescent 55 delivery molecules according to SDM -32 . moieties that are capable of undergoing Försters / fluo Disclosed herein , in certain embodiments , are selective rescence resonance energy transfer with the other; and delivery molecules according to SDM -35 . wherein [Cy - M ] is bound to at any position on A or X , Portion A [ DA -CA ] is bound to any amino acid on A , and [CB - DB ] is In some embodiments , A is a peptide with a sequence bound to any amino acid on B . 60 comprising 2 to 20 acidic amino acids . In some embodi In some embodiments , C2 , Cp , and cw are each indepen - ments , peptide portion A comprises between about 2 to about dently a 0 - 1 amino acid . In some embodiments , CA , CR , and 20 acidic amino acids . In some embodiments, peptide por CM are each independently selected from any amino acid tion A comprises between about 5 to about 20 acidic amino having a free thiol group , any amino acid having a N - ter - acids. In some embodiments , A has a sequence comprising minal amine group , and any amino acid with a side chain 65 5 to 9 acidic amino acids. In some embodiments , A has a capable of forming an oxime or hydrazone bond upon sequence comprising 5 to 8 acidic amino acids. In some reaction with a hydroxylamine or hydrazine group . In some embodiments , A has a sequence comprising 5 to 7 acidic US 9 , 840 ,537 B2 21 22 amino acids . In some embodiments , A has a sequence some embodiments , A has a sequence comprising 9 con comprising 5 acidic amino acids . In some embodiments , A secutive acidic amino acids selected from , aspartates and has a sequence comprising 6 acidic amino acids. In some glutamates . embodiments , A has a sequence comprising 7 acidic amino In some embodiments , peptide portion A comprises acids . In some embodiments , A has a sequence comprising 5 between about 2 to about 20 glutamates . In some embodi 8 acidic amino acids . In some embodiments , A has a ments , peptide portion A comprises between about 5 to about 20 glutamates. In some embodiments, A has a sequence sequence comprising 9 acidic amino acids. comprising 5 to 9 glutamates. In some embodiments, A has In some embodiments , peptide portion A comprises a sequence comprising 5 to 8 glutamates . In some embodi between about 2 to about 20 consecutive acidic amino acids . 10 ments , A has a sequence comprising 5 to 7 glutamates. In In some embodiments , peptide portion A comprises between some embodiments , A has a sequence comprising 5 gluta about 5 to about 20 consecutive acidic amino acids . In some mates. In some embodiments , A has a sequence comprising embodiments , A has a sequence comprising 5 to 9 consecu 6 glutamates . In some embodiments , A has a sequence tive acidic amino acids. In some embodiments, A has a comprising 7 glutamates. In some embodiments , A has a sequence comprising 5 to 8 consecutive acidic amino acids|. 15 sequence comprising 8 glutamates. In some embodiments , A In some embodiments , A has a sequence comprising 5 to 7 has a sequence comprising 9 glutamates . consecutive acidic amino acids . In some embodiments , A In some embodiments, peptide portion A comprises has a sequence comprising 5 consecutive acidic amino acids. between about 2 to about 20 consecutive glutamates (SEQ In some embodiments , A has a sequence comprising 6 ID NO : 15 ) . In some embodiments , peptide portion A consecutive acidic amino acids. In some embodiments , À 20 comprises between about 5 to about 20 consecutive gluta has a sequence comprising 7 consecutive acidic amino acids. mates (SEQ ID NO : 16 ) . In some embodiments , A has a In some embodiments , A has a sequence comprising 8 sequence comprising 5 to 9 consecutive glutamates (SEQ ID consecutive acidic amino acids. In some embodiments , A NO : 41 ). In some embodiments , A has a sequence compris has a sequence comprising 9 consecutive acidic amino acids. ing 5 to 8 consecutive glutamates (SEQ ID NO : 17 ) . In some In some embodiments, peptide portion A comprises 25 embodiments, A has a sequence comprising 5 to 7 consecu between about 2 to about 20 acidic amino acids selected tive glutamates ( SEQ ID NO : 18 ) . In some embodiments, A from , aspartates and glutamates. In some embodiments, has a sequence comprising 5 consecutive glutamates (SEQ peptide portion A comprises between about 5 to about 20 ID NO : 5 ) . In some embodiments , A has a sequence com prising 6 consecutive glutamates ( SEQ ID NO : 19 ) . In some acidic amino acids selected from , aspartates and glutamatesto . 30 embodiments , A has a sequence comprising 7 consecutive In some embodiments , A has a sequence comprising 5 to 9 3 glutamates (SEQ ID NO : 20 ) . In some embodiments , A has acidic amino acids selected from , aspartates and glutamates . a sequence comprising 8 consecutive glutamates (SEQ ID In some embodiments , A has a sequence comprising 5 to 8 NO : 21) . In some embodiments , A has a sequence compris acidic amino acids selected from , aspartates and glutamates . ing 9 consecutive glutamates ( SEQ ID NO : 13 ) . In some embodiments , A has a sequence comprising 5 to10 /7 35 In some embodiments , portion A comprises 5 consecutive acidic amino acids selected from , aspartates and glutamates . glutamates (SEQ ID NO : 5 ) ( i. e ., EEEEE (SEQ ID NO : 5 ) In some embodiments , A has a sequence comprising 5 acidic or eeeee ). In some embodiments , portion A comprises 9 amino acids selected from , aspartates and glutamates . In consecutive glutamates (SEQ ID NO : 13 ) (i . e . , some embodiments , A has a sequence comprising 6 acidic EEEEEEEEE (SEO ID NO : 13 ) or eeeeeeeee ). amino acids selected from , aspartates and glutamates. In 40 An acidic portion A may include amino acids that are not some embodiments , A has a sequence comprising 7 acidic acidic . Acidic portion A may comprise other moieties , such amino acids selected from , aspartates and glutamates . In as negatively charged moieties. In embodiments of a selec some embodiments , A has a sequence comprising 8 acidic tive delivery molecule disclosed herein , an acidic portion A amino acids selected from , aspartates and glutamates. In may be a negatively charged portion , preferably having some embodiments , A has a sequence comprising 9 acidic 45 about 2 to about 20 negative charges at physiological pH that amino acids selected from , aspartates and glutamates . does not include an amino acid . In some embodiments , peptide portion A comprises In some embodiments , the amount of negative charge in between about 2 to about 20 consecutive acidic amino acids portion A is approximately the same as the amount of selected from , aspartates and glutamates . In some embodi positive charge in portion B . In some embodiments, the ments, peptide portion A comprises between about 5 to about 50 amount of negative charge in portion A is not the sameas the 20 consecutive acidic amino acids selected from , aspartates amount of positive charge in portion B . In some embodi and glutamates . In some embodiments , A has a sequence m ents , improved tissue uptake is seen in a selective delivery comprising 5 to 9 consecutive acidic amino acids selected molecule wherein the amount of negative charge in portion from , aspartates and glutamates. In some embodiments , A A is not the same as the amount of positive charge in portion has a sequence comprising 5 to 8 consecutive acidic amino 55 B . In some embodiments , improved solubility is observed in acids selected from , aspartates and glutamates . In some a selective delivery molecule wherein the amount of nega embodiments , A has a sequence comprising 5 to 7 consecu - tive charge in portion A is not the same as the amount of tive acidic amino acids selected from , aspartates and gluta positive charge in portion B . In some embodiments , faster mates . In some embodiments , A has a sequence comprising tissue uptake is seen in a selective delivery molecule 5 consecutive acidic amino acids selected from , aspartates 60 wherein the amount of negative charge in portion Ais not the and glutamates . In some embodiments , A has a sequence same as the amount of positive charge in portion B . In some comprising 6 consecutive acidic amino acids selected from , embodiments , greater tissue uptake is seen in a selective aspartates and glutamates . In some embodiments , A has a delivery molecule wherein the amount of negative charge in sequence comprising 7 consecutive acidic amino acids portion A is not the same as the amount of positive charge selected from , aspartates and glutamates . In some embodi- 65 in portion B . ments , A has a sequence comprising 8 consecutive acidic Portion A is either L - amino acids or D -amino acids. In amino acids selected from , aspartates and glutamates. In embodiments of the invention , D -amino acids are preferred US 9 , 840 ,537 B2 23 24 in order to minimize immunogenicity and nonspecific cleav selected from arginines , histidines, and lysines . In some age by background peptidases or proteases . Cellular uptake embodiments , peptide portion B comprises between about 5 of oligo - D - arginine sequences is known to be as good as or to about 12 consecutive basic amino acids selected from better than that of oligo - L - arginines . arginines, histidines, and lysines. In some embodiments , It will be understood that portion A may include non - 5 peptide portion B comprises between about 7 to about 9 standard amino acids, such as , for example , hydroxylysine , consecutive basic amino acids selected from arginines , his desmosine , isodesmosine, or other non - standard amino tidines , and lysines. In some embodiments , peptide portion acids. Portion A may include modified amino acids, includ ing post - translationally modified amino acids such as , for B comprises between about 7 to about 8 consecutive basic example , methylated amino acids (e . g ., methyl histidine , 10 amino acids selected from arginines, histidines , and lysines . methylated forms of lysine, etc . ) , acetylated Amino acids, In some embodiments , peptide portion B comprises 9 con amidated amino acids, formylated amino acids, hydroxy secutive basic amino acids selected from arginines, histi lated amino acids , phosphorylated amino acids, or other dines , and lysines . In some embodiments, peptide portion B modified amino acids. Portion A may also include peptide comprises 8 consecutive basic amino acids selected from mimetic moieties , including portions linked by non - peptide 15 arginines , histidines , and lysines . In some bonds and amino acids linked by or to non -amino acid In some embodiments , peptide portion B comprises portions . between about 5 to about 20 arginines . In some embodi The Selective Delivery Molecules disclosed herein are ments, peptide portion B comprises between about 5 to effective where A is at the amino terminus or where A is at about 12 arginines. In some embodiments , peptide portion B the carboxy terminus, i. e ., either orientation of the peptide 20 comprises between about 7 to about 9 arginines. In some bonds is permissible . embodiments , peptide portion B comprises between about 7 Portion B to about 8 arginines. In some embodiments , peptide portion In some embodiments , B is a peptide with a sequence B comprises 9 arginines . In some embodiments , peptide comprising 5 to 15 basic amino acids . In some embodi- portion B comprises 8 arginines. In some embodiments , ments , peptide portion B comprises between about 5 to 25 peptide portion B comprises 7 arginines . about 20 basic amino acids. In some embodiments , peptide In some embodiments , peptide portion B comprises portion B comprises between about 5 to about 12 basic between about 5 to about 20 consecutive arginines (SEQ ID amino acids. In some embodiments , peptide portion B NO : 22 ) . In some embodiments , peptide portion B com comprises between about 7 to about 9 basic amino acids . In some embodiments , peptide portion B comprises between 30 prises between about 5 to about 12 consecutive arginines about 7 to about 8 basic amino acids . In some embodiments , (SEQ ID NO : 23 ). In some embodiments , peptide portion B peptide portion B comprises 9 basic amino acids . In some comprises between about 7 to about 9 consecutive arginines embodiments , peptide portion B comprises 8 basic amino (SEQ ID NO : 24 ). In some embodiments , peptide portion B acids. In some embodiments , peptide portion B comprises 7 comprises between about 7 to about 8 consecutive arginines basic amino acids . 25 (SEQ ID NO : 25 ). In some embodiments , peptide portion B In some embodiments , peptide portion B comprises comprises 9 consecutive arginines (SEQ ID NO : 14 ). In between about 5 to about 10 consecutive basic amino acids some embodiments, peptide portion B comprises 8 consecu In some embodiments , peptide portion B comprises between tive arginines (SEQ ID NO : 6 ) . In some embodiments , about 5 to about 12 consecutive basic amino acids. In some peptide portion B comprises 7 consecutive arginines (SEQ embodiments , peptide portion B comprises between about 7 40 ID NO : 26 ) . to about 9 consecutive basic amino acids. In some embodi- A basic portion B may include amino acids that are not ments , peptide portion B comprises between about 7 to basic . Basic portion B may comprise othermoieties , such as about 8 consecutive basic amino acids . In some embodi- positively charged moieties. In embodiments , a basic portion ments , peptide portion B comprises 9 consecutive basic B may be a positively charged portion , preferably having amino acids . In some embodiments , peptide portion B 45 between about 5 and about 20 positive charges at physi comprises 8 consecutive basic amino acids . In some o logical pH , that does not include an amino acid . In some embodiments , peptide portion B comprises 7 consecutive embodiments , the amount of negative charge in portion A is basic amino acids. approximately the same as the amount of positive charge in In some embodiments , peptide portion B comprises portion B . In some embodiments , the amount of negative between about 5 to about 20 basic amino acids selected from 50 charge in portion A is not the same as the amount of positive arginines, histidines , and lysines . In some embodiments , charge in portion B . peptide portion B comprises between about 5 to about 12 Portion B is either L - amino acids or D -amino acids . In basic amino acids selected from arginines, histidines, and embodiments of the invention , D -amino acids are preferred lysines. In some embodiments , peptide portion B comprises in order to minimize immunogenicity and nonspecific cleav between about 7 to about 9 basic amino acids selected from 55 age by background peptidases or proteases . Cellular uptake arginines, histidines , and lysines . In some embodiments, of oligo - D - arginine sequences is known to be as good as or peptide portion B comprises between about 7 to about 8 better than that of oligo - L -arginines . basic amino acids selected from arginines , histidines , and It will be understood that portion B may include non lysines. In some embodiments , peptide portion B comprises standard amino acids, such as, for example , hydroxylysine , 9 basic amino acids selected from arginines, histidines, and 60 desmosine , isodesmosine , or other non - standard amino lysines . In some embodiments , peptide portion B comprises acids. Portion B may include modified amino acids , includ 8 basic amino acids selected from arginines , histidines, and ing post- translationally modified amino acids such as, for lysines . In some embodiments , peptide portion B comprises example , methylated amino acids ( e . g ., methyl histidine , 7 basic amino acids selected from arginines , histidines, and methylated forms of lysine , etc . ) , acetylated amino acids , lysines. 65 amidated amino acids, formylated amino acids, hydroxy In some embodiments , peptide portion B comprises lated amino acids , phosphorylated amino acids, or other between about 5 to about 20 consecutive basic amino acids modified amino acids. Portion B may also include peptide US 9 , 840 ,537 B2 25 26 mimetic moieties, including portions linked by non - peptide upon reaction with a hydroxylamine or hydrazine group . In bonds and amino acids linked by or to non - amino acid some embodiments , cm comprises para - 4 -acetyl L -phenyl portions . alanine . In embodiments where X is a peptide cleavable by a In some embodiments , CA, CB , and cu are each indepen protease , it may be preferable to join the C - terminus of X to 5 dently selected from a naturally -occurring amino acid or a the N - terminus of B , so that the new amino terminus created non - naturally occurring amino acid . In some embodiments , by cleavage of X contributes an additional positive charge CAA , . ©B Cb :, andang cyCm areare each independently selected from a D that adds to the positive charges already present in B . amino acid , a L amino acid , an a - amino acid , a ß - amino acid , or a y -amino acid . In some embodiments , C4, CB , and Conjugation Group ( c ) the 10 cmare each independently any amino acid having a free thiol In some embodiments , the cargo ( e . g ., DA and DB) and the group , any amino acid containing a free amine group , any macromolecule carriers ( M ) are attached indirectly to A - X amino acid having a N - terminal amine group , and any amino B . acid with a side chain capable of forming an oxime or In some embodiments , the cargo ( e . g . , DA and DB) and the hydrazone bond upon reaction with a hydroxylamine or macromolecule carriers ( M ) are attached indirectly to A - X - B 15 hydrazine group . In some embodiments , CA , CB , and cm are by a conjugation group (CA , CB , and cm ). In some embodi each independently selected from : D - cysteine , D - glutamate , ments , the cargo ( e . g ., DA and DB ) and the macromolecule lysine, and para - 4 - acetyl L - phenylalanine. In some embodi carriers (M ) are attached indirectly to A - X - B by a reactive ments , CB is any amino acid having a free thiol group . In conjugation group ( CA, CB , and CM ) . In some embodiments , some embodiments, Cris D - cysteine . In some embodiments , the cargo ( e. g. , DA and DB) and the macromolecule carriers 20 CA is any amino acid having a N -terminal amine group. In ( M ) are attached indirectly to A - X - B by an orthogonally some embodiments , CA is D - glutamate . In some embodi reactive conjugation group (CA , CB, and cm ). In some ments , CA is lysine. In some embodiments , cm is any amino embodiments , CA , CB , and cm each independently comprise acid with a side chain capable of forming an oxime or an amino acid . In some embodiments, CA , Cp , and cw each hydrazone bond upon reaction with a hydroxylamine or independently comprise 0 - 10 amino acids. In some embodi- 25 hydrazine group . In some embodiments , Cwis para - 4 -acetyl ments , CA , CB, and cm each independently comprise 1 amino L -phenylalanine . acid . In some embodimentsments .,c CA ,c CB , and cmc . , each indepen - Cargo ( D ) dently comprise 2 amino acids. In some embodiments , CA , Imaging Agents In some embodiments , an imaging agent is a dye . In some CB , and cm each independently comprise 3 amino acids. Inlv 30 embodiments , an imaging agent is a fluorescent moiety . In some embodiments , CA, CB, and cm each independently 30 some embodiments , a fluorescent moiety is selected from : a comprise 4 amino acids. In some embodiments , CA, CB , and fluorescent protein , a fluorescent peptide, a fluorescent dye , cm each independently comprise 5 amino acids. In some a fluorescent material or a combination thereof embodiments , CA, CB, and cm each independently comprise 6 All fluorescent moieties are encompassed within the term amino acids . In some embodiments , CA , Cb, and cm each 35 " fluorescent moiety " Specific examples of fluorescentmoi independently comprise 7 amino acids. In some embodi eties given herein are illustrative and are not meant to limit ments , CA , CB, and cm each independently comprise 8 amino the fluorescent moieties for use with the targeting molecules acids. In some embodiments , CA, Cb , and cm each indepen - disclosed herein . dently comprise 9 amino acids. In some embodiments, CA Examples of fluorescent dyes include, but are not limited CB , and cm each independently comprise 10 amino acids. 40 to , xanthenes ( e . g . , rhodamines, rhodols and fluoresceins , In some embodiments , CA , CB , and cm each independently and their derivatives ) ; bimanes ; coumarins and their deriva comprise a derivatized amino acid . In some embodiments , tives (e .g ., umbelliferone and aminomethyl coumarins) ; multiple cargos ( D ) are attached to a derivatized amino acid aromatic amines ( e . g . , dansyl; squarate dyes ) ; benzofurans; conjugation group . fluorescent cyanines; indocarbocyanines ; carbazoles; dicya In some embodiments , the conjugation group comprises a 45 nomethylene pyranes ; polymethine ; oxabenzanthrane ; xan rereceptor ligand . thene ; pyrylium ; carbostyl; perylene ; acridone ; quinacri In some embodiments, C4, Cr , and Cy each independently done ; rubrene ; anthracene ; coronene ; phenanthrecene ; comprise a naturally - occurring amino acid or a non -natu - pyrene ; butadiene ; stilbene; porphyrin ; pthalocyanine ; lan rally - occurring amino acid . In some embodiments , CA, CR , thanide metal chelate complexes ; rare -earth metal chelate and cm each independently comprise from a D amino acid , 50 complexes ; and derivatives of such dyes . a L amino acid , an a -amino acid , a B - amino acid , or a Examples of fluorescein dyes include , but are not limited y - amino acid . In some embodiments, CA, Cb , and Cy each to , 5 - carboxyfluorescein , fluorescein - 5 - isothiocyanate , fluo independently comprise any amino acid having a free thiol r escein - 6 - isothiocyanate and 6 - carboxyfluorescein . group , any amino acid containing a free amine group , any Examples of rhodamine dyes include , but are not limited amino acid having a N -terminal amine group , and any amino 55 to , tetramethylrhodamine - 6 - isothiocyanate , 5 - carboxyte acid with a side chain capable of forming an oxime or tramethylrhodamine, 5 -carboxy rhodol derivatives, tetram hydrazone bond upon reaction with a hydroxylamine or ethyl and tetraethyl rhodamine , diphenyldimethyl and diphe hydrazine group . In some embodiments, CA, CB , and cm each nyldiethyl rhodamine , dinaphthyl rhodamine , rhodamine independently comprise D -cysteine , D - glutamate , lysine , 101 sulfonyl chloride ( sold under the tradename of TEXAS and para -4 -acetyl L -phenylalanine . In some embodiments , 60 RED® ). CB comprises any amino acid having a free thiol group . In Examples of cyanine dyes include, but are not limited to , some embodiments , CB comprises D -cysteine . In some Cy3, Cy3B , Cy3 .5 , Cy5 , Cy5 .5 , Cy7 , IRDYE680 , Alexa embodiments , c , comprises any amino acid having a N - ter - Fluor 750 , IRDye800CW , ICG . minal amine group . In some embodiments , CA comprises Examples of fluorescent peptides include GFP (Green D -glutamate . In some embodiments , CA comprises lysine . In 65 Fluorescent Protein ) or derivatives of GFP (e . g ., EBFP, some embodiments , cm comprises any amino acid with a EBFP2 , Azurite , mKalamal, ECFP , Cerulean , CyPet, YFP, side chain capable of forming an oxime or hydrazone bond Citrine , Venus, YPet) . US 9 , 840 ,537 B2 27 28 Fluorescent labels are detected by any suitable method . agent is selected from : a chemotherapeutic agent, a steroid , For example , a fluorescent labelmay be detected by exciting an immunotherapeutic agent, a targeted therapy, an anti the fluorochrome with the appropriate wavelength of light inflammatory agent, or a combination thereof and detecting the resulting fluorescence , e . g . , by micros - In some embodiments , the therapeutic agent is a B cell copy, visual inspection , via photographic film , by the use of 5 receptor pathway inhibitor. In some embodiments , the thera electronic detectors such as charge coupled devices (CCDs ) , peutic agent is a CD79A inhibitor, a CD79B inhibitor, a photomultipliers, etc . CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K In some embodiments , the imaging agent is labeled with inhibitor, a Blnk inhibitor , a PLCyinhibitor, a a positron - emitting isotope ( e . g ., 18F ) for positron emission PKCBinhibitor , or a combination thereof. In some embodi tomography (PET ) , gamma- ray isotope ( e . g ., 99m Tc ) for 10 ments , the therapeutic agent is an antibody, B cell receptor single photon emission computed tomography ( SPECT) , or signaling inhibitor, a PI3K inhibitor , an IAP inhibitor, an a paramagnetic molecule or nanoparticle ( e . g ., GdP + chelate mTOR inhibitor, a radioimmunotherapeutic , a DNA dam or coated magnetite nanoparticle ) for magnetic resonance aging agent, a proteosome inhibitor, a histone deacytlase imaging (MRI ) . inhibitor , a protein kinase inhibitor, a hedgehog inhibitor , an In some embodiments , the imaging agent is labeled with : 15 Hsp90 inhibitor, a telomerase inhibitor, a Jak1/ 2 inhibitor, a a gadolinium chelate , an iron oxide particle , a super para protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a magnetic iron oxide particle , an ultra small paramagnetic combination thereof. In some embodiments , the therapeutic particle , a manganese chelate or gallium containing agent. agent is selected from : chlorambucil , ifosphamide , doxoru Examples of gadolinium chelates include, but are not bicin ,mesalazine , thalidomide , lenalidomide , temsirolimus , limited to diethylene triamine pentaacetic acid (DTPA ) , 20 everolimus, fludarabine, fostamatinib , paclitaxel , docetaxel, 1 , 4 ,7 , 10 - tetraazacyclododecane - 1 , 4 ,7 , 10 -tetraacetic acid ofatumumab , rituximab , dexamethasone , prednisone , CAL (DOTA ) , and 1 ,4 , 7 - triazacyclononane - N , N ', N " - triacetic 101, ibritumomab , tositumomab , bortezomib , pentostatin , acid (NOTA ) . endostatin , bendamustine, chlorambucil, chlormethine , In some embodiments , the imaging agent is a near - cyclophosphamide , ifosfamide, melphalan , prednimustine , infrared fluorophore for near - infra red (near - IR ) imaging , a 25 trofosfamide , busulfan , mannosulfan , treosulfan , carbo luciferase ( firefly , bacterial, or coelenterate ) or other lumi- quone, thiotepa , triaziquone , carmustine , fotemustine , nescent molecule for bioluminescence imaging, or a per - lomustine , nimustine , ranimustine , semustine , streptozocin , fluorocarbon - filled vesicle for ultrasound . etoglucid , dacarbazine , mitobronitol, pipobroman , temozo In some embodiments , the imaging agent is a nuclear lomide , methotrexate , permetrexed , pralatrexate , raltitrexed , probe . In some embodiments , the imaging agent is a SPECT 30 cladribine , clofarabine , fludarabine , mercaptopurine , nelara or PET radionuclide probe. In some embodiments , the bine, thioguanine , azacitidine , capecitabine , carmofur, cyt radionuclide probe is selected from : a technetium chelate , a arabine , decitabine, fluorouracil, gemcitabine , tegafur, vin copper chelate , a radioactive fluorine , a radioactive iodine , blastine , vincristine , vindesine , vinflunine , vinorelbine , a indium chelate . etoposide, teniposide , demecolcine , docetaxel, paclitaxel, Examples of Tc chelates include , but are not limited to 35 paclitaxel poliglumex , trabectedin , dactinomycin , aclarubi HYNIC , DTPA , and DOTA . cin , daunorubicin , doxorubicin , epirubicin , idarubicin , In some embodiments , the imaging agent contains a mitoxantrone , pirarubicin , valrubicin , zorubincin , bleomy radioactive moiety , for example a radioactive isotope such as cin , ixabepilone , mitomycin , plicamycin , carboplatin , cis 211 At, 1311, 1251 , X0Y, 186Re, 188Re, 1539m , 212Bi, 32P , 64Cu , platin , oxaliplatin , satraplatin , procarbazine, aminolevulinic radioactive isotopes of Lu , and others . 40 acid , efaproxiral, methyl aminolevulinate , porfimer sodium , In some embodiments , a selective delivery molecule temoporfin , dasatinib , erlotinib , everolimus , gefitinib , ima according to Formula I comprising an imaging agent is tinib , lapatinib , nilotinib , pazonanib , sorafenib , sunitinib , employed in guided surgery . In some embodiments, the temsirolimus, alitretinoin , altretamine , amzacrine, anagrel selective delivery molecule preferentially localized to can - ide , arsenic trioxide , asparaginase, bexarotene , bortezomib , cerous , or other undesirable tissues ( i . e . necrotic tissues ) . In 45 celecoxib , denileukin diftitox , estramustine , hydroxycarb some embodiments , a selective delivery molecule according amide , irinotecan , lonidamine , masoprocol, miltefosein , to Formula I comprising an imaging agent is employed in a mitoguazone, mitotane , oblimersen , pegaspargase , pentosta guided surgery to remove colorectal cancer. In some tin , romidepsin , sitimagene ceradenovec , tiazofurine , topo embodiments , guided surgery employing the selective deliv - tecan , tretinoin , vorinostat, diethylstilbenol, ethinylestradiol, ery molecule allows a surgeon to excise as little healthy ( i . e ., 50 fosfestrol, polyestradiol phosphate , gestonorone, medroxy non -cancerous ) tissue as possible . In some embodiments , progesterone , megestrol, buserelin , goserelin , leuprorelin , guided surgery employing the selective delivery molecule triptorelin , fulvestrant, tamoxifen , toremifene , bicalutamide , allows a surgeon to visualize and excise more cancerous flutamide, nilutamide, aminoglutethimide, anastrozole , tissue than the surgeon would have been able to excise exemestane , formestane , letrozole , vorozole , abarelix , without the presence of the selective delivery molecule . In 55 degarelix , histamine dihydrochloride , mifamurtide , pidoti some embodiments , the surgery is fluorescence - guided sur - mod , plerixafor, roquinimex , thymopentin , everolimus, gus gery . perimus, leflunomide , mycophenolic acid , sirolimus , Therapeutic Agents ciclosporin , tacrolimus , azathioprine , lenalidomide , metho Disclosed herein , in certain embodiments , is the use of a trexate , thalidomide, iobenguane , ancestim , filgrastim , selective delivery molecule disclosed herein for delivering a 60 lenograstim , molgramostim , pegfilgrastim , sargramostim , therapeutic agent to a tissue or a plurality of cells . In some interferon alfa natural, interferon alfa - 2a , interferon alfa - 2b , embodiments , the therapeutic agent is an anti- inflammatory interferon alfacon - 1, interferon alfa -n1 , interferon beta natu agent. In some embodiments , the therapeutic agent is an ral, interferon beta - la , interferon beta - 1b , interferon gamma, anti -cancer agent. In some embodiments , the selective deliv - peginterferon alfa - 2a , peginterferon alfa - 2b , aldesleukin , ery molecule is used to treat colorectal cancer. 65 oprelvekin , BCG vaccine , glatiramer acetate , histamine In some embodiments , a D moiety is independently a dihydrochloride , immunocyanin , lentinan , melanoma vac therapeutic agent. In some embodiments , the therapeutic cine, mifamurtide, pegademase , pidotimod , plerixafor, poly US 9 ,840 ,537 B2 29 30 I :C , poly ICLC , roquinimex , tasonermin , thymopentin , mide, carbetimer, carboplatin , carmustine, carubicin hydro abatacept, abetimus, alefacept, antilymphocyte immuno - chloride , carzelesin , cedefingol, chlorambucil, cirolemycin , globulin ( horse ), antithymocyte immunoglobulin (rabbit ) , cladribine , crisnatol mesylate , cyclophosphamide, cytara eculizumab , efalizumab , everolimus, gusperimus , lefluno bine , dacarbazine , daunorubicin hydrochloride , decitabine , mide , muromab -CD3 , mycophenolic acid , natalizumab , 5 dexormaplatin , dezaguanine , dezaguanine mesylate , diazi sirolimus , adalimumab , afelimomab , certolizumab pegol, quone , doxorubicin , doxorubicin hydrochloride , drolox etanercept, golimumab , infliximab , anakinra , basiliximab , ifene, droloxifene citrate , dromostanolone propionate , dua canakinumab , daclizumab , mepolizumab , rilonacept, tocili zomycin , edatrexate , eflomithine hydrochloride , zumab , ustekinumab , ciclosporin , tacrolimus , azathioprine , elsamitrucin , enloplatin , enpromate , epipropidine, epirubi lenalidomide, methotrexate , thalidomide , adalimumab , 10 cin hydrochloride, erbulozole , esorubicin hydrochloride, alemtuzumab , bevacizumab , cetuximab , certolizumab pegol estramustine, estramustine phosphate sodium , etanidazole , eculizumab , efalizumab , gemtuzumab , ibritumomab tiux etoposide , etoposide phosphate , etoprine , fadrozole hydro etan , muromonab -CD3 , natalizumab , panitumumab , ranibi chloride , fazarabine , fenretinide, floxuridine , fludarabine zumab , rituximab , tositumomab , trastuzumab , catumax - phosphate , fluorouracil , flurocitabine , fosquidone , fostriecin omab , edrecolomab , ofatumumab , muromab - CD3, 15 sodium , gemcitabine , gemcitabine hydrochloride , afelimomab , golimumab , ibritumomab titmetan , abagov hydroxyurea, idarubicin hydrochloride, ifosfamide , iimofos omab , adecatumumab , alemtuzumab , anti -CD30 monoclo - ine , interleukin Il ( including recombinant interleukin II , or nal antibody Xmab2513 , anti -MET monoclonal antibody r1L2 ) , interferon alfa - 2a , interferon alfa - 2b , interferon alfa MetMab , apolizumab , apomab , arcitumomab , bispecific nl, interferon alfa - n3 , interferon beta - 1 a , interferon antibody 2B1, blinatumomab , brenttiximab vedotin , 20 gamma - 1 b , iproplatin , irinotecan hydrochloride , lanreotide capromab pendetide , cixutumumab , claudiximab , conatu acetate , letrozole , leuprolide acetate , liarozole hydrochlo mumab , dacetuzumab , denosumab , eculizumab , epratu - ride , lometrexol sodium , lomustine , losoxantrone hydro zumabzu , epratuzumab , ertumaxomab , etaracizumab , figitu chloride, masoprocol, maytansine ,mechlorethamine hydro mumab , fresolimumab , galiximab , ganitumab , gemtuzumab chloride , megestrol acetate , melengestrol acetate , ozogamicin , glembatumumab , ibritumomab , inotuzumab 25 melphalan , menogaril , mercaptopurine , methotrexate , ozogamicin , ipilimumab , lexatumumab , lintuzumab , lintu - methotrexate sodium , metoprine , meturedepa , mitindomide , zumab , lucatumumab , mapatumumab , matuzumab , mil - mitocarcin , mitocromin , mitogillin , mitomalcin , mitomycin , atuzumab , monoclonal antibody CC49 , necitumumab , mitosper , mitotane , mitoxantrone hydrochloride , mycophe nimotuzumab , ofatumumab , oregovomab , pertuzumab , nolic acid , nocodazoie , nogalamycin , ormaplatin , oxisuran , ramacurimab , ranibizumab , siplizumab , sonepcizumab , tan - 30 pegaspargase , peliomycin , pentamustine , peplomycin sul ezumab , tositumomab , trastuzumab , tremelimumab , tucotu fate , perfosfamide, pipobroman , piposulfan , piroxantrone zumab celmoleukin , veltuzumab , visilizumab , volociximab , hydrochloride, plicamycin , plomestane, porfimer sodium , zalutumumab , a syk inhibitor ( e . g . , R788 ), enzastaurin , porfiromycin , prednimustine , procarbazine hydrochloride , dasatinib , erlotinib , everolimus, gefitinib , imatinib , lapa puromycin , puromycin hydrochloride, pyrazofurin , ribo tinib , nilotinib , pazonanib , sorafenib , sunitinib , temsiroli - 35 prine , rogletimide , safingol, safingol hydrochloride , semus mus, an angiogenesis inhibitor ( e . g . , GT- 111 , JI - 101, tine, simtrazene , sparfosate sodium , sparsomycin , spiroger R1530 ), a kinase inhibitors ( e . g . , AC220 , AC480 , ACE -041 , manium hydrochloride , spiromustine , spiroplatin , AMG 900 , AP24534, Arry -614 , AT7519 , AT9283 , AV - 951, streptonigrin , streptozocin , sulofenur, talisomycin , tec axitinib , AZD1152 , AZD7762, AZD8055 , AZD8931, bafe - ogalan sodium , tegafur, teloxantrone hydrochloride , tinib , BAY 73 -4506 , BGJ398 , BGT226 , BI 811283, B16727 , 40 temoporfin , teniposide , teroxirone , testolactone , thia BIBF 1120 , BIBW 2992 , BMS -690154 , BMS - 777607 , miprine, thioguanine, thiotepa , tiazofurin , tirapazamine , BMS - 863233 , BSK - 461364 , CAL - 101 , CEP - 11981 , toremifene citrate , trestolone acetate , triciribine phosphate , CYC116 , DCC - 2036 , dinaciclib , dovitinib lactate , E7050 , trimetrexate , trimetrexate glucuronate , triptorelin , tubulo EMD 1214063, ENMD - 2076 , fostamatinib disodium , zole hydrochloride, uracil mustard , uredepa , vapreotide , GSK2256098 , GSK690693 , INCB18424 , INNO -406 , JNJ- 45 verteporfin , vinblastine sulfate , vincristine sulfate , vin 26483327 , JX -594 , KX2 -391 , linifanib , LY2603618 , desine , vindesine sulfate , vinepidine sulfate , vinglycinate MGCD265 , MK - 0457 , MK1496 , MLN8054 , MLN8237 , sulfate , vinleurosine sulfate , vinorelbine tartrate , vinrosidine MP470 , NMS- 1116354 , NMS - 1286937 , ON 01919. Na , sulfate , vinzolidine sulfate , vorozole , zeniplatin , zinostatin , OSI -027 , OSI- 930 , Btk inhibitor, PF -00562271 , zorubicin hydrochloride . In some embodiments, the thera PF -02341066 , PF - 03814735 , PF -04217903 , PF -04554878 , 50 peutic agent is selected from : 20 -epi - 1 , 25 dihydroxyvitamin PF -04691502 , PF - 3758309 , PHA -739358 , PLC3397 , pro D3 , 5 - ethynyluracil , abiraterone , aclarubicin , acylfulvene , genipoietin , R547 , R763 , ramucirumab , regorafenib , adecypenol, adozelesin , aldesleukin , ALL - TK antagonists , R05185426 , SAR103168 , S3333333CH 727965, SGI- 1176 , altretamine, ambamustine, amidox , amifostine, aminolevu SGX523 , SNS- 314 , TAK - 593 , TAK - 901, TKI258 , TLN linic acid , amrubicin , amsacrine, anagrelide, anastrozole , 232, TTP607 , XL147 , XL228, XL281R05126766 , XL418 , 55 andrographolide , angiogenesis inhibitors, antagonist D , XL765 ) , an inhibitor of mitogen -activated protein kinase antagonist G , antarelix , anti - dorsalizing morphogenetic pro signaling ( e . g ., U0126 , PD98059 , PD184352 , PD0325901 , tein - 1 , antiandrogen , prostatic carcinoma, antiestrogen , anti ARRY -142886 , SB239063, SP600125 , BAY 43 - 9006 , wort neoplaston , antisense oligonucleotides , aphidicolin glyci mannin , or LY294002 ), adriamycin , dactinomycin , bleomy - nate , apoptosis gene modulators , apoptosis regulators , cin , vinblastine, cisplatin , acivicin , aclarubicin , acodazole 60 apurinic acid , ara -CDP -DL - PTBA , arginine deaminase , asu hydrochloride , acronine , adozelesin , aldesleukin , altret - lacrine , atamestane , atrimustine , axinastatin 1 , axinastatin 2 , amine, ambomycin , ametantrone acetate , aminoglutethim - axinastatin 3 , azasetron , azatoxin , azatyrosine , baccatin III ide , amsacrine , anastrozole , anthramycin , asparaginase , derivatives, balanol, batimastat, BCR /ABL antagonists , ben asperlin , azacitidine , azetepa , azotomycin , batimastat, ben - zochlorins, benzoylstaurosporine , beta lactam derivatives , zodepa , bicalutamide , bisantrene hydrochloride , bisnafide 65 beta -alethine , betaclamycin B , betulinic acid , bFGF inhibi dimesylate, bizelesin , bleomycin sulfate , brequinar sodium , tor, bicalutamide, bisantrene , bisaziridinylspermine , bisna bropirimine, busulfan , cactinomycin , calusterone , carace fide , bistratene A , bizelesin , breflate , bropirimine , budoti US 9 , 840 , 537 B2 31 32 tane , buthionine sulfoximine , calcipotriol , calphostin C , phosphatase inhibitors , picibanil, pilocarpine hydrochloride , camptothecin derivatives, canarypox IL - 2 , capecitabine , car pirarubicin , piritrexim , placetin A , placetin B , plasminogen boxamide -amino -triazole , carboxyamidotriazole , CaRest activator inhibitor, platinum complex , platinum compounds , M3, CARN 700 , cartilage derived inhibitor , carzelesin , platinum - triamine complex , porfimer sodium , porfiromycin , casein kinase inhibitors (ICOS ) , castanospermine, cecropin 5 prednisone , propyl bis - acridone , prostaglandin J2 , protea B , cetrorelix , chlorins , chloroquinoxaline sulfonamide , some inhibitors , protein A - based immune modulator, protein cicaprost , cis -porphyrin , cladribine, clomifene analogues , kinase C inhibitor, protein kinase C inhibitors , microalgal, clotrimazole , collismycin A , collismycin B , combretastatin protein tyrosine phosphatase inhibitors , purine nucleoside A4 , combretastatin analogue , conagenin , crambescidin 816 , phosphorylase inhibitors , purpurins, pyrazoloacridine , pyri crisnatol, cryptophycin 8, cryptophycin A derivatives, cura - 10 doxylated hemoglobin polyoxyethylerie conjugate , raf cin A , cyclopentanthraquinones , cycloplatam , cypemycin , antagonists , raltitrexed , ramosetron , ras farnesyl protein cytarabine ocfosfate , cytolytic factor, cytostatin , dacliximab , transferase inhibitors , ras inhibitors, ras -GAP inhibitor, decitabine , dehydrodidenrmin B , deslorelin , dexametha - retelliptine demethylated , rhenium Re 186 etidronate , sone , dexifosfamide , dexrazoxane , dexverapamil , diazi rhizoxin , ribozymes, RII retinamide, rogletimide , rohi quone , didenrmin B , didox , diethylnorspermine , dihydro - 5 - 15 tukine , romurtide , roquinimex , rubiginone B1, ruboxyl , azacytidine , 9 - dioxamycin , diphenyl spiromustine , safingol, saintopin , SarCNU , sarcophytol A , sargramostim , docosanol, dolasetron , doxifluridine , droloxifene, dronabi- Sdi 1 mimetics, semustine , senescence derived inhibitor 1 , nol, duocarmycin SA , ebselen , ecomustine , edelfosine , sense oligonucleotides , signal transduction inhibitors , signal edrecolomab , eflornithine , elemene , emitefur, epirubicin , transduction modulators, single chain antigen -binding pro epristeride , estramustine analogue , estrogen agonists, estro - 20 tein , sizofiran , sobuzoxane , sodium borocaptate , sodium gen antagonists , etanidazole , etoposide phosphate , exemes phenylacetate , solverol, somatomedin binding protein , son tane, fadrozole , fazarabine, fenretinide , filgrastim , finas - ermin , sparfosic acid , spicamycin D , spiromustine, spleno teride , flavopiridol, flezelastine , fluasterone, fludarabine , pentin , spongistatin 1 , squalamine , stem cell inhibitor , stem fluorodaunorunicin hydrochloride , forfenimex , formestane , cell division inhibitors , stipiamide , stromelysin inhibitors , fostriecin , fotemustine , gadolinium texaphyrin , gallium 25 sulfinosine , superactive vasoactive intestinal peptide antago nitrate , galocitabine, ganirelix , gelatinase inhibitors , gem - nist , suradista , suramin , swainsonine, synthetic gly citabine , glutathione inhibitors , hepsulfam , heregulin , hex - cosaminoglycans, tallimustine , tamoxifen methiodide , tau amethylene bisacetamide, hypericin , ibandronic acid , idaru - romustine , tazarotene , tecogalan sodium , tegafur, bicin , idoxifene, idramantone , ilmofosine , ilomastat, tellurapyrylium , telomerase inhibitors, temoporfin , temozo imidazoacridones , imiquimod , immunostimulant peptides , 30 lomide , teniposide , tetrachlorodecaoxide , tetrazomine , thali insulin -such as for example growth factor - 1 receptor inhibi- blastine , thiocoraline , thrombopoietin , thrombopoietin tor, interferon agonists , interferons, interleukins, ioben mimetic , thymalfasin , thymopoietin receptor agonist, thy guane, iododoxorubicin , ipomeanol, 4 - , iroplact, irsoglad - motrinan , thyroid stimulating hormone , tin ethyl etiopurpu ine , isobengazole , isohomohalicondrin B , itasetron , rin , tirapazamine , titanocene bichloride , topsentin , tore jasplakinolide , kahalalide F , lamellarin - N triacetate, lan - 35 mifene, totipotent stem cell factor, translation inhibitors , reotide, leinamycin , lenograstim , lentinan sulfate , leptolsta - tretinoin , triacetyluridine, triciribine , trimetrexate , triptore tin , letrozole , leukemia inhibiting factor, leukocyte alpha lin , tropisetron , turosteride, tyrosine kinase inhibitors , tyr interferon , leuprolide + estrogen + progesterone , leuprorelin , phostins, UBC inhibitors , ubenimex , urogenital sinus - de levamisole, liarozole , linear polyamine analogue , lipophilic rived growth inhibitory factor, urokinase receptor disaccharide peptide, lipophilic platinum compounds, lisso - 40 antagonists , vapreotide, variolin B , vector system , erythro clinamide 7 , lobaplatin , lombricine , lometrexol, lonidamine , cyte gene therapy , velaresol, veramine , verdins , verteporfin , losoxantrone, lovastatin , loxoribine, lurtotecan , lutetium vinorelbine , vinxaltine, vitaxin , vorozole , zanoterone , zeni texaphyrin , lysofylline , lytic peptides , maitansine, mannos - platin , zilascorb , zinostatin stimalamer , mechloroethamine , tatin A , marimastat, masoprocol, maspin , matrilysin inhibi cyclophosphamide , chlorambucil, busulfan , carmustine , tors, matrix metalloproteinase inhibitors , menogaril, mer - 45 lomusitne , decarbazine , methotrexate , cytarabine , mercap barone , meterelin , methioninase , metoclopramide , MIF topurine , thioguanine , pentostatin , mechloroethamine , inhibitor, mifepristone , miltefosine , mirimostim , mis cyclophosphamide , chlorambucil , meiphalan , ethylenimine , matched double stranded RNA , mitoguazone , mitolactol, methylmelamine, hexamethlymelamine , thiotepa , busulfan , mitomycin analogues, mitonafide , mitotoxin fibroblast carmustine, lomusitne , semustine , streptozocin , decarba growth factor - saporin , mitoxantrone , mofarotene , molgra - 50 zine , fluorouracil , floxouridine , cytarabine , mercaptopurine, mostim , monoclonal antibody , human chorionic gonadotro - thioguanine , pentostatin , erbulozole ( also known as phin , monophosphoryl lipid A + myobacterium cell wall sk , R - 55104 ) , Dolastatin 10 ( also known as DLS - 10 and NSC mopidamol ,multiple drug resistance gene inhibitor, multiple 376128 ), Mivobulin isethionate (also known as CI- 980 ), tumor suppressor 1- based therapy ,mustard anticancer agent, Vincristine, NSC -639829 , Discodermolide ( also known as mycaperoxide B , mycobacterial cell wall extract , myriapor - 55 NVP - XX - A - 296 ), ABT- 751 ( Abbott , also known as one, N -acetyldinaline , N - substituted benzamides, nafarelin , E -7010 ), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin nagrestip , naloxone + pentazocine , napavin , naphterpin , nar - C ) , Spongistatins (such as Spongistatin 1 , Spongistatin 2 , tograstim , nedaplatin , nemorubicin , neridronic acid , neutral Spongistatin 3 , Spongistatin 4 , Spongistatin 5 , Spongistatin endopeptidase , nilutamide , nisamycin , nitric oxide modula 6 , Spongistatin 7 , Spongistatin 8 , and Spongistatin 9 ), tors , nitroxide antioxidant, nitrullyn , 06 -benzylguanine , oct- 60 Cemadotin hydrochloride (also known as LU - 103793 and reotide , okicenone, oligonucleotides , onapristone, ondanse - NSC -D -669356 ), Epothilones ( such as Epothilone A , Epoth tron , ondansetron , oracin , oral cytokine inducer , ormaplatin , ilone B , Epothilone C ( also known as desoxyepothilone A or osaterone , oxaliplatin , oxaunomycin , palauamine , palmi- dEpoA ) , Epothilone D ( also referred to as KOS - 862, dEpoB , toylrhizoxin , pamidronic acid , panaxytriol, panomifene , and desoxyepothilone B ), Epothilone E , Epothilone F, parabactin , pazelliptine, pegaspargase , peldesine , pentosan 65 Epothilone B N -oxide , Epothilone A N - oxide , 16 -aza - epoth polysulfate sodium , pentostatin , pentrozole , perflubron , per - ilone B , 21 - aminoepothilone B (also known as BMS fosfamide , perillyl alcohol, phenazinomycin , phenylacetate , 310705 ), 21- hydroxyepothilone D (also known as Desoxye US 9 , 840 , 537 B2 33 34 pothilone F and dEpoF ) , 26 - fluoroepothilone ), Auristatin PE monoclonal antibody (NCI , Baylor College of Medicine ) , (also known as NSC -654663 ) , Soblidotin ( also known as antibody anti -anb3 integrin (NCI ) , BIW - 8962 ( Bio Wa Inc . ) , TZT- 1027) , LS -4559 - P (Pharmacia , also known as Antibody BCS (NCI ) , antibody muJ591 (NCI ) , indium In LS - 4577 ) , LS - 4578 (Pharmacia , also known as LS - 477 - P ) , 111 monoclonal antibody MN - 14 (NCI ) , yttrium Y 90 LS - 4477 (Pharmacia ) , LS - 4559 (Pharmacia ), RPR - 112378 5 monoclonal antibody MN - 14 (NCI ) , F105 Monoclonal Anti ( Aventis ), Vincristine sulfate , DZ -3358 (Daiichi ) , body (NIAID ) , Monoclonal Antibody RAV12 ( Raven Bio FR - 182877 ( Fujisawa , also known as WS - 9885B ) , GS - 164 technologies ) , CAT- 192 (Human Anti - TGF - Betal Monoclo ( Takeda ), GS - 198 ( Takeda ), KAR -2 (Hungarian Academy of nal Antibody , Genzyme) , antibody 3F8 (NCI ) , 177Lu- J591 Sciences ) , BSF - 223651 (BASF , also known as ILX -651 and (Weill Medical College of Cornell University ) , TB -403 LU - 223651 ), SAH -49960 (Lilly /Novartis ) , SDZ - 268970 10 (BioInvent International AB ), anakinra , azathioprine , cyclo (Lilly /Novartis ), AM - 97 ( Armad /Kyowa Hakko ), AM - 132 phosphamide , cyclosporine A , leflunomide , d -penicillamine , ( Armad ) , AM - 138 (Armad / Kyowa Hakko ) , IDN -5005 ( In - amitriptyline, or nortriptyline, chlorambucil , nitrogen mus dena ), Cryptophycin 52 (also known as LY -355703 ), tard , prasterone, UP 394 (abetimus sodium ), UP 1082 (La AC - 7739 ( Ajinomoto , also known as AVE - 8063A and Jolla Pharmaceutical) , eculizumab , belibumab , rhuCD40L CS -39 . HCI ) , AC - 7700 ( Ajinomoto , also known as AVE - 15 (NIAID ) , epratuzumab , sirolimus, tacrolimus, pimecroli 8062, AVE -8062A , CS -39 - L - Ser. HCl , and RPR -258062A ), mus , thalidomide, antithymocyte globulin -equine (Atgam , Vitilevuamide , Tubulysin A , Canadensol, Centaureidin ( also Pharmacia Upjohn ) , antithymocyte globulin - rabbit ( Thymo known as NSC - 106969) , T -138067 ( Tularik , also known as globulin , Genzyme) , Muromonab -CD3 (FDA Office of T -67 , TL - 138067 and TI- 138067 ) , COBRA - 1 (Parker Orphan Products Development) , basiliximab , daclizumab , Hughes Institute , also known as DDE - 261 and WHI- 261) , 20 riluzole , cladribine , natalizumab , interferon beta - 1b , inter H10 (Kansas State University ) , H16 (Kansas State Univer - feron beta - la , tizanidine , baclofen , mesalazine , asacol, pen sity ) , Oncocidin Al (also known as BTO - 956 and DIME) , tasa ,mesalamine , balsalazide, olsalazine , 6 -mercaptopurine , DDE -313 ( Parker Hughes Institute ), Fijianolide B , Lauli - AIN457 ( Anti IL - 17 Monoclonal Antibody , Novartis ), the malide , SPA - 2 (Parker Hughes Institute ) , SPA - 1 (Parker ophylline, D2E7 ( a human anti - TNF mAb from Knoll Phar Hughes Institute , also known as SPIKET- P ) , 3 - IAABU 25 maceuticals ), Mepolizumab ( Anti - IL - 5 antibody, SB (Cytoskeleton /Mt . Sinai School of Medicine , also known as 240563 ) , Canakinumab ( Anti - IL - 1 Beta Antibody , NIAMS) , MF - 569 ) , Narcosine (also known as NSC - 5366 ) , Nascapine , Anti - IL - 2 Receptor Antibody (Daclizumab , NHLBI) , CNTO D - 24851 ( Asta Medica ) , A - 105972 ( Abbott ) , Hemiasterlin , 328 (Anti IL -6 Monoclonal Antibody , Centocor ) , ACZ885 3 -BAABU (Cytoskeleton /Mt . Sinai School of Medicine , ( fully human anti- interleukin - 1beta monoclonal antibody, also known as MF - 191 ), TMPN ( Arizona State University ) , 30 Novartis ), CNTO 1275 (Fully Human Anti- IL - 12 Monoclo Vanadocene acetylacetonate , T - 138026 ( Tularik ) , Monsa - nal Antibody, Centocor ), (3S ) - N -hydroxy - 4 - { { 4 - [ (4 -hy trol , Inanocine ( also known as NSC -698666 ) , 3 - 1AABE droxy - 2 - butynyl) oxy ]phenyl } sulfonyl ) - 2 , 2 -dimet -hyl - 3 (Cytoskeleton /Mt . Sinai School of Medicine ), A - 204197 thiomorpholine carboxamide (apratastat ) , golimumab ( Abbott) , T -607 ( Tuiarik , also known as T - 900607 ) , RPR (CNTO 148 ) , Onercept , BG9924 (Biogen Idec ), Certoli 115781 (Aventis ), Eleutherobins ( such as Desmeth - 35 zumab Pegol ( CDP870 , UCB Pharma ), AZD9056 ( Astra yleleutherobin , Desaetyleleutherobin , Isoeleutherobin A , Zeneca ), AZD5069 ( AstraZeneca ), AZD9668 (AstraZen and Z - Eleutherobin ), Caribaeoside , Caribaeolin , Halichon eca ), AZD7928 (AstraZeneca ), AZD2914 (AstraZeneca ), drin B , D -64131 (Asta Medica ), D -68144 (Asta Medica ), AZD6067 (AstraZeneca ), AZD3342 ( AstraZeneca ) , Diazonamide A , A - 293620 ( Abbott ) , NPI- 2350 (Nereus ) , AZD8309 (AstraZeneca ) , ) , ( ( IR ) - 3 -methyl - 1 - ( [ (2S ) - 3 -phe Taccalonolide A , TUB - 245 ( Aventis ), A - 259754 (Abbott ), 40 nyl- 2 -[ (pyrazin - 2 -ylcarbonyl ) amino ]propanoyl } amino )bu Diozostatin , ( - ) -Phenylahistin ( also known as NSCL - tyl] boronic acid (Bortezomib ) , AMG - 714 , (Anti - IL 15 96F037 ) , D - 68838 (Asta Medica ) , D -68836 (Asta Medica ), Human Monoclonal Antibody, Amgen ) , ABT- 874 ( Anti Myoseverin B , D -43411 (Zentaris , also known as D -81862 ), IL - 12 monoclonal antibody, Abbott Labs) , MRA ( Tocili A - 289099 (Abbott ) , A - 318315 (Abbott ) , HTI - 286 (also zumab , an Anti IL -6 Receptor Monoclonal Antibody, Chugai known as SPA - 110 , trifluoroacetate salt ) (Wyeth ), D - 82317 45 Pharmaceutical ) , CAT - 354 ( a human anti - interleukin - 13 ( Zentaris ), D -82318 (Zentaris ) , SC - 12983 (NCI ) , Resvera monoclonal antibody, Cambridge Antibody Technology , statin phosphate sodium , BPR -OY - 007 (National Health MedImmune ) , aspirin , salicylic acid , gentisic acid , choline Research Institutes ) , and SSR -250411 (Sanofi ) . magnesium salicylate , choline salicylate , choline magne In some embodiments , the therapeutic agent is an anti - sium salicylate , choline salicylate , magnesium salicylate , inflammatory agent. In some embodiments , the therapeutic 50 sodium salicylate , diflunisal , carprofen , fenoprofen , feno agent is an anti - TNF agent, an IL - 1 receptor antagonist, an profen calcium , flurobiprofen , ibuprofen , ketoprofen , nabu IL - 2 receptor antagonist , a cytotoxic agent, an immuno tone , ketolorac , ketorolac tromethamine, naproxen , oxapro modulatory agent, an antibiotic , a T - cell co - stimulatory zin , diclofenac , etodolac , indomethacin , sulindac , tolmetin , blocker, a B cell depleting agent, an immunosuppressive meclofenamate , meclofenamate sodium , mefenamic acid , agent, an alkylating agent, an anti -metabolite , a plant alka - 55 piroxicam , meloxicam , celecoxib , rofecoxib , valdecoxib , loid , a terpenoids , a topoisomerase inhibitor, an antitumour parecoxib , etoricoxib , lumiracoxib , CS -502 ( Sankyo ) , JTE antibiotic , an antibody , a hormonal therapy, an anti -diabetes 522 (Japan Tobacco Inc .) , L - 745, 337 ( Almirall ), NS398 agent, a leukotriene inhibitor, or combinations thereof. In (Sigma ) , betamethasone (Celestone ) , prednisone (Delta some embodiments , the therapeutic agent is selected from : sone ), alclometasone , aldosterone , amcinonide , beclometa alefacept, efalizumab , methotrexate , acitretin , isotretinoin , 60 sone , betamethasone , budesonide , ciclesonide , clobetasol, hydroxyurea , mycophenolate mofetil, sulfasalazine, 6 - Thio - clobetasone , clocortolone, cloprednol, cortisone , cortivazol, guanine , Dovonex , Taclonex , betamethasone , tazarotene , deflazacort, deoxycorticosterone , desonide , desoximeta hydroxychloroquine , etanercept, adalimumab , infliximab , sone, desoxycortone , dexamethasone , diflorasone , diflucor abatacept, rituximab , tratuzumab , Anti -CD45 monoclonal tolone , difluprednate , fluclorolone , fludrocortisone , antibody AHN - 12 (NC ) , Iodine - 131 Anti- B1 Antibody 65 fludroxycortide, flumetasone , flunisolide, fluocinolone ( Corixa Corp . ), anti -CD66 monoclonal antibody BW 250 / acetonide , fluocinonide, fluocortin , fluocortolone, fluo 183 (NCI , Southampton General Hospital) , anti - CD45 rometholone , fluperolone, fluprednidene , fluticasone, for US 9 , 840 ,537 B2 35 36 mocortal, formoterol , halcinonide, halometasone , hydrocor carrier enhances uptake into cancer tissue . In some embodi tisone , hydrocortisone aceponate , hydrocortisone buteprate , ments , a carrier enhances uptake into lymphatic channels hydrocortisone butyrate, loteprednol, medrysone , mepred - and /or lymph nodes. nisone , methylprednisolone , methylprednisolone aceponate , In some embodiments , a carrier increases plasma half - life mometasone furoate , paramethasone, prednicarbate , pred - 5 by reducing glomerular filtration . In some embodiments , a nisone , rimexolone , tixocortol, triamcinolone , ulobetasol, carrier modulates plasma half- life by increasing or decreases Pioglitazone , Rosiglitazone , Glimepiride , Glyburide , Chlo - metabolism or protease degradation . In some embodiments , rpropamide, Glipizide , Tolbutamide, Tolazamide, Glu a carrier increases tumor uptake due to enhanced perme cophage , Metformin , (glyburide +metformin ) , Rosiglita - ability and retention ( EPR ) of tumor vasculature . In some zone + metformin , (Rosiglitazone + glimepiride ) , Exenatide, 10 embodiments , a carrier increases the aqueous solubility of Insulin , Sitagliptin , ( glipizide and metformin ), Repaglinide , selective delivery molecule . Acarbose , Nateglinide, Orlistat , cisplatin ; carboplatin ; oxa In some embodiments , any M is independently directly or liplatin ; mechlorethamine; cyclophosphamide; chlorambu - indirectly (e .g . , via CM ) bound to A , B , or X . In some cil ; vincristine ; vinblastine ; vinorelbine ; vindesine ; mercap - embodiments , any M is independently bound to A at the topurine ; fludarabine; pentostatin ; cladribine ; 5 - fluorouracil 15 n - terminal poly glutamate . In some embodiments , any M is (5FU ) ; floxuridine ( FUDR ) ; cytosine arabinoside ; independently bound to A (or , the n -terminal poly glutamate ) trimethoprim ; pyrimethamine ; pemetrexed ; paclitaxel ; doc - by a covalent linkage . In some embodiments , any M is etaxel ; etoposide; teniposide ; irinotecan ; topotecan ; amsa independently bound to B at the c - terminal polyarginine . In crine ; etoposide; etoposide phosphate ; teniposide ; dactino - some embodiments , any M is independently bound to B (or , mycin ; doxorubicin ; daunorubicin ; valrubicine ; idarubicine; 20 the c- terminal polyarginine ) by a covalent linkage . In some epirubicin ; bleomycin ; plicamycin ; mitomycin ; finasteride ; embodiments , any M is independently directly or indirectly goserelin ; aminoglutethimide; anastrozole ; letrozole ; voro bound to linkers between X and A , X and B , B and C /N zole ; exemestane ; 4 - androstene - 3 , 6 ,17 - trione (“ 6 -OXO ” ; terminus , and A and C /N terminus . In some embodiments , 1 , 4 , 6 - androstatrien - 3 , 17 - dione ( ATD ) ; formestane ; testolac - the covalent linkage comprises an ether bond , thioether tone; fadrozole ; A - 81834 ( 3 - ( 3 - ( 1 , 1 - dimethylethylthio - 5 - 25 bond , amine bond, amide bond , oxime bond , carbon - carbon ( quinoline - 2 -ylmethoxy ) - 1 - ( 4 - chloromethylphenyl) indole - bond , carbon - nitrogen bond , carbon - oxygen bond , or car 2 - yl) - 2 , 2 - dimethylpropionaldehyde oxime- 0 - 2 -acetic acid ; bon - sulfur bond . AME103 ( Amira ) ; AME803 ( Amira ) ; atreleuton ; BAY - X - In some embodiments , M is selected from a protein , a 1005 ( ( R ) - ( + ) - alpha - cyclopentyl- 4 - ( 2 - quinolinylmethoxy ) - synthetic or natural polymer, or a dendrimer . In some Benzeneacetic acid ) ; CJ- 13610 (4 - ( 3 -( 4 - ( 2 -Methyl - imida - 30 embodiments , M is selected from dextran , a PEG polymer zol- 1 - yl) - phenylsulfanyl ) - phenyl) - tetrahydro - pyran -4 ( e. g ., PEG 5 kDa , PEG 12 kDa, PEG 20 kDa, PEG 30 kDa , carboxylic acid amide ) ; DG -031 (DeCode ); DG -051 and PEG40 kDa) , albumin , or a combination thereof. In ( DeCode ); MK886 ( 1 -[ ( 4 - chlorophenyl) methyl ] 3 - [ (1 , 1 -di - some embodiments , M is a PEG polymer . methylethyl) thio ] - a , 2 -dimethyl - 5 -( 1 -methylethyl ) - 1H - in - In some embodiments , the size of M is between 50 and 70 dole -2 -propanoic acid , sodium salt ); MK591 ( 3 -( 1 -4 [ ( 4 - 35 kD . chlorophenyl) methyl ] - 3 -[ ( t - butylthio ) - 5 - ( ( 2 - quinoly ) In some embodiments , the selective delivery molecule is methoxy ) - 1H - indole - 2 ] -, dimethylpropanoic acid ); conjugated to albumin . In certain instances , albumin is RP64966 ( [4 - [5 - ( 3 -Phenyl - propyl ) thiophen - 2 -yl ] butoxy ] excluded from the glomerular filtrate under normal physi acetic acid ) ; SA6541 ( ( R ) - S - [ [ 4 - (dimethylamino )phenyl ] ological conditions . In some embodiments , the selective methyl] - N - (3 -mercapto - 2methyl- 1 -oxopropyl - L -cysteine ); 40 delivery molecule comprises a reactive group such as SC - 56938 ( ethyl- 1 - [ 2 - [ 4 - (phenylmethyl )phenoxyJethyl ] - 4 - maleimide that can form a covalent conjugate with albumin . piperidine -carboxylate ) ; VIA - 2291 ( Via Pharmaceuticals ) ; A selective delivery molecule comprising albumin results in WY -47 ,288 ( 2 - [( 1 -naphthalenyloxy )methyl ] quinoline ); enhanced accumulation of cleaved selective delivery mol zileuton ; ZD - 2138 (6 -( ( 3 - fluoro -5 - ( tetrahydro - 4 -methoxy ecules in tumors in a cleavage dependent manner. In some 2H -pyran -4yl ) phenoxy )methyl )- 1 -methyl - 2 ( 1H )- quinloli - 45 embodiments , albumin conjugates have good pharmacoki none ) ; doxycycline ; or combinations thereof. netic properties . Macromolecular Carriers In some embodiments , the selective delivery molecule is The term “ carrier ” means an inert molecule that modu - conjugated to a PEG polymer . In some embodiments , the lates plasma half - life , solubility , or bio - distribution . In some selective delivery molecule is conjugated to a PEG 5 kDa embodiments , a carrier modulates plasma half -life of a 50 polymer . In some embodiments , the selective delivery mol selective delivery molecule disclosed herein . In some ecule is conjugated to a PEG 12 kDa polymer. In some embodiments , a carrier modulates solubility of a selective embodiments, selective delivery molecule is conjugated to a delivery molecule disclosed herein . In some embodiments, a PEG 20 kDa polymer. In some embodiments , 30 kD PEG carrier modulates bio - distribution of a selective delivery conjugates had a longer half -life as compared to free pep molecule disclosed herein . 55 tides. In some embodiments , selective delivery molecules In some embodiments , a carrier decreases uptake of a are conjugated to 20 - 40 kD PEG polymer which has hepatic selective delivery molecule by non - target cells or tissues . In and renal clearance . some embodiments , a carrier decreases uptake of a selective In some embodiments , the selective delivery molecule is delivery molecule into cartilage . In some embodiments, a conjugated to a dextran . In some embodiments, the selective carrier decreases uptake of a selective delivery molecule into 60 delivery molecule is conjugated to a 70 kDa dextran . In joints relative to target tissue . some embodiments , dextran conjugates , being a mixture of In some embodiments , a carrier increases uptake of a molecular weights , are difficult to synthesize and purify selective delivery molecule by target cells or tissues . In reproducibly. some embodiments , a carrier decreases uptake of a selective In some embodiments , the selective delivery molecule is delivery molecule into the liver relative to target tissue . In 65 conjugated to streptavidin . some embodiments , a carrier decreases uptake of a selective In some embodiments, the selective delivery molecule is delivery molecule into kidneys . In some embodiments , a conjugated to a fifth generation PAMAM dendrimer. US 9 ,840 ,537 B2 37 38 In some embodiments , a carrier is capped . In some prises an ether bond , thioether bond , amine bond , amide embodiments , capping a carrier improves the pharmacoki- bond , oxime bond , hydrazone bond, carbon - carbon bond , netics and reduces cytotoxicity of a carrier by adding carbon -nitrogen bond , carbon -oxygen bond , or carbon -sul hydrophilicity . In some embodiments , the cap is selected fur bond . from : Acetyl , succinyl, 3 - hydroxypropionyl , 2 -sulfoben - 5 In some embodiments , X comprises a peptide linkage . zoyl, glycidyl, PEG - 2 , PEG - 4 , PEG - 8 and PEG -12 . The peptide linkage comprises L - amino acids and /or Portion X (Linkers ) D -amino acids. In embodiments of the invention , D - amino In some embodiments , a linker consisting of one or more acids are preferred in order to minimize immunogenicity and amino acids is used to join peptide sequence A ( i. e . , the nonspecific cleavage by background peptidases or proteases . sequence designed to inhibit the delivery action of peptide 10 Cellular uptake of oligo - D -arginine sequences is known to B ) and peptide sequence B . Generally the peptide linker will be as good as or better than that of oligo - L - arginines . have no specific biological activity other than to join the In some embodiments , a X linker is designed for cleavage molecules or to preserve some minimum distance or other in the presence of particular conditions or in a particular spatial relationship between them . However, the constituent environment. In preferred embodiments , a X linker is cleav amino acids of the linker may be selected to influence some 15 able under physiological conditions. Cleavage of such a X property of the molecule such as the folding , net charge , or linker may, for example , be enhanced or may be affected by hydrophobicity . particular pathological signals or a particular environment In live cells , an intact selective delivery molecule dis - related to cells in which cargo delivery is desired . The design closed herein may not be able to enter the cell because of the of a X linker for cleavage by specific conditions, such as by presence of portion A . Thus, a strictly intracellular process 20 a specific enzyme , allows the targeting of cellular uptake to for cleaving X would be ineffective to cleave X in healthy a specific location where such conditions obtain . Thus, one cells since portion A , preventing uptake into cells , would not important way that selective delivery molecules provide be effectively cleaved by intracellular enzymes in healthy specific targeting of cellular uptake to desired cells , tissues , cells since it would not be taken up and would not gain or regions is by the design of the linker portion X to be access to such intracellular enzymes. However , where a cell 25 cleaved by conditions near such targeted cells , tissues , or is injured or diseased ( e . g ., cancerous cells , hypoxic cells , regions. ischemic cells , apoptotic cells , necrotic cells ) such intracel In some embodiments , X is a pH - sensitive linker. In some lular enzymes leak out of the cell and cleavage of A would embodiments , X is cleaved under basic pH conditions. In occur, allowing entry of portion B and /or cargo into the cell, some embodiments , X is cleaved under acidic pH condi effecting targeted delivery of portion B and /or cargo D to 30 tions. In some embodiments , X is cleaved by a protease , a neighboring cells. In some embodiments , X is cleaved in the matrix metalloproteinase , or a combination thereof. In some exextracellular space . embodiments , X is cleaved by a reducing agent. In some embodiments , the fact that capillaries are often In some embodiments , X is cleaved by an MMP . The leaky around tumors and other trauma sites enhances the hydrolytic activity ofmatrix metalloproteinases (MMPs ) has ability of high molecular weight molecules ( e . g ., molecular 35 been implicated in the invasive migration of metastatic weight of about 30 kDa or more ) to reach the interstitial tumor cells . In certain instances , MMPs are found near sites compartment . In some embodiments , X linkercells that do of inflammation . In certain instances, MMPs are found near not express the relevant protease but that are immediately sites of stroke ( i. e . , a disorder characterized by brain damage adjacent to expressing cells pick up cargo from a selective following a decrease in blood flow ) . Thus, uptake of mol delivery molecule because linkage of a X linker is typically 40 ecules having features of the invention are able to direct extracellular. In some embodiments , such bystander target - cellular uptake of cargo ( at least one D moiety ) to specific ing is beneficial in the treatment of tumors because of the cells , tissues , or regions having active MMPs in the extra heterogeneity of cell phenotypes and the wish to eliminate as cellular environment. In some embodiments , a X linker that high a percentage of suspicious cells as possible . includes the amino - acid sequences PLG - C (Me ) - AG (SEO In some embodiments , X is a cleavable linker. 45 ID NO : 1 ), PLGLAG ( SEQ ID NO : 2 ) which are cleaved by In some embodiments , the linker is flexible. In some the metalloproteinase enzymes MMP - 2 , MMP - 9 , or MMP - 7 embodiments , the linker is rigid . (MMPs involved in cancer and inflammation ) . In some embodiments , the linker comprises a linear In some embodiments , X is cleaved by proteolytic structure . In some embodiments, the linker comprises a enzymes or reducing environment, as may be found near non - linear structure . In some embodiments , the linker com - 50 cancerous cells . Such an environment, or such enzymes , are prises a branched structure . In some embodiments, the linker typically not found near normal cells . comprises a cyclic structure . In some embodiments , X is cleaved by serine proteases In some embodiments , X is about 5 to about 30 atoms in including but not limited to thrombin . length . In some embodiments , X is about 6 atoms in length . In some embodiments, X is cleaved in or near tissues In some embodiments , X is about 8 atoms in length . In some 55 suffering from hypoxia . In some embodiments , cleavage in embodiments , X is about 10 atoms in length . In some or near hypoxic tissues enables targeting of cancer cells and embodiments , X is about 12 atoms in length . In some cancerous tissues, infarct regions, and other hypoxic embodiments , X is about 14 atoms in length . In some regions . In some embodiments , X comprises a disulfide embodiments , X is about 16 atoms in length . In some bond . In some embodiments , a linker comprising a disulfide embodiments , X is about 18 atoms in length . In some 60 bond is preferentially cleaved in hypoxic regions and so embodiments , X is about 20 atoms in length . In some targets cargo delivery to cells in such a region . Hypoxia is embodiments , X is about 25 atoms in length . In some thought to cause cancer cells to become more resistant to embodiments , X is about 30 atoms in length . radiation and chemotherapy , and also to initiate angiogen In some embodiments , the linker binds peptide portion A esis . In a hypoxic environment in the presence of, for ( i. e ., the peptide sequence which prevents cellular uptake ) to 65 example , leaky or necrotic cells , free thiols and other peptide portion B ( i . e ., the delivery sequence ) by a covalent reducing agents become available extracellularly , while the linkage . In some embodiments , the covalent linkage com - 02 that normally keeps the extracellular environment oxi US 9 , 840 ,537 B2 39 40 dizing is by definition depleted . In some embodiments , this cleavage site in this and subsequent sequences ) ; shift in the redox balance promotes reduction and cleavage GGPRGLPG (SEQ ID NO : 34 ) ; HSSKLQ (SEQ ID NO : of a disulfide bond within a X linker . In addition to disulfide 35 ) ; LVLA -SSSFGY (SEQ ID NO : 36 ) ; GVSQNY- PIVG linkages which take advantage of thiol -disulfide equilibria , (SEQ ID NO : 37 ) ; GVVQA - SCRLA ( SEQ ID NO : 38 ) ; linkages including quinones that fall apart when reduced to 5 f ( Pip ) R - S , where “ f ” indicates D -phenylalanine and “ Pip ” hydroquinones are used in a X linker designed to be cleaved indicates piperidine - 2 - carboxylic acid ( pipecolinic acid , a in a hypoxic environment . proline analog having a six -membered ring ) ; DEVD (SEO In some embodiments, X is cleaved in a necrotic envi- ID NO : 39 ) ; GWEHDG (SEQ ID NO : 40 ) ; RPLALWRS ronment. Necrosis often leads to the release of enzymes or (SEQ ID NO : 7 ) , or a combination thereof. other cell contents that may be used to trigger cleavage of a 10 In some embodiments , X is cleaved under hypoxic con X linker. In some embodiments , cleavage of X by necrotic ditions . In some embodiments, X comprises a disulfide enzymes ( e . g ., by calpains) allows cargo to be taken up by linkage . In some embodiments , X comprises a quinine . diseased cells and by neighboring cells that had not yet In some embodiments , X is cleaved under necrotic con become fully leaky. ditions. In some embodiments , X comprises a molecule In some embodiments , X is an acid - labile linker. In some 15 cleavable by a calpain . embodiments , X comprises an acetal or vinyl ether linkage . In some embodiments , X comprises 6 -aminohexanoyl , Acidosis is observed in sites of damaged or hypoxic tissue , 5 -( amino )- 3 -oxapentanoyl , or a combination thereof. In due to the Warburg shift from oxidative phosphorylation to some embodiments , X comprises a disulfide linkage . anaerobic glycolysis and lactic acid production . In some In some embodiments , the linker is an alkyl. In some embodiments , acidosis is used as a trigger of cargo uptake by 20 embodiments , the linker is heteroalkyl . replacing some of the arginines within B by histidines , In some embodiments , the linker is an alkylene . In some which only become cationic below pH 7 . embodiments , the linker is an alkenylene. In some embodi It will be understood that a linker disclosed herein may m ents , the linker is an alkynylene . In some embodiments , include non - standard amino acids, such as , for example , the linker is a heteroalkylene . hydroxylysine , desmosine , isodesmosine , or other non -stan - 25 An " alkyl” group refers to an aliphatic hydrocarbon dard amino acids . A linker disclosed herein may include group . The alkyl moiety may be a saturated alkyl or an modified amino acids , including post- translationally modi- unsaturated alkyl. Depending on the structure , an alkyl fied amino acids such as , for example, methylated amino group can be a monoradical or a diradical ( i . e ., an alkylene acids (e . g. , methyl histidine , methylated forms of lysine , group ). etc . ) , acetylated amino acids, amidated amino acids, formy - 30 The “ alkyl ” moiety may have 1 to 10 carbon atoms lated amino acids , hydroxylated amino acids, phosphory - (whenever it appears herein , a numerical range such as “ 1 to lated amino acids, or other modified amino acids . A linker 10 ” refers to each integer in the given range ; e . g . , " 1 to 10 disclosed herein may also include peptide mimetic moieties , carbon atoms” means that the alkyl group may consist of 1 including portions linked by non - peptide bonds and amino carbon atom , 2 carbon atoms, 3 carbon atoms, etc ., up to and acids linked by or to non -amino acid portions . 35 including 10 carbon atoms, although the present definition In some embodiments , the linker X comprises an amino also covers the occurrence of the term “ alkyl ” where no acid sequence selected from : PLGLAG (SEQ ID NO : 2 ) , numerical range is designated ) . The alkyl group could also PLG - C (me ) - AG (SEQ ID NO : 1 ) , RPLALWRS (SEQ ID be a “ lower alkyl” having 1 to 6 carbon atoms. The alkyl NO : 7 ) , ESPAYYTA (SEQ ID NO : 8 ) , DPRSFL (SEQ ID group of the compounds described herein may be designated NO : 9 ) , PPRSFL (SEO ID NO : 10 ) , RLOLKL ( SEO ID NO : 40 as “ C1 - C4 alkyl” or similar designations. By way of 11 ) , and RLQLK (Ac ) ( SEQ ID NO : 12 ) . In some embodi- example only , “ C1 -C4 alkyl” indicates that there are one to ments, the linker X comprises the amino acid sequence four carbon atoms in the alkyl chain , i. e ., the alkyl chain is PLGLAG (SEQ ID NO : 2 ). In some embodiments , the linker selected from : methyl , ethyl, propyl, iso -propyl , n -butyl , X comprises the amino acid sequence PLG - C (me ) - AG (SEQ iso -butyl , sec- butyl , and t -butyl . Typical alkyl groups ID NO : 1 ) . In some embodiments , the linker X comprises the 45 include , but are in no way limited to , methyl, ethyl, propyl, amino acid sequence PLGxAG (SEQ ID NO : 27 ) , wherein isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethe x is any amino acid ( naturally -occurring or non -naturally nyl , propenyl, butenyl, and the like. occurring ) . In some embodiments , the linker X comprises In some embodiments , the linker comprises a ring struc the amino acid sequence RPLALWRS (SEO ID NO : 7 ) . In ture ( e . g . , an aryl) . As used herein , the term “ ring” refers to some embodiments , the linker X comprises the amino acid 50 any covalently closed structure. Rings include, for example , sequence ESPAYYTA ( SEQ ID NO : 8 ) . In some embodi- carbocycles ( e . g . , aryls and cycloalkyls ) , heterocycles ( e . g . , ments, the linker X comprises the amino acid sequence heteroaryls and non - aromatic heterocycles ) , aromatics ( e . g . DPRSFL (SEQ ID NO : 9 ) . In some embodiments , the linker aryls and heteroaryls ), and non -aromatics ( e . g . , cycloalkyls X comprises the amino acid sequence PPRSFL (SEQ ID and non - aromatic heterocycles) . Rings can be optionally NO : 10 ). In some embodiments , the linker X comprises the 55 substituted . Rings can be monocyclic or polycyclic . amino acid sequence RLQLKL (SEQ ID NO : 11 ) . In some As used herein , the term “ aryl” refers to an aromatic ring embodiments , the linker X comprises the amino acid wherein each of the atoms forming the ring is a carbon atom . sequence RLQLK ( Ac ) ( SEQ ID NO : 12 ) . Aryl rings can be formed by five , six , seven , eight, nine , or In some embodiments , the linker X comprises a peptide more than nine carbon atoms. Aryl groups can be optionally selected from : PR (S / T ) (L /I ) ( S / T ), where the letters in paren - 60 substituted . Examples of aryl groups include , but are not theses indicate that either one of the indicated amino acids limited to phenyl , naphthalenyl, phenanthrenyl, anthracenyl, may be at that position in the sequence ) ; GGAANLVRGG fluorenyl, and indenyl . Depending on the structure , an aryl ( SEQ ID NO : 28 ) ; SGRIGFLRTA (SEQ ID NO : 29 ) ; group can be a monoradical or a diradical ( i. e ., an arylene SGRSA (SEQ ID NO : 30 ); GFLG (SEQ ID NO : 31 ); ALAL ( SEQ ID NO : 32 ) ; FK ; PIC ( Et) F - F (SEQ ID NO : 33 ) , where 65 The term “ cycloalkyl” refers to a monocyclic or polycy C ( Et ) indicates S - ethylcysteine ( a cysteine with an ethyl clic non - aromatic radical, wherein each of the atoms form group attached to the thiol) and the “ _” indicates the typical ing the ring i. e . skeletal atoms) is a carbon atom . US 9 , 840 ,537 B2 41 42 Cycloalkyls may be saturated , or partially unsaturated . more bonds . In some embodiments , the ring is a dimer . In Cycloalkyl groups include groups having from 3 to 10 ring some embodiments , the ring is a trimer. In some embodi atoms. Cycloalkyls include, but are not limited to , cyclo ments, the ring is a substituted . propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, The term " carbocyclic ” or “ carbocycle ” refers to a ring and cyclooctyl. 5 wherein each of the atoms forming the ring is a carbon atom . In some embodiments , the ring is a cycloalkane . In some Carbocycle includes aryl and cycloalkyl. The term thus embodiments , the ring is a cycloalkene . distinguishes carbocycle from heterocycle (" heterocyclic " ) In some embodiments , the ring is an aromatic ring. The in which the ring backbone contains at least one atom which term " aromatic ” refers to a planar ring having a delocalized is different from carbon (i . e ., a heteroatom ) . Heterocycle n - electron system containing 4n + 2 o electrons , where n is an 10 includes heteroaryl and heterocycloalkyl. Carbocycles and integer. Aromatic rings can be formed from five , six , seven , heterocycles can be optionally substituted . eight, nine , or more than nine atoms. Aromatics can be In some embodiments , the linker is substituted . The term optionally substituted . The term “ aromatic ” includes both “ optionally substituted ” or “ substituted ” means that the carbocyclic aryl ( e . g . , phenyl) and heterocyclic aryl (or referenced group may be substituted with one or more " heteroary?" or " heteroaromatic ” ) groups ( e . g ., pyridine ). 15 additional group ( s ) individually and independently selected The term includes monocyclic or fused - ring polycyclic (i .e ., from C , -Coalkyl , Cz- C cycloalkyl, aryl, heteroaryl, rings which share adjacent pairs of carbon atoms) groups. C2- Cgheteroalicyclic , hydroxy, C1- C alkoxy, aryloxy, In some embodiments , the ring is a heterocycle . The term C7 - C alkylthio , arylthio , C , -Coalkylsulfoxide , arylsulfox " heterocycle ” refers to heteroaromatic and heteroalicyclic ide , C . - C alkylsulfone, arylsulfone , cyano , halo , C2- Cgacyl, groups containing one to four heteroatoms each selected 20 C2- Cgacyloxy , nitro , C7 - Cohaloalkyl, C / - C fluoroalkyl, and from O , S and N , wherein each heterocyclic group has from amino , including C , -Coalkylamino , and the protected 4 to 10 atoms in its ring system , and with the proviso that the derivatives thereof. By way of example , an optional sub ring of said group does not contain two adjacent O or S stituents may be LsRs, wherein each Ls is independently atoms. Non - aromatic heterocyclic groups include groups selected from a bond , — — - C ( O ) - , - S — , having only 3 atoms in their ring system , but aromatic 25 - S ( O ) - , S ( O ) 2 - , — NH — — NHC ( O ) - , heterocyclic groups must have at least 5 atoms in their ring C ( LO) NH , SUZO) NH?, _ NHS ( O ) 2 - , OC system . The heterocyclic groups include benzo - fused ring FO) NH — , - NHC ( O ) O - , - ( C - Cgalkyl) - , or (C2 systems. An example of a 3 -membered heterocyclic group is Coalkenyl) -; and each Rs is independently selected from H , aziridinyl. An example of a 4 -membered heterocyclic group (C , - C alkyl) , (C2 - C cycloalkyl) , heteroaryl, aryl, and is azetidinyl ( derived from azetidine ). An example of a 30 C , Coheteroalkyl. Optionally substituted non -aromatic 5 -membered heterocyclic group is thiazolyl. An example of groups may be substituted with one or more oxo ( O ) . The a 6 -membered heterocyclic group is pyridyl , and an example protecting groups that may form the protective derivatives of of a 10 -membered heterocyclic group is quinolinyl. the above substituents are known to those of skill in the art. Examples of non -aromatic heterocyclic groups are pyrro - In some embodiments , a selective delivery molecules lidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothie - 35 disclosed herein comprises a single of linker . Use of a single nyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyra - mechanism to mediate uptake of both imaging and thera nyl, piperidino , morpholino , thiomorpholino , thioxanyl, peutic cargoes is particularly valuable , because imaging piperazinyl , azetidinyl, oxetanyl, thietanyl, homopiperidi- with noninjurious tracer quantities can be used to test nyl, oxepanyl, thietanyl, oxazepinyl , diazepinyl, thiazepinyl, whether a subsequent therapeutic dose is likely to concen 1 ,2 , 3 ,6 -tetrahydropyridinyl , 2 -pyrrolinyl , 3 -pyrrolinyl , 40 trate correctly in the target tissue . indolinyl, 2H - pyranyl, 4H -pyranyl , dioxanyl, 1 , 3 - dioxola - In some embodiments , a selective delivery molecules nyl, pyrazolinyl, dithianyl, dithiolanyl , dihydropyranyl, disclosed herein comprises a plurality of linkers . Where a dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, selective delivery molecule disclosed herein includes mul imidazolidinyl , 3 - azabicyclo [ 3 . 1 . 0 ]hexanyl , 3 - azabicyclo tiple X linkages , separation of portion A from the other [ 4 . 1 . ]heptanyl , 3H - indolyl and quinolizinyl. Examples of 45 portions of the molecule requires cleavage of all X linkages. aromatic heterocyclic groups are pyridinyl, imidazolyl, Cleavage of multiple X linkers may be simultaneous or pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl , tetrazolyl, furyl, sequential. Multiple X linkages may include X linkages thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrro having different specificities , so that separation of portion A lyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, ben from the other portions of the molecule requires that more zofuranyl, cinnolinyl, indazolyl , indolizinyl, phthalazinyl, 50 than one condition or environment (" extracellular signals ” ) pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadi- be encountered by the molecule . Cleavage of multiple X X azolyl , thiadiazolyl , furazanyl, benzofurazanyl, benzothio - linkers thus serves as a detector of combinations of such phenyl, benzothiazolyl, benzoxazolyl, quinazolinyl , quinox extracellular signals . For example , a selective delivery mol alinyl, naphthyridinyl, and furopyridinyl . The foregoing ecule may include two linker portions Xa and Xb connecting groups , may be C - attached or N - attached where such is 55 basic portion B with acidic portion A . Both X linkers a and possible . For instance , a group derived from pyrrole may be Xb must be cleaved before acidic portion Ais separated from pyrrol - 1 - yl ( N -attached ) or pyrrol- 3 - yl ( C - attached ). Fur- basic portion B allowing entry of portion B and cargo moiety ther , a group derived from imidazole may be imidazol - 1 - yl C ( if any ) to enter a cell . It will be understood that a linker or imidazol - 3 - yl (both N -attached ) or imidazol- 2 - yl, imida region may link to either a basic portion B or a cargo moiety zol - 4 - yl or imidazol- 5 - yl (all C - attached ). The heterocyclic 60 C independently of another linker that may be present, and groups include benzo - fused ring systems and ring systems that, where desired , more than two linker regions X may be substituted with one or two oxo O moieties such as included . pyrrolidin - 2 - one . Depending on the structure , a heterocycle Combinations of two or more X linkers may be used to group can be a monoradical or a diradical ( i. e ., a heterocy - further modulate the targeting and delivery of molecules to clene group ) . 65 desired cells , tissue or regions. Combinations of extracellu In some embodiments , the ring is fused . The term “ fused ” lar signals are used to widen or narrow the specificity of the refers to structures in which two or more rings share one or cleavage of X linkers if desired . Where multiple X linkers US 9 , 840 , 537 B2 43 44 are linked in parallel, the specificity of cleavage is narrowed , Disclosed herein , in certain embodiments , are selective since each X linker must be cleaved before portion A may delivery molecules according to SDM - 27 . separate from the remainder of the molecule. Where mul Disclosed herein , in certain embodiments , are selective tiple X linkers are linked in series, the specificity of cleavage delivery molecules according to SDM -32 . 5 Disclosed herein , in certain embodiments , are selective is broadened , since cleavage on any one X linker allows 5 delivery molecules according to SDM - 35 . separation of portion A from the remainder of the molecule . Disclosed herein , in certain embodiments , are peptides For example , in order to detect either a protease OR hypoxia according to Peptide P - 3 . ( i. e ., to cleave X in the presence of either protease or Disclosed herein , in certain embodiments , are selective hypoxia ), a X linker is designed to place the protease - delivery molecules according to SDM - 14 . sensitive and reduction - sensitive sites in tandem , so that Disclosed herein , in certain embodiments , are selective cleavage of either would suffice to allow separation of the delivery molecules according to SDM - 15 . acidic portion A . Alternatively , in order to detect the pres Disclosed herein , in certain embodiments , are selective ence of both a protease AND hypoxia ( i . e ., to cleave X in the delivery molecules according to SDM - 23 . presence of both protease and hypoxia but not in the 15 Disclosed herein , in certain embodiments , are selective presence of only one alone ) , a X linker is designed to place 15 delivery molecules according to SDM - 24 . Disclosed herein , in certain embodiments , are selective the protease sensitive site between at least one pair of delivery molecules according to SDM - 25 . cysteines that are disulfide - bonded to each other. In that Disclosed herein , in certain embodiments , are selective case , both protease cleavage and disulfide reductionduction are delivery moleculesmo according to SDM - 26 . required in order to allow separation of portion A . 20 Disclosed herein . in certain embodiments , are selective Exemplary Selective Delivery Molecules delivery molecules according to SDM - 27 . Disclosed herein , in certain embodiments , are selective Disclosed herein , in certain embodiments , are selective delivery molecules according to SDM - 14 . delivery molecules according to SDM - 32 . Disclosed herein , in certain embodiments , are selective Disclosed herein , in certain embodiments , are selective delivery molecules according to SDM - 15 . 25 delivery molecules according to SDM -35 . Disclosed herein , in certain embodiments , are selective In some embodiments , the selective delivery molecule has delivery molecules according to SDM -23 . a structure selected from : SDM - 1 , SDM - 2 , SDM - 3 , SDM - 4 , Disclosed herein , in certain embodiments , are selective SDM - 5 , SDM -6 , SDM -7 , SDM - 8 , SDM - 9 , SDM - 10 , SDM delivery molecules according to SDM - 24 . 11 , SDM - 12 , SDM - 13 , SDM - 14 , SDM - 15 , SDM - 16 , SDM Disclosed herein , in certain embodiments , are selective 30 17 , SDM - 18 , SDM - 19 , SDM -20 , SDM - 21 , SDM -22 , SDM delivery molecules according to SDM - 25 . 23 , SDM - 24 , SDM - 25 , SDM - 26 , SDM - 27 , SDM - 28 , SDM Disclosed herein , in certain embodiments , are selective 29, SDM -30 , SDM -31 , SDM -32 , SDM - 33, SDM -34 , SDM delivery molecules according to SDM -26 . 35, SDM -36 , SDM -37 , SDM -38 , SDM - 39, and SDM -40 . US 9 ,840 , 537 B2 45 46

SO3H SO3H moltiplaat.0701 SO3H

lm H NH HONASO = ???

Z NH HN. YN OF HN*NH, HN*NH, 'NH"?? HN. OE NH'“ H?NNHSOH HNNHH?N,NHHN HN, NH HNHNHNHN. OE HN. PHOHOHO

N =Ö O

IZ NH N??-? Os HN. OE NINI

TZ SDM-1 o SDM-2 HN OOTNHH: OR come?T HN400

IZ z 0^?? ??0

HÖÖH0 O 0^?? ??0

????? 0 ?????????? 1 OHOHOHNYYNYN ??, 0OHOOH OHOEO ???

yaIZ

Mw=40,000 Mw=40,000 of US 9 ,840 , 537 B2 47 48

111 recommendcan - HN distandoof H|6 HN,?? NH ?Hx0 H EO O HN, HN,HN HN HN NH HNNHH2NCNHHENNHH?N,NH CHANHCHNNHCHÁNH H6 CHNNHCHÁNHCHN;NHHN,

H??????? Hx6 HHNCOOHOF?H3OFÖ© NH HN.HN OE

O = NH ØHx

HNHNHNHN ÖVRTNANO N ENLLLLLLLLY. - OF O IZ HNO2H,õ6 -continued SDM-3 ne SDM-4

?uneHillyouhomeWLNUNDLILLIO OH

??0HO0 ?;©Höì = ?O ;oö#ì©?Ñ; HOOHOWO NYNNrity? HOO ???????? HOOHOYO OE NANNYhet Yn OH ni I Lyswie 000?0€=MW Mw=20,000 US 9 ,840 , 537 B2 49 50 u HOS SO3H

HOS

0. 'NH FO

met H

: 'NH 0 SO HN H NH HNNH,HN*NH Z 0 'NH HN. “NH R HOSHN?N?HHNCNHHN?NH HN, . NHNH 'NH 1HNCNCHHNNCH HNqNHCHNqNHCHÁNH HN H HN180179178177178 “NH OE CNH-NHNH H HN

H -continued SDM-5 SDM-6 uninprivateCOOHHN 'SOHAN

Z KNN. HO?o HÖ?i©;ìöH;? HOGOHOOHOCOHOYO HOVO HOO HO?o

H HOYO HONAN HOCO

11 Mw=20,000 sutoyou 000?0+=MW US 9 ,840 , 537 B2 M (

SO3 HOS SO3H HOS

HO3S VSO HN HN ONUN HN. ©H3OÖ? HN, (HNMNHCHNCNHCHNNH IZ HN H??????? HN N HN,.HNNH“ HN. HN?NHHN*NH OHNLLLLLLLLLLLL HN N = O HN -continued SDM-7 Lully SDM-8

HN pelyhennettu ningen0 OE Homeone HOYO HOO HOO HOOHO0 HOVO young youyouMw=40,000 Mw=40,000 US 9 ,840 , 537 B2 54

SO3H MSO3 EC HN

NH ?

? 03803 038 6H5 ? NH HN. ? HN. ? UH ?

? HN. ? H56 NH turi HN. HNNHH?N,NH ? 'NHHN*NH,HN?NH HN*NH,HN?NH ? HNNHH?N,NHHON EZ HN. ì NH ot HN. ? m ? 56H

? HN. ? (H5 NH

? HN.

? .

? SDM-9 Z SDM-10 IZ } -continued á za you Mw=40,000

N Mw=40,000 N yitvory O ?????? ????

??? N M IZ ??????? HOH ???? SO3H O Bookingtheone ???? INNT ???? kamatosdieoor -O3S US 9 ,840 , 537 B2 55 56

503HtoSO3H SO3H

's YNYNH, o 038 0 Ozs. H

N LS

HN*NH, HN*NH, 'NH |'NH HNNHH?N,NHHN, À H?NNH,HUN HN,

YºoHO N ;???????? ANTENENUNINMUNITYO OE O

N OE - NONONONONHKNULO"YNY -continued Mw=40,000 SDM-11 NorwoyoMw=20,000 SDM-12

OUNT-

0 N.lv H oohOOH oohOOH ??? HO 0,0100HOOH

OS??????????? SO3H 0 SO3H (HOHOHOHOHOLN. DysonCortanal,os somtoplanadeos OS US 9 ,840 , 537 B2 57 58

HOS Heos OF N

O Oz

0 O 038 SEO IZ HN

H EZ OE |HN, HN, OE (HN,NH |HN,

N CHANHCHNNHCHÁNH H?N,NH3~NH“ HNNHH?N,NHHÀNHHN, IZ

MANERAEN H HN, OE NOOH00.30HH3OH IZ HN, CZ

Os IZ OE OE - IZ Os

H SDM-13 141 000?S=MW SDM-14 000?OT=MW. N?H0

-continued O ONofNoiOLU LA O OTON en

OE NUN HooHoto HOVOHOCOHOYO o;Ho# HOO oHoH HomoHofoHOWOHO*0 .H NUNLI,HLN HOS NLLLLLLLOH HOS LO arawnaiyongtelesco

webolignagyobasicSO US 9 ,840 , 537 B2 59 09

SO3H SO3 SO3H vodo NO/00040,Mw= *038 NH2

Os HN'S NH

H ? HN*NH,HNNH ? YN 'NH ZI 0 Oz H?NNH, H ZI HN nawenginemenmedenH?N,NH HN.HN.

H0 NH fo 0 HO H NH YYNYYN -NN HNCNH,HNCNHHN*NHHNCNH, LH0 NH Z HNNHH?N,NH HNHNHNHNHN FO - HNHNHN. -continued Mw=2,000 INUN SDM-15 NH SDM-16

= 0 NYNYNYYNY - IZ OOHOGOHOH OOHO-OHOSOH

SO3H #0 NI ??????? HO?0 0413,Ciptaandos HOHOHOHOHO ??

0 ?,?? Treoverlede US 9 ,840 , 537 B2 61 79

SO3 SO3H SO3 SO3H NO NO000/20,Mw= Protaatio 0005,Mw=

NH2 NH FOOO Ovo H? *S HN 0

H NH HNHN HN. HO = O NH HNCNH,HNNH SNH'NH HNCNH, CNH HNNHH?N,NHHNVNHHN HNNHHÀNHHNQNHHNVNH NH NH HNHNHN O = lil -continued ANHNH SDM-17 N SDM-18 HNHNHN H

111

- u ZI

“NH-

OH Oyonepiece?????? ?????? odoh

OH 0 odou ??? ?,?? US 9 ,840 , 537 B2 63 64

SO3H SO3H

Zuo Ozo

. 0 's HN 038 Os 03S Z ÑHN. O

HN, HN. HN*NH, HNNHH?NNHHÀNHHUN3HÝ OHONUHN oHo, 'NH HN*NH,HN?NH H?NNHHN,HANNH YNNYNYNYNYNNYNH 'NH?NH HN. OE HNKHN |HN,HN. HÖHÖHÖHÖHOI HN. HN.

I IZ HNHNHNHN THOHOHOHOHO IZ HN FO oronN SDM-19 SDM-20 -continued to H N Mw=20,000" Mw=40,000 OE H?HO= - Mw=20,000 O = O INNIHHNUNYIN HNNYNN

Ñ = O ogors HOYO ??-0 Ñ ??? ogonOOHOLOHOH = O HOVO OHHOHE ??0 SO3H Ñ SO3H LLLL Ciptaandebyon?Oqon

osCortanados 038 US 9 ,840 , 537 B2 65 99

SO3H SO3H

- 4

S *O3S 038yot 'NH 03Sy HN. Os

N HN. OE 'NHNH OE HÖÖHOSHO HN*NH,HN?NH , IZ andanorganangnatutunanberkenaat,HN. 'NHNH HN*NH, H?NNHHINHHANH HN. HNNHH?NNHNHÀ 'NH O HOHO. H DE HN 'NHNH O NIN O HN HNHNHNHN = O HN. ID10 NH 0 SDM-21 SDM-22 HN -continued ofNºN 0 Mw=20,000 OE - Mw=20,000 Mw pooHULU ·HÖ FHO Nyoyo NI HNTINÖ yangpertanyents ????

H:9 OHOOH ??,0

??? N ???? :) OHOULAN ??,0 SO3H OOH H OHOH ???? ( INTENTION• ofthelanation50"

optistamata-OS US 9 ,840 , 537 B2 67 89

HOS HOS

goYou öH O ?so IC NY CNH “NHNH O = H NH -HN?NHHN?NHH?N ???, ????????? OH3öH?30À30IZ HNNH“ CHNNHCHÁNHHN,NH NH ÖHH OE NANNYNT NHNH OE HNHNHNHN N

À SDM-23 SDM-24 -continued ÖHHN10 - IZI Mw=10,000 NYNYNYNYT 000?S=MW öHHNLOO Oz

N con otrogen

FO le?HOH M HOO HÖÎöÌ© N HOYOHOO ??????? ?????0HO0 Hotohoto E debolinagdalaFoseHOS oppostamento Bhartiere US 9 ,840 , 537 B2 69

HOS H?OS

ozco HN soV soJy SO IZ wanalimpeza,watotowatatu NH

HN *???? NH HNNH“HN,NHHANH = HNNHCHNNHCHANH öHÖHÖFÖHö HZ -HN?NHHN?NHHN*NH ANLATILI,ILIIndien NH |HI?HT?H10H10H ©Ñ HN HNHNHNHN NHNH HNHNHNHN

| OS SDM-25 O SDM-26 - os z H -continued O Mw=2,000 of 000'I=MW

NoN

OE ??0 ???0 hotohoHo? SO entorno HOO ??,0 HOO LILLINOpolonel ??0 SOZH ??,0 langereOE HanhatimagesH®OS ??0

-OS US 9 ,840 , 537 B2

HOS SO3H

wouldyougo OZO HNN( O ? HN - -S SO ?so ROh1: NH IZ E |HN, ouamere H0 ? (HN,NHCHÁNHCHNNH 20H NH :TN HN*NHHNN&HHN?NH CNHNH NHANH'NHSNH OR -HNNHHN?NH CHNNHCHNNHHN, endNH NHNH = O

? NH ÖH HNHNHNHN.

Ö OE - Ir ???? H 8NH?NANIN- I SDM-27 Mw=10,000 SDM-28 -continued N Mw=500 DON. HN MoN

HOYO HOYOHOVO HOO HOO HotoHoboHomoHO*0 OHON HOS HOYO HOHOS {laoreet LILI,UN SO3H MN HOO

T vaca. $Ho SO uso. US 9 ,840 , 537 B2 74

HOS HOS

OZO

? - So- H so FO3S. ? HN o

? IN EO HN, ? HN, |HN, -HNCNHHN?NHHN?NCHHNCNCH "NHCNHNH ?TN HNNHHNNH 30H HN HNNHH?N, CHNNHHNMNHHNqNHHN, ?

? Ho

IZ HN ? Ö

H HNHNHNHN 111 TZ O SDM-29 HOS SDM-30 continued- - Ninh O SH Mw=10,000 -POOLÖHN©?

? vseo ? HOGO ??? HOYOHOOHOVO HOS HOO ?H? HOYO IZ OE HOS NH HOYO more IZ H?os oto Mw=10,000 US 9 ,840 , 537 B2 75

SO3H SO3H

. TZ

038 03S IZ

HN.,HN SINH:.BSNT

HNNHH2NCNHH?NNHHENNHS |H16H| HN?NH,HNNHHN*NH 543H52H OHOH “NH H?NNHHNA NH'NH' HN?NH,HN*NHHNCNH IZ HN.

IZ HN

HNHNHNHN N JI HOS SDM-32 -continued LHOYYNY SDM-31 Mw=10,000

5 |0TCNHH weerterugdalo NHHo

?so IZ goHg,01ouOH TronINTNT HOYO DE

IZ ??????? ?,????? HOYO OOH DE N HOYO ofthetermsbyons

Mw=2,000 US 9 ,840 , 537 B2 77

SO3H "NH2 SO3H NH2 ? Lo ?N IN phantoo"of

OE -02 -O3Sy ? N 000Mw=10,NH'NH'NH“ H|A01 000Mw2,=NH'NH'NH“ O

N YNNyviNY' NYNYNYMOs HN*NH,HNNHCo IZ HN*NH,HN?NHbo N

H?NNH,HN,. H?NNHH?NNH HN, 1HOANINI Os ÖHÖSHOSH !

N N OE TZ N O ÖONHHOHOHOHUMUNHMENY HN

À?:ö 11

0 -continued LH SDM-33 menperiodenN SDM-34

= O

HOH = O ? NYNYNN,NYYNYYNYNY - NH??????? 0OHOOH OhohoohOOH 0OH HOHNNI

SO3H :0dvedenne er ostplanaadiono ? opptaante

-OS US 9 ,840 , 537 B2 64 0808

SO3H SO3H EO) HN

N ??0

OE ???

038 ??,0 ogmeteenenormplanto* EZ GAN opatient ??? H O 'NHNH HN*NH, ???

H?N,NHHN

NyooHOHO Os ;????? NYH OE 1 ZI OIH ÖHNNYNNYNYNYNYNYNYENZYNY 0 10 SO3H HNHNHNHNHN OE -

HNH0A SDM-35 IN SDM-36 -continued SNH“NH| - IZ NIN okeptanganBlogi ?? HNNHH?NNH, IN HNCNH,HNNHHN*NH OhOhOOF SNH'NHNH NYNYNYYN HÖÖH IN NH ??? ?????? OohoohOOHOLOH HOHO = O SO3H z

M EO HN0 Loots Mw=2,000

??????-Mw=2,000 ofron OS US 9 ,840 , 537 B2

FO HN Mw=3,000 berganomod ??0 ovomNH2 NHH

??0 ©

readingand OOH À NH

N ??,0 IHÖ NH H?NNHH2NCNH, s?NH'NH'“ HN?NH,HN*NHHNCNH Ö HOH0H TZH ??

0 HNHNHNHN ??

SDM-37 SDM-38

-continued H NH 1 OLANTNYTÀ?ANHHOH 025NHHLo^

HN. 1,ANHNH' H?NNH,HNNH HNHNHNHN HN*NH,HN?NHHNCNHHNNH NH HOYO NH' HN. HOO 0 HOS HOYO

Mw=5,000Mw=5,000 ENNO wabitiprograma NH difuzoareOS US 9 ,840 , 537 B2 €8 84

sozH EO 0003,Mw=o HN IN O = =0THB

N ,NH component OOH 0OHOOH " opophanato BONH2FO " 5 H?NNH, HNCNH,HN?NH “NHNHI NHTINTENZYNOWYMÀÀ©©H 5

_ "' z 5

HNHNHNHN ? 5 .111 IZ WN SDM-39 SDM-40 Z -continued FO

NH HNVNHH?NNH,HN- 'NH'NH HNNH,HN?NH

(H ??? ; HÖS ???? HO demento??? HÔH ???? HÖ HOS ??? SO3H Mw=2,000 informationla "batana HN US 9 , 840 ,537 B2 85 86 Further Modifications embodiments , cm is para - 4 - acetyl L -phenylalanine . In some In some embodiments , the targeting molecules of the embodiments , X is cleavable by a protease . In some embodi present invention are optionally conjugated to high molecu ments , X is cleavable by a matrix metalloproteinase. In some lar weight molecules that increase the multivalency and embodiments , X comprises an amino acid sequence that is avidity of labeling . In some embodiments, the high molecu - 5 cleavable by MMP2 , MMP7 , MMP9, or MMP14 . In some lar weight molecules are water - soluble polymers . Examples embodiments , X comprises a peptide linkage . In some of suitable water- soluble polymers include, but are not embodiments , X comprises an amino acid sequence selected limited to, peptides, saccharides, poly ( vinyls ), poly (ethers ), from : PLGLAG (SEQ ID NO : 2 ), PLG - C (me )- AG (SEQ ID poly (amines ), poly ( carboxylic acids ) and the like . In some NO : 1 ) , RPLALWRS ( SEQ ID NO : 7 ) , ESPAYYTA ( SEQ embodiments , the water- soluble polymer is dextran , poly - , ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID ethylene glycol (PEG ), polyoxyalkylene , polysialic acid , NO : 10 ) , RLQLKL (SEQ ID NO : 11 ), and RLQLK (AC ) starch , or hydroxyethyl starch . Any suitable method is used (SEQ ID NO : 12 ) . In some embodiments , X comprises the to conjugate peptides to water - soluble polymers ( see Her amino acid sequence PLGLAG (SEQ ID NO : 2 ) . In some manson G ., Bioconjugate Techniques 2nd Ed ., Academic embodiments, X comprises the amino acid sequence PLG Press, Inc . 2008 ) . C (me ) - AG (SEQ ID NO : 1 ) . In some embodiments , X Pharmaceutical Compositions 15 comprises the amino acid sequence RPLALWRS (SEQ ID Disclosed herein , in certain embodiments , are pharma NO : 7 ). In some embodiments , X comprises the amino acid ceutical compositions comprising a selective delivery mol sequence DPRSFL (SEQ ID NO : 9 ) . In some embodiments , ecule of Formula I , having the structure : X comprises the amino acid sequence RLQLKL (SEQ ID NO : 11 ) . In some embodiments , X comprises the amino acid [DA - CA ] -A - [ CAM ]- X - B - [CB - DB ] Formula I 20 sequence RLQLK ( Ac ) (SEQ ID NO : 12 ) . In some embodi ments , M is selected from a protein , a natural polymer , a wherein , synthetic polymer , or a dendrimer . In some embodiments , M X is a cleavable linker ; is selected from dextran , a PEG polymer, albumin , or a A is a peptide with a sequence comprising 5 to 9 acidic combination thereof. In some embodiments, M is a PEG . In amino acids ; o hori 25 some embodiments, M is selected from PEG 5 kDa, PEG 12 B is a peptide with a sequence comprising 7 to 9 basic 25 kDa, PEG 20 kDa , PEG 30 kDa, and PEG40 kDa. In some amino acids ; embodiments , D , and DR are a pair of acceptor and donor CA, CB , and cm each independently comprise 0 -1 amino fluorescent moieties that are capable of undergoing Försters / acid ; fluorescence resonance energy transfer with the other . In M is a macromolecule ; and some embodiments , D , and DR are Cy5 and Cy7 . In some DA and DB are each independently selected from an 30 embodiments , D , and D , are Cy5 and IRDye750 . In some imaging agent and a therapeutic ; and embodiments , D , and De are Cy5 and IRDye800 . In some wherein [cm - M ] is bound to at any position on A or X , embodiments , D? and Dg are Cy5 and ICG . In some embodi [ D , -ca ] is bound to any amino acid on A , and [ CB -DB ) is ments , DA and De are a fluorescent moiety and a fluores bound to any amino acid on B . cence - quenching moiety . In some embodiments, the mol In some embodiments , A and B do not have an equal 353 ecule of Formula I is : SDM - 14 , SDM - 15 , SDM - 23 , SDM number?? of acidic and basic amino acids. In some embodi ments, the number of basic amino acids in B is greater than 24 , SDM - 25 , SDM - 26 , SDM -27 , SDM - 32 , or SDM - 35 . the number of acidic amino acids in A . In some embodi Disclosed herein , in certain embodiments , are pharma ments , A is a peptide comprising 5 or 9 consecutive gluta ceutical compositions comprising a selective delivery mol mates (SEQ ID NO : 3 ) . In some embodiments , B is a peptide ecule of Formula I , having the structure : comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In 40 Formula I some embodiments , A is a peptide comprising 5 or 9 [DA - Ca ] - A -[ crrM ]- X -B -[ CB -DB ] consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide wherein , comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In X is a cleavable linker; some embodiments , A is a peptide comprising 5 consecutive A is a peptide with a sequence comprising 5 to 9 acidic glutamates ( SEQ ID NO : 5 ) and B is a peptide comprising 45 8 consecutive arginines (SEQ ID NO : 6 ) . In some embodi- B is a peptide with a sequence comprising 7 to 9 basic ments , C4, CR , and cy are each independently a 0 - 1 amino amino acids ; acid . In some embodiments, CA , CB , and cu are each inde CA, CB, and cm each independently comprise 0 - 1 amino pendently selected from a naturally -occurring amino acid or acid ; a non -naturally occurring amino acid . In some embodi- 50 M is a polyethylene glycol (PEG ) polymer , and ments , CA, CR , and cy are each independently selected from DA and Do are each independently an imaging agent; and a D amino acid , a L amino acid , an a -amino acid , a ß -amino wherein [Cy - M ] is bound to at any position on A or X , acid , or a y -amino acid . In some embodiments , CA, CB , and Cy are each independently selected from any amino acid [DA - CA ] is bound to any amino acid on A , and [CB - D ] having a free thiol group , any amino acid having a N - ter is bound to any amino acid on B . minal amine group , and any amino acid with vinga side a chainles 55 In some embodiments , A and B do not have an equal capable of forming an oxime or hydrazone bond upon number of acidic and basic amino acids . In some embodi reaction with a hydroxylamine or hydrazine group . In some ments , the number of basic amino acids in B is greater than embodiments , CA , CR , and cy are each independently selected the number of acidic amino acids in A . In some embodi from D -cysteine , D - glutamate , lysine , and para - 4 - acetyl ments , A is a peptide comprising 5 or 9 consecutive gluta L -phenylalanine . In some embodiments , CB is any amino060 6 mates (SEQ ID NO : 3 ). In some embodiments , B is a peptide acid having a free thiol group . In some embodiments , Cris comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In D - cysteine. In some embodiments , c , is any amino acid some embodiments , A is a peptide comprising 5 or 9 having a N - terminal amine group . In some embodiments , consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide is D - glutamate . In some embodiments , c , is lysine . In some comprising 8 or 9 consecutive arginines ( SEQ ID NO : 4 ) . In embodiments, Cy is any amino acid with a side chain 65 some embodiments , A is a peptide comprising 5 consecutive capable of forming an oxime or hydrazone bond upon glutamates (SEQ ID NO : 5 ) and B is a peptide comprising reaction with a hydroxylamine or hydrazine group . In some 8 consecutive arginines (SEQ ID NO : 6 ). In some embodi US 9 ,840 ,537 B2 87 88 ments , C4, CB , and cm are each independently a 0 - 1 amino B is a peptide with a sequence comprising 8 or 9 con acid . In some embodiments, CA , CB , and cy are each inde secutive arginines ( SEQ ID NO : 4 ) ; CA , CR, and cw each pendently selected from a naturally -occurring amino acid or independently comprise 0 - 1 amino acid ; a non - naturally occurring amino acid . In some embodi Mis a polyethylene glycol (PEG ) polymer; and ments , c . cp , and c , are each independently selected from 5 DA and DB are a pair of acceptor and donor fluorescent moieties that are capable of undergoing Försters / fluo a D amino acid , a L amino acid , an a - amino acid , a ß - amino rescence resonance energy transfer with the other ; and acid , or a y -amino acid . In some embodiments , CA, CB , and wherein [cn - M ] is bound to at any position on A or X , CM are each independently selected from any amino acid [DA - CA ] is bound to any amino acid on A , and [Co -DB ) is having a free thiol group , any amino acid having a N -ter 10 bound to any amino acid on B . minal amine group , and any amino acid with a side chain In some embodiments , A and B do not have an equal capable of forming an oxime or hydrazone bond upon number of acidic and basic amino acids . In some embodi reaction with a hydroxylamine or hydrazine group . In some ments , CA, CB , and cm are each independently selected from embodiments , CA , CR , and cy are each independently selected any amino acid having a free thiol group , any amino acid from D - cysteine, D - glutamate , lysine , and para - 4 - acetyl 15 having a N -terminal amine group , and any amino acid with L -phenylalanine . In some embodiments , CB is any amino a side chain capable of forming an oxime or hydrazone bond acid having a free thiol group . In some embodiments , Cris D - cysteine . In some embodiments , CA is any amino acid upon reaction with a hydroxylamine or hydrazine group . In having a N - terminal amine group . In some embodiments , CA some embodiments, C4 , CB , and cy are each independently a is D - glutamate . In some embodiments , CA is lysine. In some 2 0 - 1 amino acid . In some embodiments , CA , CB , and cy are embodiments , CM is any amino acid with a side chain 20 each independently selected from D - cysteine, D - glutamate , capable of forming an oxime or hydrazone bond upon lysine , and para - 4 - acetyl L - phenylalanine . In some embodi reaction with a hydroxylamine or hydrazine group . In some ments , CB is any amino acid having a free thiol group . In embodiments , Cy is para - 4 - acetyl L -phenylalanine . In some some embodiments , co is D -cysteine . In some embodiments , embodiments , X is cleavable by a protease . In some embodi CA is any amino acid having a N - terminal amine group . In ments , X is cleavable by a matrix metalloproteinase . In some 25 some embodiments , C , is D - glutamate . In some embodi embodiments , X comprises an amino acid sequence that is ments, Cy is any amino acid with a side chain capable of cleavable by MMP2, MMP7 , MMP9 , or MMP14 . In some forming an oxime or hydrazone bond upon reaction with a embodiments , X comprises a peptide linkage . In some hydroxylamine or hydrazine group . In some embodiments , embodiments , X comprises an amino acid sequence selected Cy is para - 4 - acetyl L - phenylalanine . In some embodiments, from : PLGLAG (SEQ ID NO : 2 ) , PLG - C (me ) - AG (SEQ ID 30 X comprises the amino acid sequence PLGLAG (SEQ ID NO : 1 ) , RPLALWRS ( SEQ ID NO : 7 ) , ESPAYYTA (SEQ NO : 2 ). In some embodiments , X comprises the amino acid ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID sequence PLG - C (me ) - AG (SEQ ID NO : 1 ) . In some NO : 10 ), RLQLKL (SEQ ID NO : 11) , and RLQLK ( Ac ) embodiments , DA and Dg are Cy5 and Cy7. In some embodi (SEQ ID NO : 12 ). In some embodiments , X comprises the , ments , DA and Do are Cy5 and Cyn . amino acid sequence PLGLAG (SEQ ID NO : 2 ) . Inises some me 35 Disclosed herein , in certain embodiments , are pharma embodiments , X comprises the amino acid sequence PLG ceutical compositions comprising a selective delivery mol C (me ) - AG (SEQ ID NO : 1) . In some embodiments , X ecule of Formula I, having the structure : comprises the amino acid sequence RPLALWRS ( SEQ ID [DA - CA ] - A - [CAM ]- X - B -[ CB - D } ] Formula I NO : 7 ). In some embodiments , X comprises the amino acid 40 wherein , sequence DPRSFL (SEQ ID NO : 9 ). In some embodiments , X comprises the amino acid sequence PPRSFL (SEQ ID X is a peptide linker cleavable by a matrix metallopro NO : 10 ) . In some embodiments , X comprises the amino acid teinase ; sequence RLQLKL ( SEQ ID NO : 11 ) . In some embodi A is a peptide with a sequence comprising 5 consecutive ments , X comprises the amino acid sequence RLQLK (Ac ) 45 B isglutamates a peptide (with SEQ aID sequence NO : 5 ) ;comprising 8 consecutive ( SEQ ID NO : 12 ) . In some embodiments , DA and Do are a arginines (SEQ ID NO : 6 ); pair of acceptor and donor fluorescent moieties that are CA, CB, and cm each independently comprise 0 - 1 amino capable of undergoing Försters/ fluorescence resonance acid ; energy transfer with the other. In some embodiments , D , and M is a polyethylene glycol (PEG ) polymer; and Do are Cy5 and Cy7 . In some embodiments , DA and Do are 50 DA and DB are a pair of acceptor and donor fluorescent Cy5 and IRDye750 . In some embodiments , DA and Do are moieties that are capable of undergoing Försters/ fluo Cy5 and IRDye800 . In some embodiments , D , and D , are rescence resonance energy transfer with the other ; and Cy5 and ICG . In some embodiments , DA and Do are a wherein [Cy - M ] is bound to at any position on A or X , fluorescent moiety and a fluorescence- quenching moiety . In [DA - CA ] is bound to any amino acid on A , and [Co -DB ) is some embodiments , the molecule of Formula I is : SDM - 14 ·, 55so bound to any amino acid on B . SDM - 15 , SDM - 23 , SDM - 24 , SDM - 25 , SDM - 26 , SDM - 27, In some embodiments , CA , CB, and cm are each indepen SDM - 32 ; or SDM - 35 . dently a 0 - 1 amino acid . In some embodiments , CA, CB , and Disclosed herein , in certain embodiments , are pharma CM are each independently selected from any amino acid ceutical compositions comprising a selective delivery mol having a free thiol group , any amino acid having a N -ter ecule of Formula I, having the structure : 60 minal amine group , and any amino acid with a side chain capable of forming an oxime or hydrazone bond upon [DA - CA ] - A -[ CAM ]- X -B - [ CB -D } ] Formula I reaction with a hydroxylamine or hydrazine group . In some wherein , embodiments , C4, CB , and cw are each independently selected X is a peptide linker cleavable by a matrix metallopro - from D - cysteine, D - glutamate, lysine , and para - 4 - acetyl teinase ; 65 L - phenylalanine . In some embodiments, CB is any amino A is a peptide with a sequence comprising 5 or 9 con acid having a free thiol group . In some embodiments , CB is secutive glutamates (SEQ ID NO : 3 ) ; D -cysteine . In some embodiments , ca is any amino acid US 9 , 840 ,537 B2 89 90 having a N - terminal amine group . In some embodiments , Disclosed herein , in certain embodiments , are pharma is D - glutamate . In some embodiments , Cy is any amino acid ceutical compositions comprising a selective delivery mol with a side chain capable of forming an oxime or hydrazone ecule according to SDM -23 . bond upon reaction with a hydroxylamine or hydrazine Disclosed herein , in certain embodiments , are pharma group . In some embodiments , Cm is para - 4 - acetyl L -phenyl - 5 ceutical compositions comprising a selective delivery mol alaninee . InIn some embodiments , &X comprises the amino acid ecule according to SDM - 24 . sequence PLGLAG (SEQ ID NO : 2 ). In some embodiments , Disclosed herein , in certain embodiments , are pharma X comprises the amino acid sequence PLG - C (me ) - AG ( SEQ ceutical compositions comprising a selective delivery mol ID NO : 1 ) . In some embodiments , X comprises the amino acid sequence RPLALWRS (SEQ ID NO : 7) . In some 10 ecule according to SDM - 25 . embodiments , D and D . are Cy5 and Cy7 . In some embodi Disclosed herein , in certain embodiments , are pharma ments , D , and D are Cy5 and IRDye750 . In some embodi ceutical compositions comprising a selective delivery mol ments , DA and DB are Cy5 and IRDye800 . In some embodi ecule according to SDM - 26 . ments , D , and Deare Cy5 and ICG . Disclosed herein , in certain embodiments , are pharma Disclosed herein , in certain embodiments , are pharmana - 1515 ceuticalceu compositions comprising a selective delivery mol ceutical compositions comprising a selective delivery mol ecule according to SDM - 27 . Disclosed herein , in certain embodiments , are pharma ecule of Formula I , having the structure : ceutical compositions comprising a selective delivery mol [DA - Ca ] - A -[ ex M ]- X - B - [Co - Dp ] Formula I ecule according to SDM - 32 . wherein , 20 Disclosed herein , in certain embodiments , are pharma X is a peptide linker cleavable by a matrix metallopro - ceutical compositions comprising a selective delivery mol teinase ; ecule according to SDM -35 . A is a peptide with a sequence comprising 9 consecutive Disclosed herein , in certain embodiments , are selective glutamates (SEQ ID NO : 13 ) ; delivery molecules according to SDM - 14 . B is a peptide with a sequence comprising 9 consecutive 25 Disclosed herein , in certain embodiments , are selective arginines (SEQ ID NO : 14 ) ; delivery molecules according to SDM - 15 . CA, CB, and cm each independently comprise 0 - 1 amino Disclosed herein , in certain embodiments , are selective acid ; delivery molecules according to SDM -23 . M is a polyethylene glycol (PEG ) polymer , and Disclosed herein , in certain embodiments , are selective DA and Dg are a pair of acceptor and donor fluorescent 30 delivery molecules according to SDM - 24 . moieties that are capable of undergoing Försters / fluo - Disclosed herein , in certain embodiments , are selective rescence resonance energy transfer with the other , and delivery molecules according to SDM - 25 . wherein [cy - M ] is bound to at any position on A or X , Disclosed herein , in certain embodiments , are selective [DA -CA ] is bound to any amino acid on A , and [Co -DB ) is delivery molecules according to SDM - 26 . bound to any amino acid on B . 35 Disclosed herein , in certain embodiments , are selective In some embodiments , CA, CB, and cm are each indepen - delivery molecules according to SDM -27 . dently a 0 - 1 amino acid . In some embodiments, CA, CB , and Disclosed herein , in certain embodiments , are selective Cy are each independently selected from any amino acid delivery molecules according to SDM -32 . having a free thiol group , any amino acid having a N - ter- Disclosed herein , in certain embodiments , are selective minal amine group , and any amino acid with a side chain 40 delivery molecules according to SDM - 35 . capable of forming an oxime or hydrazone bond upon Pharmaceutical compositions herein are formulated using reaction with a hydroxylamine or hydrazine group . In some one or more physiologically acceptable carriers including embodiments , CA, CR, and cy are each independently selected excipients and auxiliaries which facilitate processing of the from D - cysteine , D - glutamate , lysine , and para - 4 -acetyl active agents into preparations which are used pharmaceu L - phenylalanine . In some embodiments , Co is any amino 45 tically. Proper formulation is dependent upon the route of acid having a free thiol group . In some embodiments , Cris administration chosen . A summary of pharmaceutical com D - cysteine . In some embodiments , c4 is any amino acid positions is found, for example , in Remington : The Science having a N - terminal amine group . In some embodiments , ca and Practice of Pharmacy , Nineteenth Ed (Easton , Pa. : Mack is D - glutamate . In some embodiments , Cwis any amino acid Publishing Company , 1995 ) ; Hoover, John E ., Remington ' s with a side chain capable of forming an oxime or hydrazone 50 Pharmaceutical Sciences , Mack Publishing Co . , Easton , Pa . bond upon reaction with a hydroxylamine or hydrazine 1975 ; Liberman , H . A . and Lachman , L ., Eds. , Pharmaceu group . In some embodiments , Cyis para - 4 - acetyl L -phenyl tical Dosage Forms, Marcel Decker, New York , N . Y . , 1980 ; alanine. In some embodiments , X comprises the amino acid and Pharmaceutical Dosage Forms and Drug Delivery Sys sequence PLGLAG ( SEQ ID NO : 2 ). In some embodiments, tems, Seventh Ed . (Lippincott Williams & Wilkins , 1999 ) . X comprises the amino acid sequence PLG - C (me ) - AG (SEQ 55 In certain embodiments , a pharmaceutical composition ID NO : 1 ). In some embodiments , X comprises the amino disclosed herein further comprises a pharmaceutically acid sequence RPLALWRS (SEQ ID NO : 7) . In some acceptable diluent( s ), excipient( s ), or carrier( s ). In some embodiments , D? and Do are Cy5 and Cy7 . In some embodi embodiments , the pharmaceutical compositions includes ments , D , and Do are Cy5 and IRDye750 . In some embodi- other medicinal or pharmaceutical agents , carriers , adju ments , DA and DB are Cy5 and IRDye800 . In some embodi- 60 vants , such as preserving , stabilizing , wetting or emulsifying ments , DA and DB are Cy5 and ICG . agents , solution promoters , salts for regulating the osmotic Disclosed herein , in certain embodiments , are pharma - pressure , and / or buffers . In addition , the pharmaceutical ceutical compositions comprising a selective delivery mol compositions also contain other therapeutically valuable ecule according to SDM - 14 . substances . Disclosed herein , in certain embodiments , are pharma- 65 In certain embodiments , a pharmaceutical composition ceutical compositions comprising a selective delivery mol- disclosed herein is administered to a subject by any suitable ecule according to SDM - 15 . administration route , including but not limited to , parenteral US 9 , 840 ,537 B2 91 ( intravenous, subcutaneous , intraperitoneal, intramuscular , enable targeted delivery of one or more cargos ( e . g ., thera intravascular, intrathecal , intravitreal, infusion , or local) peutic agents or imaging agents ) to a cell tissue. administration . Disclosed herein , in certain embodiments , are methods of Formulations suitable for intramuscular , subcutaneous, delivering cargo to a tissue of interest , comprising contact peritumoral , or intravenous injection include physiologi - 5 ing the tissue of interest with a molecule of Formula I: cally acceptable sterile aqueous or non -aqueous solutions, dispersions, suspensions or emulsions, and sterile powders [DACA ]- A -[ ( x M ]- X -B -[ Co -De ] Formula I for reconstitution into sterile injectable solutions or disper wherein , sions. Examples of suitable aqueous and non -aqueous car X is a cleavable linker; riers , diluents , solvents , or vehicles including water , ethanol, 10 A is a peptide with a sequence comprising 5 to 9 acidic polyols (propyleneglycol , polyethylene - glycol, glycerol, amino acids; cremophor and the like ), suitable mixtures thereof, vegetable B is a peptide with a sequence comprising 7 to 9 basic oils ( such as olive oil ) and injectable organic esters such as amino acids ; ethyl oleate . Proper fluidity is maintained , for example , by 15 CA, CB, and cm each independently comprise 0 - 1 amino the use of a coating such as lecithin , by the maintenance of M is a macromolecule ; and the required particle size in the case of dispersions, and by DA and Do are each independently selected from an the use of surfactants . Formulations suitable for subcutane imaging agent and a therapeutic ; and ous injection also contain optional additives such as pre wherein [ Cr - M ] is bound to at any position on A or X , serving, wetting, emulsifying, and dispensing agents . 20 [D4 - ca ] is bound to any amino acid on A , and [Co -DB ) is For intravenous injections , an active agent is optionally bound to any amino acid on B . formulated in aqueous solutions, preferably in physiologi In some embodiments , A and B do not have an equal cally compatible buffers such as Hank ' s solution , Ringer' s number of acidic and basic amino acids . In some embodi solution , or physiological saline buffer . ments , the number of basic amino acids in B is greater than Parenteral injections optionally involve bolus injection or 25 the number of acidic amino acids in A . In some embodi continuous infusion . Formulations for injection are option - ments , A is a peptide comprising 5 or 9 consecutive gluta ally presented in unit dosage form , e . g ., in ampoules or in mates (SEQ ID NO : 3 ) . In some embodiments , B is a peptide multi dose containers , with an added preservative . In some comprising 8 or 9 consecutive arginines ( SEQ ID NO : 4 ) . In embodiments , the pharmaceutical composition described some embodiments , A is a peptide comprising 5 or 9 herein are in a form suitable for parenteral injection as a 30 consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide sterile suspensions, solutions or emulsions in oily or aque- comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In ous vehicles, and contain formulatory agents such as sus some embodiments , A is a peptide comprising 5 consecutive pending , stabilizing and / or dispersing agents . Pharmaceuti - glutamates (SEQ ID NO : 5 ) and B is a peptide comprising cal formulations for parenteral administration include 8 consecutive arginines ( SEQ ID NO : 6 ) . In some embodi aqueous solutions of an active agent in water soluble form . 35 ments , C4 , CR , and Cy are each independently a 0 - 1 amino Additionally , suspensions are optionally prepared as appro acid . In some embodiments , CA, CB , and cm are each inde priate oily injection suspensions . pendently selected from a naturally - occurring amino acid or In some embodiments , the pharmaceutical composition a non - naturally - occurring amino acid . In some embodi described herein is in unit dosage forms suitable for single ments , CA, CR , and cy are each independently selected from administration of precise dosages . In unit dosage form , the 40 a D amino acid , a L amino acid , an a -amino acid , a ß - amino formulation is divided into unit doses containing appropriate acid , or a y - amino acid . In some embodiments , CA , CB , and quantities of an active agent disclosed herein . In some cy are each independently selected from any amino acid embodiments , the unit dosage is in the form of a package having a free thiol group , any amino acid having a N - ter containing discrete quantities of the formulation . Non - lim - minal amine group , and any amino acid with a side chain iting examples are packaged tablets or capsules , and pow - 45 capable of forming an oxime or hydrazone bond upon ders in vials or ampoules . In some embodiments , aqueous reaction with a hydroxylamine or hydrazine group . In some suspension compositions are packaged in single - dose non - embodiments , CA , CB , and cyare each independently selected reclosable containers. Alternatively , multiple - dose reclos - from D - cysteine , D - glutamate , lysine , and para - 4 - acetyl able containers are used , in which case it is typical to include L -phenylalanine . In some embodiments , CR is any amino a preservative in the composition . By way of example only , 50 acid having a free thiol group . In some embodiments , CB is formulations for parenteral injection are presented in unit D -cysteine . In some embodiments , CA is any amino acid dosage form , which include, but are not limited to ampoules , having a N - terminal amine group . In some embodiments , CA or in multi dose containers , with an added preservative . is D - glutamate . In some embodiments , CA is lysine . In some Methods of Use embodiments , cm is any amino acid with a side chain The selective delivery molecules of Formula I allow the 55 capable of forming an oxime or hydrazone bond upon targeted delivery of therapeutic agents and /or imaging reaction with a hydroxylamine or hydrazine group . In some agents to specific cells and /or tissues. The molecules com - embodiments , Cy is para - 4 - acetyl L -phenylalanine . In some prise a basic peptide sequence ( B ) which is designed to be embodiments , X is cleavable by a protease . In some embodi transported across a cellular membrane , an acidic peptide m ents , X is cleavable by a matrix metalloproteinase . In some sequence ( A ) which inhibits uptake of peptide B into cells , 60 embodiments , X comprises an amino acid sequence that is a linker X which is cleavable under specific conditions , cleavable by MMP2 , MMP7, MMP9 , or MMP14 . In some cargo moieties (at least D , and DB) bound to peptides A and embodiments , X comprises a peptide linkage . In some B , or X and a macromolecular carrier . In some embodi- embodiments , X comprises an amino acid sequence selected ments, cleavage of the linker X linker frees peptide B from from : PLGLAG (SEQ ID NO : 2 ) , PLG - C (me ) - AG (SEQ ID peptide A and allows the transport of peptide B (and any 65 NO : 1 ) , RPLALWRS ( SEO ID NO : 7 ) , ESPAYYTA (SEO cargo attached thereto ) across a cellular membrane . In some ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID embodiments , the selective delivery molecules of Formula I NO : 10 ), RLQLKL (SEQ ID NO : 11) , and RLQLK (Ac ) US 9 ,840 ,537 B2 93 94 (SEQ ID NO : 12 ) . In some embodiments , X comprises the having a free thiol group , any amino acid having a N -ter amino acid sequence PLGLAG (SEQ ID NO : 2 ). In some minal amine group , and any amino acid with a side chain embodiments , X comprises the amino acid sequence PLG - capable of forming an oxime or hydrazone bond upon C (me ) - AG (SEQ ID NO : 1) . In some embodiments , X reaction with a hydroxylamine or hydrazine group . In some comprises the amino acid sequence RPLALWRS ( SEQ ID 5 embodiments , C4, Cp , and cyare each independently selected NO : 7 ) . In some embodiments , X comprises the amino acid from D - cysteine , D - glutamate , lysine , and para - 4 -acetyl sequence DPRSFL (SEQ ID NO : 9 ) . In some embodiments, L -phenylalanine . In some embodiments , CR is any amino X comprises the amino acid sequence RLQLKL (SEQ ID acid having a free thiol group . In some embodiments , CB is NO : 11 ) . In some embodiments, X comprises the amino acid D -cysteine . In some embodiments, c , is any amino acid sequence RLQLK ( Ac ) (SEQ ID NO : 12 ) . In some embodi- 10 having a N - terminal amine group . In some embodiments , CA ments , M is selected from a protein , a natural polymer, a is D - glutamate . In some embodiments , CA is lysine. In some synthetic polymer , or a dendrimer . In some embodiments , M embodiments , cy is any amino acid with a side chain is selected from dextran , a PEG polymer , albumin , or a capable of forming an oxime or hydrazone bond upon combination thereof. In some embodiments , M is a PEG . In reaction with a hydroxylamine or hydrazine group . In some some embodiments , M is selected from PEG 5 kDa, PEG 12 15 embodiments , Cm is para - 4 -acetyl L -phenylalanine . In some kDa, PEG 20 kDa , PEG 30 kDa, and PEG40 kDa. In some embodiments , X is cleavable by a protease . In some embodi embodiments , DA and DB are a pair of acceptor and donor ments , X is cleavable by a matrix metalloproteinase . In some fluorescentmoieties that are capable of undergoing Försters / embodiments , X comprises an amino acid sequence that is fluorescence resonance energy transfer with the other. In cleavable by MMP2 , MMP7 , MMP9 , or MMP14 . In some some embodiments, DA and Do are Cy5 and Cy7. In some 20 embodiments , X comprises a peptide linkage . In some embodiments , D , and DR are Cy5 and IRDye750 . In some embodiments , X comprises an amino acid sequence selected embodiments , D and DR are Cy5 and IRDye800 . In some from : PLGLAG ( SEQ ID NO : 2 ) , PLG - C (me ) - AG (SEO ID embodiments, DA and Do are Cy5 and ICG . In some embodi NO : 1 ), RPLALWRS (SEQ ID NO : 7 ), ESPAYYTA (SEQ ments , DA and DB are a fluorescent moiety and a fluores ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID cence - quenching moiety . In some embodiments , the mol- 25 NO : 10 ), RLQLKL (SEQ ID NO : 11 ), and RLQLK ( Ac ) ecule of Formula I is : SDM - 14 , SDM - 15 , SDM - 23 , SDM - (SEQ ID NO : 12 ) . In some embodiments , X comprises the 24 , SDM - 25 , SDM - 26 , SDM -27 , SDM - 32 , or SDM - 35 . amino acid sequence PLGLAG (SEQ ID NO : 2 ) . In some Disclosed herein , in certain embodiments , are methods of embodiments , X comprises the amino acid sequence PLG delivering cargo to a tissue of interest, comprising contact - C (me ) - AG ( SEQ ID NO : 1 ) . In some embodiments , X ing the tissue of interest with a molecule of Formula I: 30 comprises the amino acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodiments , X comprises the amino acid [DA - CA ] - A -[ eMM ]- X -B - [ CB -D } ] Formula I sequence DPRSFL (SEQ ID NO : 9 ) . In some embodiments , wherein , X comprises the amino acid sequence PPRSFL (SEQ ID X is a cleavable linker; NO : 10 ) . In some embodiments , X comprises the amino acid A is a peptide with a sequence comprising 5 to 9 acidic 35 sequence RLQLKL (SEQ ID NO : 11) . In some embodi amino acids ; ments , X comprises the amino acid sequence RLQLK ( Ac ) B is a peptide with a sequence comprising 7 to 9 basic (SEQ ID NO : 12 ). amino acids; Disclosed herein , in certain embodiments , are methods of CA, CB, and cm each independently comprise 0 - 1 amino delivering cargo to a tissue of interest , comprising contact acid ; 40 ing the tissue of interest with a molecule of Formula I: M is a polyethylene glycol (PEG ) polymer; and DA and Dg are each independently selected from imaging [DA - CA ]- A -[ Cr - M ] -X -B -[ CB - DB ] Formula I agents and therapeutic agents ; and wherein , wherein [ CM - M ] is bound to at any position on A or X , X is a peptide linker cleavable by a matrix metallopro DA- CA ] is bound to any amino acid on A , and CR -DRl 45 teinase ; is bound to any amino acid on B . A is a peptide with a sequence comprising 5 or 9 con In some embodiments , A and B do not have an equal secutive glutamates (SEQ ID NO : 3 ) ; number of acidic and basic amino acids. In some embodi- B is a peptide with a sequence comprising 8 or 9 con ments , the number of basic amino acids in B is greater than secutive arginines (SEQ ID NO : 4 ) ; the number of acidic amino acids in A . In some embodi - 50 CA , CR , and Cy each independently comprise 0 - 1 amino ments , A is a peptide comprising 5 or 9 consecutive gluta acid ; mates ( SEQ ID NO : 3 ) . In some embodiments , B is a peptide M is a polyethylene glycol ( PEG ) polymer ; and comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In D , and De are independently selected from imagining some embodiments , A is a peptide comprising 5 or 9 agents and therapeutic agents ; and consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide 55 wherein [co - M ] is bound to at any position on A or X , comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In [ D -CA ] is bound to any amino acid on A , and [ CB -DB ) is some embodiments, A is a peptide comprising 5 consecutive bound to any amino acid on B . glutamates ( SEQ ID NO : 5 ) and B is a peptide comprising In some embodiments , A and B do not have an equal 8 consecutive arginines (SEQ ID NO : 6 ) . In some embodi- number of acidic and basic amino acids . In some embodi ments , CA, CB , and cy are each independently a 0 - 1 amino 60 ments , CA , CB , and cy are each independently a 0 - 1 amino acid . In some embodiments , CA , CB , and cy are each inde- acid . In some embodiments , CA , CB , and Cy are each inde pendently selected from a naturally -occurring amino acid or pendently selected from any amino acid having a free thiol a non - naturally -occurring amino acid . In some embodi- group , any amino acid having a N - terminal amine group , ments , CA , CR , and cy are each independently selected from and any amino acid with a side chain capable of forming an a D amino acid , a L amino acid , an a - amino acid , a ß - amino 65 oxime or hydrazone bond upon reaction with a hydroxylam acid , or a y -amino acid . In some embodiments , CA , CR , and ine or hydrazine group . In some embodiments, CA , CB , and Cm are each independently selected from any amino acid Cu are each independently selected from D - cysteine , D - glu US 9 , 840 ,537 B2 95 96 tamate , lysine, and para - 4 - acetyl L -phenylalanine . In some CA, CB, and cm each independently comprise 0 - 1 amino embodiments , Cris any amino acid having a free thiol group . acid ; In some embodiments , CB is D -cysteine . In some embodi M dciais a ; polyethylene glycol (PEG ) polymer, and ments , ca is any amino acid having a N - terminal amine DA and DB are independently selected from imaging group . In some embodiments , CA is D - glutamate . In some 5 agents and therapeutic agents ; and embodiments , cy is any amino acid with a side chain wherein [Cy - M ] is bound to at any position on A or X , capable of forming an oxime or hydrazone bond upon [ D , - ] is bound to any amino acid on A , and [Cz - D ] is reaction with a hydroxylamine or hydrazine group . In some bound to any amino acid on B . embodiments , Cwis para - 4 -acetyl L -phenylalanine . In some In some embodiments , CA, CR , and cw are each indepen embodiments , X comprises the amino acid sequence 10 dently a 0 - 1 amino acid . In some embodiments , CA, CR , and PLGLAG (SEQ ID NO : 2 ) . In some embodiments , X Cy are each independently selected from any amino acid comprises the amino acid sequence PLG - C (me ) - AG (SEQ having a free thiol group , any amino acid having a N - ter ID NO : 1 ) . minal amine group , and any amino acid with a side chain Disclosed herein , in certain embodiments , are methods of capable of forming an oxime or hydrazone bond upon delivering cargo to a tissue of interest, comprising contact - 15 reaction with a hydroxylamine or hydrazine group . In some ing the tissue of interest with a molecule of Formula 1 : embodiments , CA , CB , and Cy are each independently selected from D - cysteine , D - glutamate , lysine, and para - 4 - acetyl [D4 - ca ] - A -[ c _ M ]- X -B -[ CB- DB ] Formula I L -phenylalanine . In some embodiments , CR is any amino wherein , acid having a free thiol group . In some embodiments , Cris X is a peptide linker cleavable by a matrix metallopro - 20 D -cysteine . In some embodiments , CA is any amino acid teinase ; having a N - terminal amine group . In some embodiments , ca A is a peptide with a sequence comprising 5 consecutive is D -glutamate . In some embodiments , Cy is any amino acid glutamates (SEQ ID NO : 5 ); with a side chain capable of forming an oxime or hydrazone B is a peptide with a sequence comprising 8 consecutive bond upon reaction with a hydroxylamine or hydrazine arginines (SEQ ID NO : 6 ); 25 group . In some embodiments , Cyis para - 4 - acetyl L -phenyl CA , CB , and cm each independently comprise 0 - 1 amino alanine . In some embodiments , X comprises the amino acid acid ; sequence PLGLAG (SEQ ID NO : 2 ) . In some embodiments , M is a polyethylene glycol (PEG ) polymer; and X comprises the amino acid sequence PLG - C (me ) -AG (SEQ DA and De are independently selected from imaging ID NO : 1 ) . In some embodiments , X comprises the amino agents and therapeutic agents ; and 30 acid sequence RPLALWRS ( SEQ ID NO : 7 ) . wherein [ cm - M ] is bound to at any position on A or X , Tissue of Interest [DA - CA ] is bound to any amino acid on A , and [ CB- DB ] is In some embodiments , the tissue of interest is cancerous bound to any amino acid on B . tissue ( or , cancer) . In some embodiments , the cancerous In some embodiments , CA , CB , and cm are each indepen - tissue is : breast cancer tissue , colon cancer tissue, squamous dently a 0 - 1 amino acid . In some embodiments , CA , CR , and 35 cell carcinoma tissue , prostate cancer tissue , melanoma Cy are each independently selected from any amino acid tissue, or thyroid cancer tissue . In some embodiments , the having a free thiol group , any amino acid having a N - ter - cancerous tissue is breast cancer tissue . In some embodi minal amine group , and any amino acid with a side chain ments , the cancerous tissue is colon cancer tissue . capable of forming an oxime or hydrazone bond upon In some embodiments , the cancer is AIDS- related cancers reaction with a hydroxylamine or hydrazine group . In some 40 ( e . g . , AIDS -related lymphoma ), anal cancer , basal cell car embodiments , CA , CB , and cy are each independently selected cinoma, bile duct cancer ( e . g . , extrahepatic ), bladder cancer, from D -cysteine , D - glutamate , lysine , and para - 4 - acetyl bone cancer , (osteosarcoma and malignant fibrous histiocy L - phenylalanine . In some embodiments , ce is any amino toma) , breast cancer , cervical cancer, colon cancer, colorec acid having a free thiol group . In some embodiments , Cg is tal cancer , endometrial cancer ( e . g . , uterine cancer) , D - cysteine . In some embodiments , CA is any amino acid 45 ependymoma, esophageal cancer, eye cancer ( e . g . , intraocu having a N -terminal amine group . In some embodiments , cA lar melanoma and retinoblastoma ), gastric (stomach ) cancer, is D - glutamate . In some embodiments , wis any amino acid germ cell tumor, ( e . g . , extracranial, extragonadal, ovarian ) , with a side chain capable of forming an oxime or hydrazone head and neck cancer, leukemia , lip and oral cavity cancer, bond upon reaction with a hydroxylamine or hydrazine liver cancer, lung cancer ( e . g ., small cell lung cancer, group . In some embodiments , Cyis para - 4 -acetyl L -phenyl - 50 non - small cell lung cancer, adenocarcinoma of the lung , and alanine. In some embodiments , X comprises the amino acid squamous carcinoma of the lung ), ovarian cancer , pancreatic sequence PLGLAG (SEQ ID NO : 2 ) . In some embodiments , cancer, pituitary tumor , prostate cancer , renal cancer, skin X comprises the amino acid sequence PLG - C (me ) -AG ( SEQ cancer , small intestine cancer, squamous cell cancer, testicu ID NO : 1 ). In some embodiments , X comprises the amino lar cancer, throat cancer , thyroid cancer, urethral cancer, and acid sequence RPLALWRS (SEQ ID NO : 7 ) . 55 post- transplant lymphoproliferative disorder (PTLD ) . Disclosed herein , in certain embodiments , are methods of In some embodiments , the cancer is a lymphoid cancer delivering cargo to a tissue of interest , comprising contact - ( e . g . , lymphoma) . ing the tissue of interest with a molecule of Formula I: In some embodiments , the cancer is a B - cell cancer . In some embodiments , the cancer is precursor B -cell cancers [DA - CA ] - A -[ CM - M ]- X - B - [ Co - D ] Formula I 60 ( e . g ., precursor B - lymphoblastic leukemia / lymphoma) and wherein , peripheral B - cell cancers ( e . g ., B - cell chronic lymphocytic X is a peptide linker cleavable by a matrix metallopro - leukemia /prolymphocytic leukemia / small lymphocytic lym teinase ; phoma ( small lymphocytic (SL ) NHL ) , lymphoplasmacy A is a peptide with a sequence comprising 9 consecutive toid lymphoma/ immunocytoma, mantel cell lymphoma, fol glutamates (SEQ ID NO : 13 ) ; 65 licle center lymphoma, follicular lymphoma ( e . g . , cytologic B is a peptide with a sequence comprising 9 consecutive grades: I ( small cell ) , II (mixed small and large cell ), III arginines (SEQ ID NO : 14 ) ; (large cell ) and / or subtype: diffuse and predominantly small US 9 , 840 ,537 B2 97 98 cell type ), low grade/ follicular non -Hodgkin ' s lymphoma the prostate cancer is metastatic prostate cancer. In some (NHL ) , intermediate grade/ follicular NHL , marginal zone embodiments , the individual is a human who has a gene , B - cell lymphoma ( e . g ., extranodal ( e . g . , MALT- type + / genetic mutation , or polymorphism associated with prostate monocytoid B cells ) and / or Nodal ( e . g . , + / - monocytoid B cancer ( e . g . , RNASEL /HPC1 , ELAC2/ HPC2 , SR - A /MSR1 , cells )) , splenic marginal zone lymphoma (e . g. , + / - villous 5 CHEK2, BRCA2, PON1, OGG1, MIC - 1, TLR4 , and PTEN ) lymphocytes ) , Hairy cell leukemia , plasmacytoma /plasma or has one or more extra copies of a gene associated with cell myeloma ( e . g ., myeloma and multiple myeloma ), dif - prostate cancer . In some embodiments , the prostate cancer is fuse large B - cell lymphoma ( e . g ., primary mediastinal ( thy - HER2 positive . In some embodiments , the prostate cancer is mic ) B -cell lymphoma) , intermediate grade diffuse NHL , HER2 negative. Burkitt ' s lymphoma , High - grade B - cell lymphoma, Burkitt - 10 In some embodiments , the cancer has metastasized and is like, high grade immunoblastic NHL , high grade lympho characterized by circulating tumor cells . blastic NHL , high grade small non -cleaved cellNHL , bulky Imaging Uses disease NHL , AIDS -related lymphoma, and Waldenstrom ’s The selective delivery molecules of Formula 1 allow the macroglobulinemia ). targeted delivery of imaging agents to specific cells and /or In some embodiments , the cancer is a T -cell and /or 15 tissues ( e . g . , cancerous tissues ) . The molecules comprise a putative NK -cell cancer. In some embodiments, the cancer is basic peptide sequence ( B ) which is designed to be trans precursor T - cell cancer (precursor T - lymphoblastic lym - ported across a cellular membrane or retained by tissue , an phoma/ leukemia ) and peripheral T - cell and NK - cell cancers acidic peptide sequence ( A ) which inhibits uptake and ( e . g ., T - cell chronic lymphocytic leukemia / prolymphocytic retention of peptide B into cells , a linker X which is leukemia , and large granular lymphocyte leukemia (LGL ) 20 cleavable under specific conditions, imaging moieties bound ( e . g . , T -cell type and / or NK -cell type ), cutaneous T - cell to peptides A and B , or X and a macromolecular carrier. In lymphoma ( e . g . , mycosis fungoides / Sezary syndrome) , pri some embodiments , cleavage of the linker X linker frees mary T -cell lymphomas unspecified ( e. g ., cytological cat peptide B from peptide A and allows the transport of peptide egories ( e . g . , medium - sized cell, mixed medium and large B ( and any imaging moieties attached thereto ) across a cell ), large cell , lymphoepitheloid cell , subtype hepatos - 25 cellular membrane or retention of B to tissue . In some plenic yd T - cell lymphoma, and subcutaneous panniculitic embodiments , the selective delivery molecules of Formula I T - cell lymphoma ) , angioimmunoblastic T -cell lymphoma enable targeted delivery of one or more imaging agents to a ( AILD ) , angiocentric lymphoma, intestinal T - cell lymphoma cell or tissue . In some embodiments , targeted delivery of an ( e . g . , + / - enteropathy associated ) , adult T - cell lymphoma imaging agent to a cell or tissue enables a medical profes leukemia (ATL ) , anaplastic large cell lymphoma (ALCL ) 30 sional to visualize / image a specific tissue . ( e . g . , CD30 + , T - and null - cell types ) , anaplastic large - cell Disclosed herein , in certain embodiments , are methods of lymphoma , and Hodgkin ' s like ). delivering imaging agents to a tissue of interest , comprising In some embodiments , the cancer is Hodgkin ' s disease. contacting the tissue of interest with a molecule of Formula In some embodiments , the cancer is leukemia . In some I: embodiments , the cancer is chronic myelocytic I ( granulo - 35 cytic ) leukemia , chronic myelogenous, and chronic lympho [DA - CA ] - A - [CxM ] -X - B - [ CB -DB ] Formula I cytic leukemia ( CLL ) , acute lymphoblastic leukemia ( ALL ), wherein , acute myeloid leukemia , acute lymphocytic leukemia , and X is a cleavable linker ; acute myelocytic leukemia (e . g. , myeloblastic , promyelo - A is a peptide with a sequence comprising 5 to 9 acidic cytic , myelomonocytic , monocytic , and erythroleukemia ) . 40 amino acids ; In some embodiments , the cancer is a liquid tumor or B is a peptide with a sequence comprising 7 to 9 basic plasmacytoma . In some embodiments , the cancer is amino acids ; extramedullary plasmacytoma , a solitary myeloma, and CA , Cb , and cm each independently comprise 0 - 1 amino multiple myeloma. In some embodiments , the plasmacy acid ; toma is multiple myeloma . 45 M is a polyethylene glycol ( PEG ) polymer; and In some embodiments , the cancer is lung cancer . DA and Do are each independently an imaging agent; and In some embodiments , the cancer is prostate cancer . In wherein [ cv - M ] is bound to at any position on A or X , some embodiments , the prostate cancer is an adenocarci [ DA- CA ] is bound to any amino acid on A , and [ Co - D ] noma . In some embodiments, the prostate cancer is a sar is bound to any amino acid on B . coma , neuroendocrine tumor, small cell cancer , ductal can - 50 In some embodiments , A and B do not have an equal cer, or a lymphoma . In some embodiments , the prostate number of acidic and basic amino acids . In some embodi cancer is stage A prostate cancer ( the cancer cannot be feltm ents , the number of basic amino acids in B is greater than during a rectal exam ) . In some embodiments , the prostate the number of acidic amino acids in A . In some embodi cancer is stage B prostate cancer ( i. e ., the tumor involves ments , A is a peptide comprising 5 or 9 consecutive gluta more tissue within the prostate , it can be felt during a rectal 55 mates (SEQ ID NO : 3 ) . In some embodiments , B is a peptide exam , or it is found with a biopsy that is done because of a comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In high PSA level) . In some embodiments , the prostate cancer some embodiments , A is a peptide comprising 5 or 9 is stage C prostate cancer ( i . e . , the cancer has spread outside consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide the prostate to nearby tissues ) . In some embodiments , the comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In prostate cancer is stage D prostate cancer . In some embodi- 60 some embodiments , Ais a peptide comprising 5 consecutive ments, the prostate cancer is androgen independent prostate glutamates (SEQ ID NO : 5 ) and B is a peptide comprising cancer (AIPC ) . In some embodiments , the prostate cancer is 8 consecutive arginines ( SEQ ID NO : 6 ) . In some embodi androgen dependent prostate cancer. In some embodiments , ments , CA , CB , and cy are each independently a 0 - 1 amino the prostate cancer is refractory to hormone therapy . In some acid . In some embodiments , CA, CR , and Cy are each inde embodiments , the prostate cancer is substantially refractory 65 pendently selected from a naturally -occurring amino acid or to hormone therapy . In some embodiments , the prostate a non - naturally - occurring amino acid . In some embodi cancer is refractory to chemotherapy . In some embodiments , ments , CA, CB , and cm are each independently selected from US 9 ,840 ,537 B2 99 100 a D amino acid , a L amino acid , an a -amino acid , a ß - amino wherein [cy - M ] is bound to at any position on A or X , acid , or a y -amino acid . In some embodiments , CA, CR , and [DA - CA ] is bound to any amino acid on A , and [CR -D2 ] is Cm are each independently selected from any amino acid bound to any amino acid on B . having a free thiol group , any amino acid having a N - ter - In some embodiments , A and B do not have an equal minal amine group , and any amino acid with a side chain 5 number of acidic and basic amino acids . In some embodi capable of forming an oxime or hydrazone bond upon ments , CA , CB , and cm are each independently a 0 - 1 amino reaction with a hydroxylamine or hydrazine group . In some acid . In some embodiments , CA, CB , and cm are each inde pendently selected from any amino acid having a free thiol embodiments , CA, Cb , and cm are each independently selected group , any amino acid having a N - terminal amine group , from D -cysteine , D - glutamate , lysine , and para - 4 - acetyl 10 and any amino acid with a side chain capable of forming an L -phenylalanine . In some embodiments , CB is any amino oxime or hydrazone bond upon reaction with a hydroxylam acid having a free thiol group . In some embodiments , Cg is ine or hydrazine group . In some embodiments , CA , CB , and D - cysteine. In some embodiments , CA is any amino acid Cuare each independently selected from D - cysteine , D - glu having a N -terminal amine group . In some embodiments , CA tamate , lysine , and para - 4 - acetyl L - phenylalanine . In some is D - glutamate . In some embodiments , CA is lysine. Inin some 15 embodiments , CB is any amino acid having a free thiol group . embodiments , cm is any amino acid with a side chain In some embodiments , CB is D - cysteine . In some embodi capable of forming an oximexime oror hydrazone bond upon ments, CA is any amino acid having a N -terminal amine reaction with a hydroxylamine or hydrazine group . In some group . In some embodiments , cx is D - glutamate . In some embodiments , cy is para - 4 -acetyl L -phenylalanine . In some embodiments , cv is any amino acid with a side chain embodiments , X is cleavable by a protease . In some embodi- 20 capable of forming an oxime or hydrazone bond upon ments, X is cleavable by a matrix metalloproteinase . In some reaction with a hydroxylamine or hydrazine group . In some embodiments , X comprises an amino acid sequence that is embodiments , Cy is para - 4 - acetyl L -phenylalanine . In some cleavable by MMP2 , MMP7 , MMP9 , or MMP14 . In some embodiments , X comprises the amino acid sequence embodiments , X comprises a peptide linkage . In some RPLALWRS (SEQ ID NO : 7 ) . In some embodiments , X embodiments , X comprises an amino acid sequence selected 25 comprises the amino acid sequence DPRSFL ( SEQ ID NO : from : PLGLAG (SEO ID NO : 2 ) , PLG - C (me ) - AG ( SEO ID 9 ) . In some embodiments , X comprises the amino acid NO : 1 ), RPLALWRS ( SEO ID NO : 7 ) , ESPAYYTA (SEO sequence PPRSFL ( SEQ ID NO : 10 ) . In some embodiments , X comprises the amino acid sequence RLQLKL (SEQ ID ID NO : 8 ), DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID NO : 11 ) . In some embodiments, X comprises the amino acid NO : 10 ), RLQLKL (SEQ ID NO : 11) , and RLQLK ( Acthe ) 30 sequence RLQLK (Ac ) (SEQ ID NO : 12 ). In some embodi ( SEQ ID NO : 12 ). In some embodiments , X comprises the ments , D , and DR are a pair of acceptor and donor fluores amino acid sequence PLGLAG (SEQ ID NO : 2 ). In some cent moieties that are capable of undergoing Försters/ fluo embodiments , X comprises the amino acid sequence PLG rescence resonance energy transfer with the other. In some C (me ) - AG (SEQ ID NO : 1 ) . In some embodiments , X embodiments , D? and DR are Cy5 and Cy7 . In some embodi comprises the amino acid sequence RPLALWRS (SEQ ID 35 ments , DA and Do are Cy5 and IRDye750 . In some embodi NO : 7 ) . In some embodiments , X comprises the amino acid ments, DA and DR are Cy5 and IRDye800 . In some embodi sequence DPRSFL (SEQ ID NO : 9 ). In some embodiments , ments , D , and D , are Cy5 and ICG . In some embodiments , X comprises the amino acid sequence PPRSFL (SEQ ID D , and DR are a fluorescent moiety and a fluorescence NO : 10 ). In some embodiments , X comprises the amino acid quenching moiety . sequence RLQLKL ( SEQ ID NO : 11) . In some embodi- 4010 Disclosed herein , in certain embodiments , are methods of ments, X comprises the amino acid sequence RLQLK ( Ac ) delivering imaging agents to a tissue of interest , comprising (SEQ ID NO : 12 ) . In some embodiments , DA and Do are a pair of acceptor and donor fluorescent moieties that are icontacting. the tissue of interest with a molecule of Formula capable of undergoing Försters/ fluorescence resonance energy transfer with the other. In some embodiments, D? and 45 [DA - CA ]- A - [Cr - M ]- X - B - [CB -DB ] Formula I DB are Cy5 and Cy7 . In some embodiments , DA and Do are wherein , Cy5 and IRDye750 . In some embodiments, D? and DB are X is a peptide linker cleavable by a matrix metallopro Cy5 and IRDye800 . In some embodiments , DA and Do are teinase ; Cy5 and ICG . In some embodiments, D , and Do are a A is a peptide with a sequence comprising 5 consecutive fluorescent moiety and a fluorescence - quenching moiety . O glutamates (SEQ ID NO : 5 ) ; Disclosed herein , in certain embodiments , are methods of B is a peptide with a sequence comprising 8 consecutive delivering imaging agents to a tissue of interest, comprising arginines (SEQ ID NO : 6 ) ; contacting the tissue of interest with a molecule of Formula CA , CB , and Cy each independently comprise 0 - 1 amino acid ; 55 M is a polyethylene glycol (PEG ) polymer; and [DA - CA ] - A -[ CxM ]- X - B- [ CB -D } ] Formula I DA and DB are each independently an imaging agent; and wherein , wherein [ Cy - M ] is bound to at any position on A or X , X is a peptide linker cleavable by a matrix metallopro - [DA - CA ] is bound to any amino acid on A , and [CB -DB ) is teinase ; bound to any amino acid on B . A is a peptide with a sequence comprising 5 or 9 con - 60 In some embodiments , CA, CR , and cw are each indepen secutive glutamates (SEQ ID NO : 3 ) ; dently a 0 - 1 amino acid . In some embodiments , CA, CB , and B is a peptide with a sequence comprising 8 or 9 con - cm are each independently selected from any amino acid secutive arginines (SEQ ID NO : 4 ) ; having a free thiol group , any amino acid having a N - ter CA , CB , and cm each independently comprise 0 - 1 amino minal amine group , and any amino acid with a side chain acid ; 65 capable of forming an oxime or hydrazone bond upon M is a polyethylene glycol (PEG ) polymer; and reaction with a hydroxylamine or hydrazine group . In some DA and DB are each independently an imaging agent; and embodiments , CA, CB , and Cy are each independently selected US 9 , 840 , 537 B2 101 102 from D -cysteine , D -glutamate , lysine , and para - 4 -acetyl acid sequence PPRSFL (SEQ ID NO : 10 ) . In some embodi L -phenylalanine . In some embodiments , CB is any amino ments , X comprises the amino acid sequence RLQLKL acid having a free thiol group . In some embodiments , Cp is (SEQ ID NO : 11 ) . In some embodiments , X comprises the D - cysteine . In some embodiments , ca is any amino acid amino acid sequence RLQLK ( Ac) (SEQ ID NO : 12 ) . In having a N -terminal amine group . In some embodiments , ca 5 some embodiments , D , and DR are a pair of acceptor and is D - glutamate . In some embodiments , Cwis any amino acid donor fluorescent moieties that are capable of undergoing with a side chain capable of forming an oxime or hydrazone Försters / fluorescence resonance energy transfer with the bond upon reaction with a hydroxylamine or hydrazine other. In some embodiments , D , and DR are Cy5 and Cy7 . group . In some embodiments, cv is para - 4 - acetyl L - phenyl- In some embodiments, D , and D . are Cy5 and IRDye750 . alanine . In some embodiments , X comprises the amino acid 10 In some embodiments , D , and DR are Cy5 and IRDye800 . sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodi- In some embodiments , D , and D are Cy5 and ICG . In some ments, X comprises the amino acid sequence DPRSFL (SEQ embodiments , DA and Do are a fluorescent moiety and a ID NO : 9 ) . In some embodiments , X comprises the amino fluorescence - quenching moiety . acid sequence PPRSFL (SEQ ID NO : 10 ) . In some embodi Disclosed herein , in certain embodiments , are methods of ments , X comprises the amino acid sequence RLQLKL 15 delivering a pair of acceptor and donor fluorescentmoieties (SEQ ID NO : 11 ) . In some embodiments , X comprises the that are capable of undergoing Försters / fluorescence reso amino acid sequence RLQLK (Ac ) (SEQ ID NO : 12 ) . In nance energy transfer with the other to a tissue of interest, some embodiments , D , and De are a pair of acceptor and comprising contacting the tissue of interest with a molecule donor fluorescent moieties that are capable of undergoing Försters/ fluorescence resonance energy transfer with the 20 other. In some embodiments , D , and D , are Cy5 and Cy7 . [ DA- CA ]- A - [CoM ] - X - B - [ CB -DB ] Formula I In some embodiments , D , and DR are Cy5 and IRDye750 . wherein , In some embodiments , DA and Do are Cy5 and IRDye800 . X is a cleavable linker , In some embodiments , D? and Do are Cy5 and ICG . In some A is a peptide with a sequence comprising 5 to 9 acidic embodiments , DA and DB are a fluorescent moiety and a 25 amino acids ; fluorescence - quenching moiety . B is a peptide with a sequence comprising 7 to 9 basic Disclosed herein , in certain embodiments , are methods of amino acids ; delivering imaging agents to a tissue of interest, comprising CA, CB, and cm each independently comprise 0 - 1 amino contacting the tissue of interest with a molecule of Formula acid ; 30 M is a polyethylene glycol (PEG ) polymer , and DA and DB are a pair of acceptor and donor fluorescent [DA - CA ] -A - [CoM ]- X - B - [CB - Db ] Formula I moieties that are capable of undergoing Försters/ fluo wherein , rescence resonance energy transfer with the other ; and X is a peptide linker cleavable by a matrix metallopro wherein [Cr - M ] is bound to at any position on A or X , teinase ; [DA - CA ] is bound to any amino acid on A , and [CB - DB ] A is a peptide with a sequence comprising 9 consecutive is bound to any amino acid on B . glutamates (SEQ ID NO : 13 ) ; In some embodiments , A and B do not have an equal B is a peptide with a sequence comprising 9 consecutive number of acidic and basic amino acids . In some embodi arginines (SEQ ID NO : 14 ) ; ments , the number of basic amino acids in B is greater than CA , CB , and cm each independently comprise 0 - 1 amino 40 the number of acidic amino acids in A . In some embodi acid ; ments , A is a peptide comprising 5 or 9 consecutive gluta M is a polyethylene glycol (PEG ) polymer, and mates ( SEQ ID NO : 3 ) . In some embodiments , B is a peptide DA and D , are each independently an imaging agent; and comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In wherein [ CM - M ] is bound to at any position on A or X , some embodiments , A is a peptide comprising 5 or 9 [DA -CA ] is bound to any amino acid on A , and [ CR -DB ] is 45 consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide bound to any amino acid on B . comprising 8 or 9 consecutive arginines ( SEQ ID NO : 4 ). In In some embodiments, CA , CR , and cy are each indepen - some embodiments, A is a peptide comprising 5 consecutive dently a 0 - 1 amino acid . In some embodiments, CA , CB , and 8glutamates (SEQ ID NO : 5 ) and B is a peptide comprising Cy are each independently selected from any amino acid 8 consecutive arginines ( SEQ ID NO : 6 ) . In some embodi having a free thiol group , any amino acid having a N -ter - 50 ments , CA , CB , and cm are each independently a 0 - 1 amino minal amine group , and any amino acid with a side chain acid . In some embodiments , CA, CB , and Cy are each inde capable of forming an oxime or hydrazone bond upon pendently selected from a naturally -occurring amino acid or reaction with a hydroxylamine or hydrazine group . In some a non - naturally -occurring amino acid . In some embodi embodiments , CA , CB , and cw are each independently selected ments , CA , CB , and cy are each independently selected from from D - cysteine , D - glutamate , lysine , and para - 4 -acetyl 55 a D amino acid , a L amino acid , an a - amino acid , a ß - amino L - phenylalanine . In some embodiments , ce is any amino acid , or a y - amino acid . In some embodiments, CA , CB , and acid having a free thiol group . In some embodiments , Cg is Cy are each independently selected from any amino acid D - cysteine. In some embodiments , cx is any amino acid having a free thiol group , any amino acid having a N -ter having a N -terminal amine group . In some embodiments , CA minal amine group , and any amino acid with a side chain is D - glutamate . In some embodiments , Cyis any amino acid 60 capable of forming an oxime or hydrazone bond upon with a side chain capable of forming an oxime or hydrazone reaction with a hydroxylamine or hydrazine group . In some bond upon reaction with a hydroxylamine or hydrazine embodiments , CA, CB , and cyare each independently selected group . In some embodiments, Cm is para - 4 -acetyl L -phenyl from D -cysteine , D - glutamate , lysine , and para -4 - acetyl alanine . In some embodiments , X comprises the amino acid L -phenylalanine . In some embodiments , Cg is any amino sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodi - 65 acid having a free thiol group . In some embodiments , Co is ments , X comprises the amino acid sequence DPRSFL ( SEQ D - cysteine . In some embodiments , cx is any amino acid ID NO : 9 ) . In some embodiments , X comprises the amino having a N - terminal amine group . In some embodiments, CA US 9 ,840 ,537 B2 103 104 is D - glutamate . In some embodiments , c , is lysine . In some ine or hydrazine group . In some embodiments, CA, CB , and embodiments , cy is any amino acid with a side chain Cy are each independently selected from D - cysteine , D - glu capable of forming an oxime or hydrazone bond upon tamate , lysine , and para- 4 -acetyl L -phenylalanine . In some reaction with a hydroxylamine or hydrazine group . In some embodiments , CB is any amino acid having a free thiol group . embodiments , Cwis para - 4 - acetyl L - phenylalanine . In some 5 In some embodiments , Ce is D - cysteine . In some embodi embodiments , X is cleavable by a protease . In some embodiments , ca is any amino acid having a N - terminal amine ments, X is cleavable by a matrix metalloproteinase . In some group . In some embodiments , C , is D - glutamate . In some embodiments , X comprises an amino acid sequence that is embodiments , cv is any amino acid with a side chain cleavable by MMP2, MMP7 , MMP9, or MMP14 . In some capable of forming an oxime or hydrazone bond upon embodiments , X comprises a peptide linkage . In some 10 reaction with a hydroxylamine or hydrazine group . In some embodiments , X comprises an amino acid sequence selected embodiments, Cm is para - 4 -acetyl L -phenylalanine . In some from : PLGLAG (SEQ ID NO : 2 ), PLG -C (me ) - AG ( SEQ ID embodiments , X comprises the amino acid sequence NO : 1 ) , RPLALWRS ( SEQ ID NO : 7 ) , ESPAYYTA (SEQ RPLALWRS (SEQ ID NO : 7) . In some embodiments , X ID NO : 8 ) , DPRSFL (SEQ ID NO : 9 ) , PPRSFL (SEQ ID comprises the amino acid sequence DPRSFL (SEQ ID NO : NO : 10 ) , RLQLKL (SEQ ID NO : 11 ) , and RLQLK (Ac ) 15 9 ) . In some embodiments , X comprises the amino acid (SEQ ID NO : 12 ) . In some embodiments , X comprises the sequence PPRSFL (SEQ ID NO : 10 ) . In some embodiments , amino acid sequence PLGLAG ( SEQ ID NO : 2 ) . In some X comprises the amino acid sequence RLQLKL (SEQ ID embodiments , X comprises the amino acid sequence PLG NO : 11) . In some embodiments , X comprises the amino acid C (me ) - AG (SEQ ID NO : 1 ) . In some embodiments , Xcom sequence RLQLK ( Ac ) (SEQ ID NO : 12 ) . In some embodi prises the amino acid sequence RPLALWRS (SEQ ID NO : 20 ments , DA and Dg are Cy5 and Cy7 . In some embodiments , 7 ) . In some embodiments , X comprises the amino acid D , and D , are Cy5 and Cy7 . sequence DPRSFL (SEQ ID NO : 9 ). In some embodiments , Disclosed herein , in certain embodiments , are methods of X comprises the amino acid sequence PPRSFL (SEQ ID delivering a pair of acceptor and donor fluorescentmoieties NO : 10 ) . In some embodiments , X comprises the amino acid that are capable of undergoing Försters / fluorescence reso sequence RLQLKL ( SEQ ID NO : 11 ) . In some embodi- 25 nance energy transfer with the other to a tissue of interest , ments , X comprises the amino acid sequence RLQLK (Ac ) comprising contacting the tissue of interest with a molecule ( SEQ ID NO : 12 ). In some embodiments , D , and De are a of Formula I : pair of acceptor and donor fluorescent moieties that are capable of undergoing Försters/ fluorescence resonance [DA - CA ] - A - [CM ]- X - B- [ CB -DB ] Formula I energy transfer with the other. In some embodiments , D4 and 30 wherein , Do are Cy5 and Cy7 . In some embodiments , D? and Do are X is a peptide linker cleavable by a matrix metallopro Cy5 and IRDye750 . In some embodiments , D , and D , are teinase ; Cy5 and IRDye800 . In some embodiments , D , and D , are A is a peptide with a sequence comprising 5 consecutive Cy5 and ICG . In some embodiments , DA and Do are a glutamates (SEQ ID NO : 5 ) ; fluorescent moiety and a fluorescence - quenching moiety . 35 B is a peptide with a sequence comprising 8 consecutive Disclosed herein , in certain embodiments , are methods of arginines (SEQ ID NO : 6 ) ; delivering a pair of acceptor and donor fluorescentmoieties CA , CB , and cu each independently comprise 0 - 1 amino that are capable of undergoing Försters/ fluorescence reso acid ; nance energy transfer with the other to a tissue of interest, M is a polyethylene glycol (PEG ) polymer ; and comprising contacting the tissue of interest with a molecule 40 D , and D , are a pair of acceptor and donor fluorescent of Formula 1: moieties that are capable of undergoing Försters / fluo rescence resonance energy transfer with the other ; and [DA - c4 ] - A -[ CxM ]- X - B- [Cp - De ] Formula I wherein [Cy - M ] is bound to at any position on A or X , wherein , [DA - CA ] is bound to any amino acid on A , and [ Co - DB ] is X is a peptide linker cleavable by a matrix metallopro - 45 bound to any amino acid on B . teinase ; In some embodiments , CA, CB , and cm are each indepen A is a peptide with a sequence comprising 5 or 9 con - dently a 0 - 1 amino acid . In some embodiments, CA , CR , and secutive glutamates (SEQ ID NO : 3 ) ; Cm are each independently selected from any amino acid B is a peptide with a sequence comprising 8 or 9 con - having a free thiol group , any amino acid having a N - ter secutive arginines (SEQ ID NO : 4 ) ; 50 minal amine group , and any amino acid with a side chain CA, CB , and cm each independently comprise 0 - 1 amino capable of forming an oxime or hydrazone bond upon acid ; reaction with a hydroxylamine or hydrazine group . In some M is a polyethylene glycol (PEG ) polymer ; and embodiments , C4, CB , and cw are each independently selected DA and Do are a pair of acceptor and donor fluorescent from D - cysteine , D - glutamate, lysine, and para- 4 -acetyl moieties that are capable of undergoing Försters/ fluo - 55 L -phenylalanine . In some embodiments , Cg is any amino rescence resonance energy transfer with the other ; and acid having a free thiol group . In some embodiments , Cris wherein [Cy - M ] is bound to at any position on A or X , D -cysteine . In some embodiments , CA is any amino acid [ D , - C ) is bound to any amino acid on A , and [ CR -DR ] is having a N - terminal amine group . In some embodiments , ca bound to any amino acid on B . is D - glutamate . In some embodiments , Cy is any amino acid In some embodiments , A and B do not have an equal 60 with a side chain capable of forming an oxime or hydrazone number of acidic and basic amino acids . In some embodi - bond upon reaction with a hydroxylamine or hydrazine ments, CA , CR , and cy are each independently a 0 - 1 amino group . In some embodiments, Cy is para - 4 - acetyl L -phenyl acid . In some embodiments , CA , CR , and cv are each inde alanine . In some embodiments , X comprises the amino acid pendently selected from any amino acid having a free thiol sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodi group , any amino acid having a N - terminal amine group , 65 ments , X comprises the amino acid sequence DPRSFL (SEQ and any amino acid with a side chain capable of forming an ID NO : 9 ) . In some embodiments , X comprises the amino oxime or hydrazone bond upon reaction with a hydroxylam acid sequence PPRSFL (SEQ ID NO : 10 ) . In some embodi US 9 ,840 ,537 B2 105 106 ments , X comprises the amino acid sequence RLQLKL that are capable of undergoing Försters/ fluorescence reso (SEQ ID NO : 11 ) . In some embodiments , X comprises the nance energy transfer with the other to a tissue of interest, amino acid sequence RLQLK (Ac ) (SEQ ID NO : 12 ) . In comprising contacting the tissue of interest with SDM - 15 . some embodiments , DA and DB are Cy5 and Cy7 . In some Disclosed herein , in certain embodiments , are methods of embodiments , D , and DR are Cy5 and IRDye750 . In some 5 delivering a pair of acceptor and donor fluorescentmoieties embodiments , D , and DR are Cy5 and IRDye800 . In some that are capable of undergoing Försters / fluorescence reso embodiments , D , and DR are Cy5 and ICG . nance energy transfer with the other to a tissue of interest , Disclosed herein , in certain embodiments , are methods of comprising contacting the tissue of interest with SDM -23 . delivering a pair of acceptor and donor fluorescent moieties Disclosed herein , in certain embodiments , are methods of that are capable of undergoing Försters/ fluorescence reso - 10 delivering a pair of acceptor and donor fluorescentmoieties nance energy transfer with the other to a tissue of interest, that are capable of undergoing Försters / fluorescence reso comprising contacting the tissue of interest with a molecule nance energy transfer with the other to a tissue of interest , of Formula 1: comprising contacting the tissue of interest with SDM - 24 . Disclosed herein , in certain embodiments, are methods of [DA - cal - A - [CxM ] - X - B - [ CB- DB] Formulahula I! 15 delivering a pair of acceptor and donor fluorescent moieties wherein , that are capable of undergoing Försters/ fluorescence reso X is a peptide linker cleavable by a matrix metallopro nance energy transfer with the other to a tissue of interest , teinase ; comprising contacting the tissue of interest with SDM - 25 . A is a peptide with a sequence comprising 9 consecutive Disclosed herein , in certain embodiments , are methods of glutamates (SEQ ID NO : 13) ; 20 delivering a pair of acceptor and donor fluorescentmoieties B is a peptide with a sequence comprising 9 consecutive that are capable of undergoing Försters / fluorescence reso arginines (SEQ ID NO : 14 ); nance energy transfer with the other to a tissue of interest , CA, CB, and cm each independently comprise 0 - 1 amino comprising contacting the tissue of interest with SDM - 26 . acid ; Disclosed herein , in certain embodiments, are methods of M is a polyethylene glycol (PEG ) polymer; and 25 delivering a pair of acceptor and donor fluorescent moieties D , and D , are a pair of acceptor and donor fluorescent that are capable of undergoing Försters / fluorescence reso moieties that are capable of undergoing Försters / fluo - nance energy transfer with the other o to a tissue of interest , rescence resonance energy transfer with the other , and comprising contacting the tissue of interest with SDM - 27 . wherein [ Cy - M ] is bound to at any position on A or X , Disclosed herein , in certain embodiments, are methods of [DA -CA ] is bound to any amino acid on A , and [ CR -DB ) is 30 delivering a pair of acceptor and donor fluorescent moieties bound to any amino acid on B . that are capable of undergoing Försters / fluorescence reso In some embodiments, CA , CR , and Cy are each indepen - nance energy transfer with the other to a tissue of interest , dently selected from any amino acid having a free thiol comprising contacting the tissue of interest with SDM - 32 . group , any amino acid having a N - terminal amine group , Disclosed herein , in certain embodiments , are methods of and any amino acid with a side chain capable of forming an 35 delivering a pair of acceptor and donor fluorescentmoieties oxime or hydrazone bond upon reaction with a hydroxylam - that are capable of undergoing Försters/ fluorescence reso ine or hydrazine group . In some embodiments , CA , CR , and nance energy transfer with the other to a tissue of interest, CM are each independently a 0 - 1 amino acid . In some comprising contacting the tissue of interest with SDM - 35 . embodiments , CA , CR , and cy are each independently selected Disclosed herein , in certain embodiments , are methods of from D - cysteine , D - glutamate , lysine , and para - 4 -acetyl 40 visualizing a tissue of interest in an individual in need L - phenylalanine . In some embodiments , Cg is any amino thereof , comprising : acid having a free thiol group . In some embodiments , CB is (a ) administering to the individual a molecule of Formula I D - cysteine . In some embodiments , cx is any amino acid that localizes to the tissue of interest in the individual, having a N - terminal amine group . In some embodiments , ca is D - glutamate . In some embodiments , Cm is any amino acid 45 [DA - CA ] - A - [CxM ]- X - B - [Co - Dp ]; Formula I with a side chain capable of forming an oxime or hydrazone w herein , bond upon reaction with a hydroxylamine or hydrazine X is a cleavable linker; group . In some embodiments , Cy is para - 4 -acetyl L - phenyl- A is a peptide with a sequence comprising 5 to 9 acidic alanine . In some embodiments , X comprises the amino acid amino acids; sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodi- 50 B is a peptide with a sequence comprising 7 to 9 basic ments , X comprises the amino acid sequence DPRSFL (SEQ amino acids; ID NO : 9 ) . In some embodiments, X comprises the amino CA, CB , and cm each independently comprise 0 - 1 amino acid sequence PPRSFL (SEQ ID NO : 10 ) . In some embodi acid ; ments, X comprises the amino acid sequence RLQLKL M is a polyethylene glycol (PEG ) polymer; and (SEQ ID NO : 11 ) . In some embodiments , X comprises the 55 DA and Do are each independently an imaging agent; and amino acid sequence RLQLK ( Ac ) (SEQ ID NO : 12 ) . In wherein [Cx - M ] is bound to at any position on A or X , some embodiments , D , and D , are Cy5 and Cy7 . In some [DA - CA ] is bound to any amino acid on A , and [ CB- DB ] embodiments , D? and Do are Cy5 and IRDye750 . In some is bound to any amino acid on B ; and embodiments , D , and DR are Cy5 and IRDye800 . In some (b ) visualizing at least one of the imaging agents . embodiments , DA and DB are Cy5 and ICG . 60 In some embodiments , the tissue is cancerous . In some Disclosed herein , in certain embodiments , are methods of embodiments , the cancerous tissue is : breast cancer tissue , delivering a pair of acceptor and donor fluorescentmoieties colorectal cancer tissue, squamous cell carcinoma tissue , that are capable of undergoing Försters / fluorescence reso - prostate cancer tissue, melanoma tissue , or thyroid cancer nance energy transfer with the other to a tissue of interest , tissue . In some embodiments , the cancerous cell or tissue is comprising contacting the tissue of interest with SDM - 14 . 65 breast cancer tissue . In some embodiments , the cancerous Disclosed herein , in certain embodiments , are methods of cell or tissue is colon cancer tissue . In some embodiments , delivering a pair of acceptor and donor fluorescent moieties the method further comprises surgically removing the tissue US 9 , 840 , 537 B2 107 108 of interest from the individual. In some embodiments , the ments , DA and Dg are Cy5 and IRDye750 . In some embodi surgical margin surrounding the tissue of interest is ments , D , and D , are Cy5 and IRDye800 . In some embodi decreased . In some embodiments , the method further com ments , D? and DB are Cy5 and ICG . In some embodiments , prises preparing a tissue sample from the removed cell or the method further comprises visualizing Försters / fluores tissue of interest. In some embodiments , the method further 5 cence resonance energy transfer between DA and Dr. In comprises staging the cancerous tissue . In some embodi- some embodiments , DA and DR are a fluorescentmoiety and ments , A and B do not have an equal number of acidic and a fluorescence - quenching moiety . In some embodiments , the basic amino acids. In some embodiments , the number of molecule is chosen from : SDM - 14 , SDM - 15 , SDM - 23 , basic amino acids in B is greater than the number of acidic SDM -24 , SDM - 25 , SDM - 26 , SDM - 27 , SDM - 32 , and SDM amino acids in A . In some embodiments , A is a peptide 10 35 . comprising 5 or 9 consecutive glutamates ( SEO ID NO : 3 ) . Disclosed herein , in certain embodiments , are methods of In some embodiments, B is a peptide comprising 8 or 9 visualizing a tissue of interest in an individual in need consecutive arginines (SEQ ID NO : 4 ) . In some embodi - thereof, comprising : ments , A is a peptide comprising 5 or 9 consecutive gluta - ( a ) administering to the individual a molecule of Formula I mates (SEQ ID NO : 3 ) and B is a peptide comprising 8 or 15 that localizes to the tissue of interest in the individual , 9 consecutive arginines (SEQ ID NO : 4 ) . In some embodi ments, A is a peptide comprising 5 consecutive glutamates [DA - c4 ] - A - [exrM ]- X - B -[ CB - D } ] Formula I (SEQ ID NO : 5 ) and B is a peptide comprising 8 consecutive wherein , arginines (SEQ ID NO : 6 ) . In some embodiments , CA , CB , X is a peptide linker cleavable by a matrix metallopro and cm are each independently a 0 - 1 amino acid . In some 20 teinase ; embodiments , C4 , Cp , andcare each independently selected A is a peptide with a sequence comprising 5 or 9 from a naturally -occurring amino acid or a non - naturally consecutive glutamates (SEQ ID NO : 3 ) ; occurring amino acid . In some embodiments, CA , CR , and cm B is a peptide with a sequence comprising 8 or 9 are each independently selected from a D amino acid , a L consecutive arginines ( SEQ ID NO : 4 ) ; amino acid , an a - amino acid , a ß - amino acid , or a y -amino 25 CA, CB, and cm each independently comprise 0 - 1 amino acid . In some embodiments, CA , CB , and cy are each inde acid ; pendently selected from any amino acid having a free thiol M is a polyethylene glycol (PEG ) polymer ; and group , any amino acid having a N - terminal amine group , D , and D , are a pair of acceptor and donor fluorescent and any amino acid with a side chain capable of forming an moieties that are capable of undergoing Försters / oxime or hydrazone bond upon reaction with a hydroxylam - 30 fluorescence resonance energy transfer with the ine or hydrazine group . In some embodiments, CA , CB , and other; and Cm are each independently selected from D -cysteine , D -glu wherein [Cx - M ] is bound to at any position on A or X , tamate , lysine , and para - 4 - acetyl L -phenylalanine . In some [ D , -ca ] is bound to any amino acid on A , and [ CR - D ] embodiments , CB is any amino acid having a free thiol group . is bound to any amino acid on B ; and In some embodiments , Cris D - cysteine . In some embodi- 35 ( b ) visualizing at least one of the imaging agents . ments , CA is any amino acid having a N - terminal amine In some embodiments , A and B do not have an equal group . In some embodiments , CA is D - glutamate . In some number of acidic and basic amino acids. In some embodi embodiments , C , is lysine . In some embodiments , Cwis any ments , C4 , CR , and cy are each independently a 0 - 1 amino amino acid with a side chain capable of forming an oxime acid . In some embodiments , CA, CB , and cy are each inde or hydrazone bond upon reaction with a hydroxylamine or 40 pendently selected from any amino acid having a free thiol hydrazine group . In some embodiments , Cy is para - 4 - acetyl group , any amino acid having a N -terminal amine group , L - phenylalanine . In some embodiments , X is cleavable by a and any amino acid with a side chain capable of forming an protease . In some embodiments , X is cleavable by a matrix oxime or hydrazone bond upon reaction with a hydroxylam metalloproteinase . In some embodiments , X comprises an ine or hydrazine group . In some embodiments , CA , CB , and amino acid sequence that is cleavable by MMP2, MMP7 , 45 Cy are each independently selected from D - cysteine , D - glu MMP9 , or MMP14 . In some embodiments , X comprises a tamate , lysine , and para - 4 - acetyl L -phenylalanine . In some peptide linkage . In some embodiments , X comprises an embodiments , Cris any amino acid having a free thiol group . amino acid sequence selected from : PLGLAG (SEQ ID NO : In some embodiments , CB is D - cysteine . In some embodi 2 ) , PLG - C (me ) -AG ( SEQ ID NO : 1 ) , RPLALWRS (SEQ ID ments , C , is any amino acid having a N -terminal amine NO : 7 ), ESPAYYTA (SEQ ID NO : 8 ), DPRSFL (SEQ ID 50 group . In some embodiments , CA is D - glutamate . In some NO : 9 ) , PPRSFL (SEQ ID NO : 10 ), RLQLKL (SEQ ID NO : embodiments , Cm is any amino acid with a side chain 11) , and RLQLK (Ac ) (SEQ ID NO : 12 ) . In some embodi capable of forming an oxime or hydrazone bond upon ments, X comprises the amino acid sequence PLGLAG reaction with a hydroxylamine or hydrazine group . In some (SEQ ID NO : 2 ) . In some embodiments , X comprises the embodiments , cy is para - 4 - acetyl L -phenylalanine . In some amino acid sequence PLG - C (me ) - AG (SEQ ID NO : 1 ) . In 55 embodiments , X comprises the amino acid sequence some embodiments , X comprises the amino acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodiments , X RPLALWRS (SEQ ID NO : 7 ). In some embodiments , X comprises the amino acid sequence DPRSFL (SEQ ID NO : comprises the amino acid sequence DPRSFL (SEQ ID NO : 9 ). In some embodiments , X comprises the amino acid 9 ) . In some embodiments , X comprises the amino acid sequence PPRSFL (SEQ ID NO : 10 ) . In some embodiments , sequence PPRSFL (SEQ ID NO : 10 ) . In some embodiments , 60 X comprises the amino acid sequence RLQLKL ( SEQ ID X comprises the amino acid sequence RLQLKL (SEQ ID NO : 11 ) . In some embodiments , X comprises the amino acid NO : 11 ). In some embodiments , X comprises the amino acid sequence RLQLK ( Ac) ( SEQ ID NO : 12 ) . In some embodi sequence RLQLK (Ac ) (SEQ ID NO : 12 ) . In some embodi ments , DA and DB are Cy5 and Cy7. In some embodiments , ments , DA and DB are a pair of acceptor and donor fluores - DA and Do are Cy5 and Cy7 . cent moieties that are capable of undergoing Försters / fluo - 65 Disclosed herein , in certain embodiments , are methods of rescence resonance energy transfer with the other. In some visualizing a tissue of interest in an individual in need embodiments , D? and Do are Cy5 and Cy7 . In some embodi - thereof , comprising : US 9 , 840 ,537 B2 109 110 ( a ) administering to the individual a molecule of Formula I M is a polyethylene glycol (PEG ) polymer; and that localizes to the tissue of interest in the individual, DA and DR are a pair of acceptor and donor fluorescent moieties that are capable of undergoing Försters / [DA - ch ] - A -[ CxM ]- X -B - [ CB -De ] Formula I fluorescence resonance energy transfer with the wherein , 5 other; and X is a peptide linker cleavable by a matrix metallopro wherein C[ M ] is bound to at any position on A or X , teinase ; A is a peptide with a sequence comprising 5 consecu [ DA- CA ] is bound to any amino acid on A , and [ CB -DB ] tive glutamates (SEQ ID NO : 5 ) ; is bound to any amino acid on B ; and B is a peptide with a sequence comprising 8 consecu - 10 ( b ) visualizing at least one of the imaging agents . tive arginines (SEQ ID NO : 6 ) ; In some embodiments , CA, CB, and cm are each indepen CA , CB , and cm each independently comprise 0 - 1 amino dently a 0 - 1 amino acid . In some embodiments , CA, CB, and acid ; CM are each independently selected from any amino acid M is a polyethylene glycol (PEG ) polymer ; and having a free thiol group , any amino acid having a N - ter D and De are a pair of acceptor and donor fluorescent 15 minal amine group , and any amino acid with a side chain moieties that are capable of undergoing Försters / capable of forming an oxime or hydrazone bond upon fluorescence resonance energy transfer with the reaction with a hydroxylamine or hydrazine group . In some other ; and embodiments , C4, CB , and cw are each independently selected wherein [cv - M ] is bound to at any position on A or X , from D - cysteine , D - glutamate , lysine, and para - 4 - acetyl [DA - CA ] is bound to any amino acid on A , and [Cz - D ] 20 L -phenylalanine . In some embodiments , Cg is any amino is bound to any amino acid on B ; and acid having a free thiol group . In some embodiments , CB is ( b ) visualizing at least one of the imaging agents . D - cysteine . In some embodiments , ca is any amino acid In some embodiments , CA, CB, and cm are each indepen - having a N - terminal amine group . In some embodiments, CA dently a 0 - 1 amino acid . In some embodiments , CA, CB , and is D - glutamate . In some embodiments , cy is any amino acid Cy are each independently selected from any amino acid 25 with a side chain capable of forming an oxime or hydrazone having a free thiol group , any amino acid having a N - ter - bond upon reaction with a hydroxylamine or hydrazine minal amine group , and any amino acid with a side chain capable of forming an oxime or hydrazone bond upon group . In some embodiments , cm is para - 4 - acetyl L - phenyl reaction with a hydroxylamine or hydrazine group . In some alanine . In some embodiments , X comprises the amino acid embodiments , CA , CR , andcare each independently selected 30 sequence RPLALWRS ( SEQ ID NO : 7 ) . In some embodi from D - cysteine, D - glutamate , lysine , and para - 4 - acetyl ments , X comprises the amino acid sequence DPRSFL (SEQ L - phenylalanine. In some embodiments , Cg is any amino ID NO : 9 ) . In some embodiments , X comprises the amino acid having a free thiol group . In some embodiments , CR is acid sequence PPRSFL (SEQ ID NO : 10 ) . In some embodi D -cysteine . In some embodiments , ca is any amino acid ments , X comprises the amino acid sequence RLQLKL having a N - terminal amine group . In some embodiments , cx 35 (SEQ ID NO : 11) . In some embodiments , X comprises the is D - glutamate . In some embodiments , Cy is any amino acid amino acid sequence RLQLK ( Ac ) (SEQ ID NO : 12 ). In with a side chain capable of forming an oxime or hydrazone some embodiments , DA and DR are Cy5 and Cy7. In some bond upon reaction with a hydroxylamine or hydrazine embodiments , DA and Do are Cy5 and IRDye750 . In some group . In some embodiments , Cy is para - 4 - acetyl L - phenyl- embodiments , DA and DB are Cy5 and IRDye800 . In some alanine. In some embodiments , X comprises the amino acid 40 embodiments , DA and Ds are Cy5 and ICG . sequence RPLALWRS ( SEQ ID NO : 7 ) . In some embodi Disclosed herein , in certain embodiments , are methods of ments, X comprises the amino acid sequence DPRSFL (SEQ visualizing a tissue of interest in an individual in need ID NO : 9 ) . In some embodiments , X comprises the amino thereof, comprising , comprising ( a ) administering SDM - 14 acid sequence PPRSFL (SEQ ID NO : 10 ) . In some embodi - to the individual, and ( b ) visualizing at least one of the ments , X comprises the amino acid sequence RLQLKL 45 imaging agents . ( SEO ID NO : 11 ) . In some embodiments , X comprises the Disclosed herein , in certain embodiments , are methods of amino acid sequence RLQLK (Ac ) (SEQ ID NO : 12 ) . In visualizing a tissue of interest in an individual in need some embodiments , DA and DR are Cy5 and Cy7 . In some thereof, comprising, comprising ( a ) administering SDM - 15 embodiments , D , and DR are Cy5 and IRDye750 . In some to the individual, and ( b ) visualizing at least one of the embodiments , DA and DB are Cy5 and IRDye800 . In some 50 imaging agents . embodiments , D , and DR are Cy5 and ICG . Disclosed herein , in certain embodiments , are methods of Disclosed herein , in certain embodiments , are methods of visualizing a tissue of interest in an individual in need visualizing a tissue of interest in an individual in need thereof, comprising , comprising ( a ) administering SDM - 23 thereof, comprising : to the individual, and ( b ) visualizing at least one of the ( a ) administering to the individual a molecule of Formula I 55 imaging agents . that localizes to the tissue of interest in the individual : Disclosed herein , in certain embodiments , are methods of visualizing a tissue of interest in an individual in need [ DA -CA ]- A - [CM - M ] - X - B -[ cg - Del Formula I thereof, comprising , comprising ( a ) administering SDM - 24 wherein , to the individual, and ( b ) visualizing at least one of the X is a peptide linker cleavable by a matrix metallopro - 60 imaging agents . teinase ; Disclosed herein , in certain embodiments , are methods of A is a peptide with a sequence comprising 9 consecu - visualizing a tissue of interest in an individual in need tive glutamates (SEQ ID NO : 13 ) ; thereof, comprising , comprising ( a ) administering SDM - 25 B is a peptide with a sequence comprising 9 consecu - to the individual, and ( b ) visualizing at least one of the tive arginines (SEQ ID NO : 14 ) ; 65 imaging agents . CA, CB, and cm each independently comprise 0 - 1 amino Disclosed herein , in certain embodiments , are methods of acid ; visualizing a tissue of interest in an individual in need US 9 , 840 ,537 B2 111 112 thereof, comprising , comprising ( a ) administering SDM - 26 employed in guided surgery . In some embodiments , the to the individual, and (b ) visualizing at least one of the selective delivery molecule preferentially localized to can imaging agents . cerous, or other pathological tissues with up - regulated pro Disclosed herein , in certain embodiments , are methods of tease activity ( e . g . tissues undergoing inflammatory visualizing a tissue of interest in an individual in need 5 response ) . In some embodiments , a selective delivery mol thereof, comprising , comprising (a ) administering SDM -27 ecule according to Formula I comprising an imaging agent to the individual, and ( b ) visualizing at least one of the is employed in a guided surgery to remove colorectal cancer. imaging agents . In some embodiments , guided surgery employing the selec Disclosed herein , in certain embodiments , are methods of tive delivery molecule allows a surgeon to excise as little visualizing a tissue of interest in an individual in need 10 healthy i . e ., non - cancerous ) tissue as possible . In some thereof, comprising , comprising ( a ) administering SDM - 32 embodiments , guided surgery employing the selective deliv to the individual, and ( b ) visualizing at least one of the ery molecule allows a surgeon to visualize and excise more imaging agents . cancerous tissue than the surgeon would have been able to Disclosed herein , in certain embodiments , are methods of excise without the presence of the selective delivery mol visualizing a tissue of interest in an individual in need 15 ecule . In some embodiments , the surgery is fluorescence thereof, comprising, comprising ( a ) administering SDM -35 guided surgery . to the individual , and ( b ) visualizing at least one of the imaging agents . Imaging Agents In some embodiments , targeted delivery of an imaging In some embodiments , an imaging agent is a dye . In some agent to a cell or tissue enables a medical professional to embodiments, an imaging agent is a fluorescent moiety . In visualize / image a specific tissue ( e . g ., cancerous tissue ). In 20 some embodiments, a fluorescent moiety is selected from : a some embodiments , targeted delivery of an imaging agent to fluorescent protein , a fluorescent peptide , a fluorescent dye , a cell or tissue enables a medical professional to remove ( or, a fluorescent material or a combination thereof. surgically excise ) the tissue of interest ( e . g ., cancerous All fluorescentmoieties are encompassed within the term tissue ) . In some embodiments , targeted delivery of an imag " fluorescent moiety .” Specific examples of fluorescent moi ing agent to a cell or tissue enables a medical professional 25 eties given herein are illustrative and are notmeant to limit to remove (or , surgically excise ) the tissue of interest ( e . g ., the fluorescentmoieties for use with the targeting molecules cancerous tissue ) with a decrease in surgical margins. In disclosed herein . some embodiments , targeted delivery of an imaging agent to Examples of fluorescent dyes include , but are not limited a cell or tissue enables a medical professional to remove (or , to , xanthenes ( e . g ., rhodamines, rhodols and fluoresceins , surgically excise ) a tumor/ cancerous tissue and decreases 30 and their derivatives ); bimanes; coumarins and their deriva the chance that some of the tumor / cancerous tissue will not tives ( e . g ., umbelliferone and aminomethyl coumarins ) ; be removed . In some embodiments , targeted delivery of an aromatic amines (e . g ., dansyl; squarate dyes ); benzofurans; imaging agent to a cell or tissue enables a medical profes fluorescent cyanines ; indocarbocyanines ; carbazoles; dicya sional to maximally debulk a tumor / cancerous tissue. In nomethylene pyranes; polymethine ; oxabenzanthrane ; xan some embodiments , targeted delivery of an imaging agent to 35 thene ; pyrylium ; carbostyl; perylene ; acridone ; quinacri cancerous breast tissue decreases the chances of an unnec done ; rubrene; anthracene ; coronene ; phenanthrecene; essary operations and re - operations. pyrene ; butadiene ; stilbene ; porphyrin ; pthalocyanine ; lan In some embodiments , targeted delivery of an imaging thanide metal chelate complexes; rare - earth metal chelate agent to a cell or tissue enables a medical professional to complexes ; and derivatives of such dyes . more accurately sample ( e . g . , biopsy ( e . g ., excision biopsy, 40 Examples of fluorescein dyes include , but are not limited incision , biopsy, aspiration biopsy, or needle biopsy ) ) tissue to , 5 - carboxyfluorescein , fluorescein -5 - isothiocyanate , fluo oftargeted interest delivery ( e . g ., cancerousof an imaging tissue )agent . In some to a embodimentscell or tissue , rescein -6 - isothiocyanate and 6 - carboxyfluorescein . enables a medical professional to visualize/ image a specific Examples of rhodamine dyes include , but are not limited tissue ( e . g ., cancerous tissue ) within an excised tissue con - to , tetramethylrhodamine - 6 - isothiocyanate , 5 -carboxyte taining healthy tissue . Enabling identification of target tissue 45 tramethylrhodamine , 5 - carboxy rhodol derivatives , tetram ( e . g . , cancerous tissue ) can guide the pathologist on where ethyl and tetraethyl rhodamine , diphenyldimethyl and diphe to section of pathological evaluation and decreases the nyldiethyl rhodamine , dinaphthyl rhodamine , rhodamine chances of a pathologist missing unhealthy tissue ( e . g ., 101 sulfonyl chloride (sold under the tradename of TEXAS cancerous tissue ) and sampling healthy tissue which may R ED® ) . produce a false negative . In some embodiments , tissue ( e .g ., 50 Examples of cyanine dyes include, but are not limited to , cancerous tissue ) removed following use of a compound of Cy3 , Cy3B , Cy3 . 5 , Cy5 , Cy5 . 5 , Cy7 , IRDYE680 , Alexa Formula I is used to prepare a pathology section or slide . In Fluor 750 , IRDye800CW , ICG . some embodiments, cancerous tissue removed following use Examples of fluorescent peptides include GFP (Green of a compound of Formula I is used to prepare a pathology Fluorescent Protein ) or derivatives of GFP (e . g . , EBFP, section or slide which is used to diagnose a tissue as 55 EBFP2. Azurite , mKalamal . ECFP. Cerulean . CvPet . YFP . malignant or benign . In some embodiments , targeted delivery of an imaging Citrine , Venus, YPet ). agent to cancerous breast tissue enables a medical profes Fluorescent labels are detected by any suitable method . sional to accurately stage cancer enabling medical treatment For example , a fluorescent label may be detected by exciting decisions . In some embodiments , targeted delivery of an the fluorochrome with the appropriate wavelength of light imaging agent to cancerous tissue enables a medical pro - 60 and detecting the resulting fluorescence , e . g ., by micros fessional to observe the size of a tumor ( cancerous tissue ) or copy , visual inspection , via photographic film , by the use of the spread ( e . g . , metastatic lesions ) of cancerous tissue. In electronic detectors such as charge coupled devices (CCDs ) , some embodiments , targeted delivery of an imaging agent to photomultipliers, etc . a cell or tissue enables a medical professional to design an In some embodiments , the imaging agent is labeled with efficacious treatment regimen . 65 a positron -emitting isotope ( e .g ., 8F ) for positron emission In some embodiments , a selective delivery molecule tomography (PET ) , gamma- ray isotope ( e . g ., 99MTC ) for according to Formula I comprising an imaging agent is single photon emission computed tomography (SPECT ) , or US 9 , 840 ,537 B2 113 114 a paramagnetic molecule or nanoparticle ( e . g ., Gd + chelate In some embodiments , A and B do not have an equal or coated magnetite nanoparticle ) for magnetic resonance number of acidic and basic amino acids. In some embodi imaging (MRI ) . ments , the number of basic amino acids in B is greater than In some embodiments , the imaging agent is labeled with : the number of acidic amino acids in A . In some embodi a gadolinium chelate , an iron oxide particle , a super para - 5 ments , A is a peptide comprising 5 or 9 consecutive gluta magnetic iron oxide particle , an ultra small paramagnetic mates (SEQ ID NO : 3 ) . In some embodiments, B is a peptide particle , a manganese chelate or gallium containing agent comprising 8 or 9 consecutive arginines ( SEQ ID NO : 4 ) . In Examples of gadolinium chelates include , but are not some embodiments , A is a peptide comprising 5 or 9 limited to diethylene triamine pentaacetic acid (DTPA ), consecutive glutamates (SEQ ID NO : 3 ) and B is a peptide 1 , 4 , 7 , 10 - tetraazacyclododecane - 1 , 4 , 7 , 10 - tetraacetic acid 10 comprising 8 or 9 consecutive arginines (SEQ ID NO : 4 ) . In ( DOTA ) , and 1 , 4 , 7 -triazacyclononane - N , N ', N " - triacetic some embodiments , A is a peptide comprising 5 consecutive acid (NOTA ). glutamates (SEQ ID NO : 5 ) and B is a peptide comprising In some embodiments , the imaging agent is a near 8 consecutive arginines (SEQ ID NO : 6 ). In some embodi infrared fluorophore for near - infra red (near - IR ) imaging , a ments , C4, CB , and cm are each independently a 0 - 1 amino luciferase ( firefly , bacterial, or coelenterate ) or other lumi- 15 acid . In some embodiments , CA , CR , and cy are each inde nescent molecule for bioluminescence imaging , or a per - pendently selected from a naturally - occurring amino acid or fluorocarbon - filled vesicle for ultrasound . a non -naturally - occurring amino acid . In some embodi In some embodiments , the imaging agent is a nuclear m ents , CA , CB , and cy are each independently selected from probe . In some embodiments , the imaging agent is a SPECT a D amino acid , a L amino acid , an a -amino acid , a ß -amino or PET radionuclide probe. In some embodiments, the 20 acid , or a y -amino acid . In some embodiments, CA , CB , and radionuclide probe is selected from : a technetium chelate , a cm are each independently selected from any amino acid copper chelate , a radioactive fluorine , a radioactive iodine , having a free thiol group , any amino acid having a N - ter a indium chelate . minal amine group , and any amino acid with a side chain Examples of Tc chelates include , but are not limited to capable of forming an oxime or hydrazone bond upon HYNIC , DTPA , and DOTA . 25 reaction with a hydroxylamine or hydrazine group . In some In some embodiments , the imaging agent contains a embodiments , CA , CR , and cw are each independently selected radioactivemoiety , for example a radioactive isotope such as from D - cysteine , D - glutamate , lysine, and para - 4 - acetyl 211 At, 1311 , 1251, 90Y, 186Re, 188Re, 153Sm , 212Bi, 32P , 64Cu , L -phenylalanine . In some embodiments , CB is any amino radioactive isotopes of Lu , and others . acid having a free thiol group . In some embodiments, Cris Therapeutic Uses 30 D -cysteine . In some embodiments, cx is any amino acid The selective delivery molecules of Formula I allow the having a N - terminal amine group . In some embodiments , CA targeted delivery of therapeutic agents to specific cells is D -glutamate . In some embodiments , CA is lysine . In some and / or tissues ( e . g . , cancerous tissues ) . The molecules com - embodiments , cm is any amino acid with a side chain prise a basic peptide sequence ( B ) which is designed to be capable of forming an oxime or hydrazone bond upon transported across a cellular membrane , an acidic peptide 35 reaction with a hydroxylamine or hydrazine group . In some sequence ( A ) which inhibits uptake of peptide B into cells , embodiments , Cy is para - 4 - acetyl L -phenylalanine . In some a linker X which is cleavable under specific conditions, embodiments , X is cleavable by a protease . In some embodi therapeutic agents bound to peptides A and B , or X and a ments, X is cleavable by a matrix metalloproteinase. In some macromolecular carrier. In some embodiments , cleavage of embodiments , X comprises an amino acid sequence that is the linker X linker frees peptide B from peptide A and allows 40 cleavable by MMP2 , MMP7 , MMP9 , or MMP14 . In some the transport of peptide B ( and any therapeutic agents embodiments , X comprises a peptide linkage . In some attached thereto ) across a cellular membrane . In some embodiments , X comprises an amino acid sequence selected embodiments , the selective delivery molecules of Formula I from : PLGLAG (SEQ ID NO : 2 ) , PLG - C (me ) - AG (SEQ ID enable targeted delivery of one ormore therapeutic agents to NO : 1 ) , RPLALWRS (SEQ ID NO : 7 ) , ESPAYYTA (SEQ a cell or tissue . In some embodiments , targeted delivery of 45 ID NO : 8 ) , DPRSFL ( SEQ ID NO : 9 ) , PPRSFL (SEQ ID a therapeutic agent to a cell or tissue enables a medical NO : 10 ) , RLQLKL (SEQ ID NO : 11 ), and RLQLK (Ac ) professional to treat a specific tissue . ( SEQ ID NO : 12 ) . In some embodiments , X comprises the Disclosed herein , in certain embodiments , are methods of amino acid sequence PLGLAG (SEQ ID NO : 2 ). In some delivering a therapeutic agent to a tissue of interest , com embodiments , X comprises the amino acid sequence PLG prising contacting the tissue of interest with a molecule of 50 C (me ) - AG ( SEQ ID NO : 1 ). In some embodiments , X Formula 1 : comprises the amino acid sequence RPLALWRS (SEQ ID NO : 7 ) . In some embodiments , X comprises the amino acid [DA - CA ]- A -[ ©n -M ]- X -B -[ CB -Dp ] Formula I sequence DPRSFL (SEQ ID NO : 9 ) . In some embodiments , wherein , X comprises the amino acid sequence PPRSFL (SEQ ID X is a cleavable linker; 55 NO : 10 ) . In some embodiments , X comprises the amino acid A is a peptide with a sequence comprising 5 to 9 acidic sequence RLQLKL (SEQ ID NO : 11 ). In some embodi amino acids; ments , X comprises the amino acid sequence RLQLK ( Ac ) B is a peptide with a sequence comprising 7 to 9 basic (SEQ ID NO : 12 ). amino acids ; Disclosed herein , in certain embodiments , are methods of CA , CB, and cm each independently comprise 0 - 1 amino 60 delivering a therapeutic agent to a tissue of interest, com acid ; prising contacting the tissue of interest with a molecule of M is a polyethylene glycol (PEG ) polymer ; and Formula I: at least one of DA and Dg is independently a therapeutic agent; and [DA - CA] - A - [ex - M ] - X - B - [ch - De ] Formula I wherein [ Cy - M ] is bound to at any position on A or X , 65 wherein , [DA - CA ] is bound to any amino acid on A , and [ CB- DB ] is X is a peptide linker cleavable by a matrix metallopro bound to any amino acid on B . teinase ; US 9 , 840 ,537 B2 115 116 A is a peptide with a sequence comprising 5 or 9 con D - cysteine . In some embodiments , ca is any amino acid secutive glutamates (SEQ ID NO : 3 ) ; having a N - terminal amine group . In some embodiments , CA B is a peptide with a sequence comprising 8 or 9 con - is D - glutamate . In some embodiments , Cy is any amino acid secutive arginines (SEQ ID NO : 4 ) ; with a side chain capable of forming an oxime or hydrazone CA, CB , and cm each independently comprise 0 - 1 amino 5 bond upon reaction with a hydroxylamine or hydrazine acid ; group . In some embodiments , Cm is para - 4 -acetyl L - phenyl M is a polyethylene glycol (PEG ) polymer, and alanine . In some embodiments , X comprises the amino acid at least one of DA and DB is independently a therapeutic sequence PLGLAG ( SEO ID NO : 2 ) . In some embodiments . agent; and wherein [cm - M ] is bound to at any position on A or X , 10 iX comprises the amino acid sequence PLG - C (me ) - AG ( SEQ [D4 - ca ] is bound to any amino acid on A , and [CB - DB ] is ID NO : 1 ). In some embodiments , X comprises the amino bound to any amino acid on B . acid sequence RPLALWRS ( SEQ ID NO : 7 ) . In some embodiments , A and B do not have an equal Disclosed herein , in certain embodiments , are methods of number of acidic and basic amino acids. In some embodi delivering a therapeutic agent to a tissue of interest , com ments , CA, CB, and Cy are each independently a 0 - 1 aminono 1515 prisprising contacting the tissue of interest with a molecule of acid . In some embodiments, CA , CB , and cy are each inde Formula 1 : pendently selected from any amino acid having a free thiol group , any amino acid having a N -terminal amine group , [DA - CA ] -A -[ CM - M ]- X - B -[ CB -DB ] Formula I and any amino acid with a side chain capable of forming an wherein , oxime or hydrazone bond upon reaction with a hydroxylam - 20 X is a peptide linker cleavable by a matrix metallopro ine or hydrazine group . In some embodiments , CA , CR , and teinase ; cm are each independently selected from D -cysteine , D -glu A is a peptide with a sequence comprising 9 consecutive tamate , lysine , and para - 4 -acetyl L -phenylalanine . In some glutamates (SEQ ID NO : 13 ) ; embodiments , CB is any amino acid having a free thiol group . B is a peptide with a sequence comprising 9 consecutive In some embodiments , Cris D - cysteine . In some embodi- 25 arginines (SEQ ID NO : 14 ) ; ments , ca is any amino acid having a N - terminal amine C A , CB, and cm each independently comprise 0 - 1 amino group . In some embodiments , CA is D - glutamate . In some acid ; embodiments , Cm is any amino acid with a side chain M is a polyethylene glycol (PEG ) polymer ; and capable of forming an oxime or hydrazone bond upon at least one of DA and DB is independently a therapeutic reaction with a hydroxylamine or hydrazine group . In some 30 agent; and embodiments , cy is para - 4 - acetyl L -phenylalanine . In some wherein [cv - M ] is bound to at any position on A or X , embodiments , X comprises the amino acid sequence [DA -CA ] is bound to any amino acid on A , and [ Co - DB] is PLGLAG ( SEQ ID NO : 2 ) . In some embodiments , X bound to any amino acid on B . comprises the amino acid sequence PLG - C (me ) - AG (SEQ In some embodiments , CA , CB, and cm are each indepen ID NO : 1 ). 35 dently a 0 - 1 amino acid . In some embodiments , C4 , CR , and Disclosed herein , in certain embodiments , are methods of Cm are each independently selected from any amino acid delivering a therapeutic agent to a tissue of interest , com having a free thiol group , any amino acid having a N - ter prising contacting the tissue of interest with a molecule of minal amine group , and any amino acid with a side chain Formula I : capable of forming an oxime or hydrazone bond upon 40 reaction with a hydroxylamine or hydrazine group . In some [DA - ca ] - A - [ C - M ]- X - B -[ CB - DB ] Formula I embodiments , CA , CB, and cm are each independently selected wherein , from D - cysteine , D - glutamate , lysine, and para - 4 - acetyl X is a peptide linker cleavable by a matrix metallopro L -phenylalanine . In some embodiments , ce is any amino teinase ; acid having a free thiol group . In some embodiments , CB is A is a peptide with a sequence comprising 5 consecutive 45 D - cysteine . In some embodiments , cx is any amino acid glutamates (SEQ ID NO : 5 ) ; having a N -terminal amine group . In some embodiments , CA B is a peptide with a sequence comprising 8 consecutive is D - glutamate . In some embodiments , Cy is any amino acid arginines (SEQ ID NO : 6 ) ; with a side chain capable of forming an oxime or hydrazone CA , CB , and Cy each independently comprise 0 - 1 amino bond upon reaction with a hydroxylamine or hydrazine acid ; 50 group . In some embodiments , Cyis para - 4 - acetyl L -phenyl M is a polyethylene glycol (PEG ) polymer; and alanine . In some embodiments , X comprises the amino acid at least one of DA and DR is independently a therapeutic sequence PLGLAG (SEQ ID NO : 2 ) . In some embodiments , agent; and X comprises the amino acid sequence PLG - C (me ) - AG (SEQ wherein [Cy - M ] is bound to at any position on A or X , ID NO : 1 ). In some embodiments , X comprises the amino [DA - CA ] is bound to any amino acid on A , and [ CB- DB ) is 55 acid sequence RPLALWRS (SEQ ID NO : 7 ) . bound to any amino acid on B . In some embodiments , targeted delivery of a therapeutic In some embodiments , CA , CB , and Cy are each indepen - agent to a cell or tissue enables a medical professional to dently a 0 - 1 amino acid . In some embodiments , CA , CR , and treat a specific tissue ( e . g . , cancerous tissue ) . In some Cm are each independently selected from any amino acid embodiments , targeted delivery of a therapeutic agent to a having a free thiol group , any amino acid having a N - ter - 60 cell or tissue decreases the dosage of the therapeutic agent. minal amine group , and any amino acid with a side chain In some embodiments , targeted delivery of a therapeutic capable of forming an oxime or hydrazone bond upon agent to a cell or tissue decreases contact of the therapeutic reaction with a hydroxylamine or hydrazine group . In some agent with healthy tissue . In some embodiments , targeted embodiments , C4 , CR , and cy are each independently selected delivery of a therapeutic agent to a cell or tissue decreases from D - cysteine , D - glutamate , lysine , and para - 4 -acetyl 65 unwanted side - effects arising from use of high concentra L - phenylalanine . In some embodiments , CB is any amino tions of a therapeutic agent or contact . In some embodi acid having a free thiol group . In some embodiments , CB is ments , targeted delivery of a therapeutic agent to a cell or US 9 , 840 , 537 B2 117 118 tissue decreases unwanted side - effects arising from contact feron gamma , peginterferon alfa - 2a , peginterferon alfa - 2b , between the therapeutic agent and healthy tissue . aldesleukin , oprelvekin , BCG vaccine , glatiramer acetate , Therapeutic Agents histamine dihydrochloride, immunocyanin , lentinan , mela In some embodiments , a therapeutic agent is selected noma vaccine , mifamurtide , pegademase, pidotimod , from : a chemotherapeutic agent, a steroid , an immunothera - 5 plerixafor, poly I: C , poly ICLC , roquinimex , tasonermin , peutic agent, a targeted therapy, an anti - inflammatory agent, thymopentin , abatacept, abetimus , alefacept , antilympho or a combination thereof. cyte immunoglobulin ( horse ), antithymocyte immunoglobu In some embodiments , a therapeutic agent is a B cell lin ( rabbit ) , eculizumab , efalizumab , everolimus, gusperi receptor pathway inhibitor. In some embodiments , a thera - mus, leflunomide , muromab -CD3 , mycophenolic acid , peutic agent is a CD79A inhibitor, a CD79B inhibitor, a 10 natalizumab , sirolimus, adalimumab , afelimomab , certoli CD19 inhibitor , a Lyn inhibitor , a Syk inhibitor, a PI3K zumab pegol, etanercept, golimumab , infliximab , anakinra , inhibitor, a Bink inhibitor , a PLCyinhibitor, a basiliximab , canakinumab , daclizumab , mepolizumab , PKCBinhibitor, or a combination thereof. In some embodi rilonacept , tocilizumab , ustekinumab , ciclosporin , tacroli ments, a therapeutic agent is an antibody, B cell receptor mus, azathioprine , lenalidomide , methotrexate , thalidomide , signaling inhibitor, a PI3K inhibitor, an IAP inhibitor , an 15 adalimumab , alemtuzumab , bevacizumab , cetuximab , cer mTOR inhibitor, a radioimmunotherapeutic , a DNA dam - tolizumab pegol eculizumab , efalizumab , gemtuzumab , ibri aging agent , a proteosome inhibitor, a histone deacytlase tumomab tiuxetan , muromonab - CD3 , natalizumab , panitu inhibitor , a protein kinase inhibitor, a hedgehog inhibitor, an m umab , ranibizumab , rituximab , tositumomab , Hsp90 inhibitor, a telomerase inhibitor, a Jak1/ 2 inhibitor , a trastuzumab , catumaxomab , edrecolomab , ofatumumab , protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a 20 muromab -CD3 , afelimomab , golimumab , ibritumomab tiux combination thereof. In some embodiments, a therapeutic etan , abagovomab , adecatumumab , alemtuzumab , anti agent is selected from : chlorambucil , ifosphamide , doxoru CD30 monoclonal antibody Xmab2513 , anti -MET mono bicin ,mesalazine , thalidomide, lenalidomide , temsirolimus , clonal antibody MetMab , apolizumab , apomab , everolimus , fludarabine , fostamatinib , paclitaxel , docetaxel, arcitumomab , bispecific antibody 2B1, blinatumomab , bren ofatumumab , rituximab , dexamethasone , prednisone , CAL - 25 tuximab vedotin , capromab pendetide , cixutumumab , clau 101, ibritumomab , tositumomab , bortezomib , pentostatin , diximab , conatumumab , dacetuzumab , denosumab , eculi endostatin , bendamustine , chlorambucil , chlormethine , zumab , epratuzumab , epratuzumab , ertumaxomab , cyclophosphamide , ifosfamide, melphalan , prednimustine , etaracizumab , figitumumab , fresolimumab , galiximab , gani trofosfamide , busulfan , mannosulfan , treosulfan , carbo - tumab , gemtuzumab ozogamicin , glembatumumab , ibritu quone , thiotepa , triaziquone , carmustine , fotemustine, 30 momab , inotuzumab ozogamicin , ipilimumab , lexatu lomustine , nimustine , ranimustine , semustine , streptozocin , mumab , lintuzumab , lintuzumab , lucatumumab , etoglucid , dacarbazine , mitobronitol, pipobroman , temozo - mapatumumab , matuzumab , milatuzumab ,monoclonal anti lomide , methotrexate , permetrexed , pralatrexate , raltitrexed , body CC49, necitumumab , nimotuzumab , ofatumumab , cladribine, clofarabine , fludarabine , mercaptopurine , nelara oregovomab , pertuzumab , ramacurimab , ranibizumab , sipli bine, thioguanine , azacitidine , capecitabine , carmofur, cyt - 35 zumab , sonepcizumab , tanezumab , tositumomab , trastu arabine , decitabine , fluorouracil, gemcitabine , tegafur, vin - zumab , tremelimumab , tucotuzumab celmoleukin , veltu blastine , vincristine, vindesine , vinflunine, vinorelbine , zumab , visilizumab , volociximab , zalutumumab , a syk etoposide , teniposide, demecolcine, docetaxel, paclitaxel, inhibitor ( e . g ., R788 ) , enzastaurin , dasatinib , erlotinib , paclitaxel poliglumex , trabectedin , dactinomycin , aclarubi everolimus, gefitinib , imatinib , lapatinib , nilotinib , pazo cin , daunorubicin , doxorubicin , epirubicin , idarubicin , 40 nanib , sorafenib , sunitinib , temsirolimus , an angiogenesis mitoxantrone , pirarubicin , valrubicin , zorubincin , bleomy - inhibitor ( e . g ., GT - 111 , JI - 101 , R1530 ) , a kinase inhibitors cin , ixabepilone , mitomycin , plicamycin , carboplatin , cis - (e . g ., AC220, AC480 , ACE -041 , AMG 900 , AP24534 , Arry platin , oxaliplatin , satraplatin , procarbazine , aminolevulinic 614 , AT7519 , AT9283 , AV - 951, axitinib , AZD1152 , acid , efaproxiral, methyl aminolevulinate , porfimer sodium , AZD7762 , AZD8055 , AZD8931 , bafetinib , BAY 73 -4506 , temoporfin , dasatinib , erlotinib , everolimus , gefitinib , ima- 45 BGJ398, BGT226 , BI 811283, B16727, BIBF 1120 , BIBW tinib , lapatinib , nilotinib , pazonanib , sorafenib , sunitinib , 2992 , BMS- 690154 , BMS -777607 , BMS- 863233 , BSK temsirolimus, alitretinoin , altretamine, amzacrine , anagrel 461364 , CAL - 101 , CEP - 11981, CYC116 , DCC - 2036 . ide , arsenic trioxide, asparaginase , bexarotene , bortezomib , dinaciclib , dovitinib lactate , E7050 , EMD 1214063 , ENMD celecoxib , denileukin diftitox , estramustine, hydroxycarb 2076 , fostamatinib disodium , GSK2256098 , GSK690693 , amide , irinotecan , lonidamine , masoprocol, miltefosein , 50 INCB18424 , INNO - 406 , JNJ- 26483327 , JX -594 , KX2 - 391 , mitoguazone, mitotane , oblimersen , pegaspargase , pentosta linifanib , LY2603618 , MGCD265 , MK -0457 , MK1496 , tin , romidepsin , sitimagene ceradenovec , tiazofurine, topo - MLN8054 , MLN8237 , MP470 , NMS - 1116354 , NMS tecan , tretinoin , vorinostat, diethyl stilbenol, ethinylestra - 1286937 , ON 01919 .Na , OSI -027 , OSI - 930 , Btk inhibitor, diol, fosfestrol, polyestradiol phosphate , gestonorone , PF -00562271 , PF - 02341066 , PF -03814735 , PF -04217903 , medroxyprogesterone, megestrol, buserelin , goserelin , leu - 55 PF -04554878 , PF -04691502 , PF -3758309 , PHA -739358 , prorelin , triptorelin , fulvestrant, tamoxifen , toremifene , PLC3397 , progenipoietin , R547 , R763 , ramucirumab , rego bicalutamide , flutamide , nilutamide, aminoglutethimide, rafenib , RO5185426 , SAR103168 , S3333333CH 727965 , anastrozole , exemestane, formestane, letrozole , vorozole , SGI- 1176 , SGX523 , SNS - 314 , TAK -593 , TAK - 901 , abarelix , degarelix , histamine dihydrochloride, mifamurtide, TK1258, TLN -232 , TTP607, XL147, XL228, pidotimod , plerixafor, roquinimex , thymopentin , everoli - 60 XL281R05126766 , XL418 , XL 765 ) , an inhibitor ofmito mus , gusperimus , leflunomide , mycophenolic acid , siroli - gen - activated protein kinase signaling ( e . g ., U0126 , mus , ciclosporin , tacrolimus , azathioprine , lenalidomide , PD98059 , PD184352 , PD0325901 , ARRY - 142886 , methotrexate , thalidomide , iobenguane, ancestim , fil - SB239063 , SP600125 , BAY 43 - 9006 , wortmannin , or grastim , lenograstim , molgramostim , pegfilgrastim , sargra LY294002 ) , adriamycin , dactinomycin , bleomycin , vinblas mostim , interferon alfa natural , interferon alfa - 2a , interferon 65 tine , cisplatin , acivicin , aclarubicin , acodazole hydrochlo alfa - 2b , interferon alfacon - 1 , interferon alfa -nl , interferon ride, acronine , adozelesin , aldesleukin , altretamine , beta natural, interferon beta -la , interferon beta- 1b , inter - ambomycin , ametantrone acetate , aminoglutethimide , amsa US 9 ,840 ,537 B2 119 120 crine , anastrozole , anthramycin , asparaginase , asperlin , derivatives, balanol, batimastat, BCR/ ABL antagonists , ben azacitidine , azetepa , azotomycin , batimastat, benzodepa , zochlorins , benzoyl staurosporine , beta lactam derivatives , bicalutamide , bisantrene hydrochloride , bisnafide dimesy beta -alethine , betaclamycin B , betulinic acid , bFGF inhibi late , bizelesin , bleomycin sulfate , brequinar sodium , tor, bicalutamide, bisantrene , bisaziridinylspermine , bisna bropirimine, busulfan , cactinomycin , calusterone , carace - 5 fide , bistratene A , bizelesin , breflate , bropirimine , budoti mide , carbetimer, carboplatin , carmustine , carubicin hydro - tane , buthionine sulfoximine , calcipotriol, calphostin C , chloride, carzelesin , cedefingol, chlorambucil , cirolemycin , camptothecin derivatives, canarypox IL - 2 , capecitabine, car cladribine , crisnatol mesylate , cyclophosphamide , cytara - boxamide - amino -triazole , carboxyamidotriazole , CaRest bine, dacarbazine , daunorubicin hydrochloride , decitabine , M3 , CARN 700 , cartilage derived inhibitor , carzelesin , dexormaplatin , dezaguanine , dezaguanine mesylate , diazi - 10 casein kinase inhibitors (ICOS ) , castanospermine , cecropin quone, doxorubicin , doxorubicin hydrochloride, drolox B , cetrorelix , chlorins, chloroquinoxaline sulfonamide , ifene , droloxifene citrate , dromostanolone propionate, dua - cicaprost , cis - porphyrin , cladribine , clomifene analogues , zomycin , edatrexate , eflornithine hydrochloride , clotrimazole , collismycin A , collismycin B , combretastatin elsamitrucin , enloplatin , enpromate , epipropidine, epirubi A4 , combretastatin analogue , conagenin , crambescidin 816 , cin hydrochloride , erbulozole, esorubicin hydrochloride, 15 crisnatol, cryptophycin 8 , cryptophycin A derivatives , cura estramustine, estramustine phosphate sodium , etanidazole , cin A , cyclopentanthraquinones, cycloplatam , cypemycin , etoposide , etoposide phosphate , etoprine , fadrozole hydro cytarabine ocfosfate , cytolytic factor, cytostatin , dacliximab , chloride , fazarabine , fenretinide, floxuridine , fludarabine decitabine, dehydrodidemnin B , deslorelin , dexamethasone , phosphate , fluorouracil, flurocitabine , fosquidone, fostriecin dexifosfamide , dexrazoxane , dexverapamil, diaziquone , sodium , gemcitabine, gemcitabine hydrochloride, 20 didemnin B , didox , diethylnorspermine, dihydro - 5 - azacyti hydroxyurea , idarubicin hydrochloride, ifosfamide, iimofos dine, 9 - dioxamycin , diphenyl spiromustine , docosanol, ine , interleukin Il ( including recombinant interleukin II , or dolasetron , doxifluridine, droloxifene , dronabinol, duocar r1L2) , interferon alfa - 2a , interferon alfa - 2b , interferon alfa - mycin SA , ebselen , ecomustine, edelfosine , edrecolomab , nl , interferon alfa -n3 , interferon beta - 1 a , interferon eflornithine , elemene , emitefur, epirubicin , epristeride , gamma - 1 b , iproplatin , irinotecan hydrochloride , lanreotide 25 estramustine analogue , estrogen agonists , estrogen antago acetate , letrozole, leuprolide acetate , liarozole hydrochlo - nists , etanidazole , etoposide phosphate, exemestane , fadro ride , lometrexol sodium , lomustine , losoxantrone hydro - zole , fazarabine , fenretinide , filgrastim , finasteride , fla chloride , masoprocol, maytansine , mechlorethamine hydro vopiridol, flezelastine , fluasterone , fludarabine , chloride , megestrol acetate , melengestrol acetate , fluorodaunorunicin hydrochloride , forfenimex , formestane , melphalan , menogaril, mercaptopurine, methotrexate , 30 fostriecin , fotemustine, gadolinium texaphyrin , gallium methotrexate sodium , metoprine, meturedepa , mitindomide , nitrate , galocitabine , ganirelix , gelatinase inhibitors, gem mitocarcin , mitocromin , mitogillin , mitomalcin , mitomycin , citabine , glutathione inhibitors, hepsulfam , heregulin , hex mitosper, mitotane , mitoxantrone hydrochloride , mycophe - amethylene bisacetamide , hypericin , ibandronic acid , idaru nolic acid , nocodazoie , nogalamycin , ormaplatin , oxisuran , bicin , idoxifene , idramantone , ilmofosine , ilomastat, pegaspargase , peliomycin , pentamustine , peplomycin sul- 35 imidazoacridones, imiquimod , immunostimulant peptides , fate , perfosfamide, pipobroman , piposulfan , piroxantrone insulin - such as for example growth factor - 1 receptor inhibi hydrochloride , plicamycin , plomestane , porfimer sodium , tor, interferon agonists , interferons, interleukins, ioben porfiromycin , prednimustine, procarbazine hydrochloride , guane , iododoxorubicin , ipomeanol, 4 - , iroplact, irsoglad puromycin , puromycin hydrochloride, pyrazofurin , ribo i ne , isobengazole , isohomohalicondrin B , itasetron , prine , rogletimide, safingol , safingol hydrochloride , semus - 40 jasplakinolide, kahalalide F , lamellarin - N triacetate , lan tine , simtrazene , sparfosate sodium , sparsomycin , spiroger - reotide , leinamycin , lenograstim , lentinan sulfate , leptolsta manium hydrochloride, spiromustine, spiroplatin , tin , letrozole , leukemia inhibiting factor, leukocyte alpha streptonigrin , streptozocin , sulofenur, talisomycin , tec - interferon , leuprolide + estrogen + progesterone , leuprorelin , ogalan sodium , tegafur, teloxantrone hydrochloride , levamisole , liarozole , linear polyamine analogue , lipophilic temoporfin , teniposide , teroxirone , testolactone , thia - 45 disaccharide peptide , lipophilic platinum compounds, lisso miprine, thioguanine, thiotepa , tiazofurin , tirapazamine , clinamide 7 , lobaplatin , lombricine , lometrexol, lonidamine , toremifene citrate , trestolone acetate , triciribine phosphate , losoxantrone , lovastatin , loxoribine , lurtotecan , lutetium trimetrexate , trimetrexate glucuronate , triptorelin , tubulo - texaphyrin , lysofylline , lytic peptides , maitansine, mannos zole hydrochloride , uracil mustard , uredepa , vapreotide , tatin A , marimastat, masoprocol, maspin , matrilysin inhibi verteporfin , vinblastine sulfate , vincristine sulfate , vin - 50 tors, matrix metalloproteinase inhibitors , menogaril , mer desine , vindesine sulfate , vinepidine sulfate , vinglycinate barone , meterelin , methioninase , metoclopramide , MIF sulfate , vinleurosine sulfate , vinorelbine tartrate, vinrosidine inhibitor, mifepristone , miltefosine , mirimostim , mis sulfate , vinzolidine sulfate , vorozole , zeniplatin , zinostatin , matched double stranded RNA , mitoguazone , mitolactol, zorubicin hydrochloride . In some embodiments , a therapeu - mitomycin analogues , mitonafide , mitotoxin fibroblast tic agent is selected from : 20 - epi - 1 , 25 dihydroxyvitamin 55 growth factor -saporin , mitoxantrone, mofarotene , molgra D3 , 5 - ethynyluracil, abiraterone , aclarubicin , acylfulvene, mostim , monoclonal antibody , human chorionic gonadotro adecypenol, adozelesin , aldesleukin , ALL - TK antagonists , phin , monophosphoryl lipid A +myobacterium cell wall sk , altretamine , ambamustine , amidox , amifostine , aminolevu mopidamol, multiple drug resistance gene inhibitor ,multiple linic acid , amrubicin , amsacrine, anagrelide , anastrozole , tumor suppressor 1 -based therapy, mustard anticancer agent , andrographolide , angiogenesis inhibitors, antagonist D , 60 mycaperoxide B , mycobacterial cell wall extract, myriapor antagonist G , antarelix , anti -dorsalizing morphogenetic pro one , N - acetyldinaline , N - substituted benzamides , nafarelin , tein - 1 , antiandrogen , prostatic carcinoma, antiestrogen , anti- nagrestip , naloxone + pentazocine, napavin , naphterpin , nar neoplaston , antisense oligonucleotides , aphidicolin glyci - tograstim , nedaplatin , nemorubicin , neridronic acid , neutral nate , apoptosis gene modulators , apoptosis regulators , endopeptidase , nilutamide , nisamycin , nitric oxide modula apurinic acid , ara -CDP - DL -PTBA , arginine deaminase , asu - 65 tors, nitroxide antioxidant, nitrullyn , 06 -benzylguanine , oct lacrine , atamestane , atrimustine , axinastatin 1 , axinastatin 2 , reotide , okicenone , oligonucleotides , onapristone , ondanse axinastatin 3 , azasetron , azatoxin , azatyrosine, baccatin III tron , ondansetron , oracin , oral cytokine inducer, ormaplatin , US 9 ,840 ,537 B2 121 122 osaterone, oxaliplatin , oxaunomycin , palauamine, palmi- dEpoA ), Epothilone D ( also referred to as KOS - 862, dEpoB , toylrhizoxin , pamidronic acid , panaxytriol, panomifene , and desoxyepothilone B ) , Epothilone E , Epothilone F , parabactin , pazelliptine, pegaspargase , peldesine, pentosan Epothilone B N -oxide , Epothilone A N -oxide , 16 - aza - epoth polysulfate sodium , pentostatin , pentrozole , perflubron , per - ilone B , 21- aminoepothilone B ( also known as BMS fosfamide , perillyl alcohol, phenazinomycin , phenylacetate , 5 310705 ) , 21 - hydroxyepothilone D ( also known as Desoxye phosphatase inhibitors , picibanil, pilocarpine hydrochloride , pothilone F and dEpoF ), 26 - fluoroepothilone ), Auristatin PE pirarubicin , piritrexim , placetin A , placetin B , plasminogen ( also known as NSC -654663 ) , Soblidotin (also known as activator inhibitor , platinum complex , platinum compounds, TZT- 1027 ) , LS - 4559- P ( Pharmacia , also known as platinum - triamine complex , porfimer sodium , porfiromycin , LS -4577 ) , LS - 4578 (Pharmacia , also known as LS - 477 - P ) , prednisone , propyl bis -acridone , prostaglandin J2 , protea - 10 LS - 4477 (Pharmacia ), LS -4559 (Pharmacia ), RPR - 112378 some inhibitors, protein A - based immune modulator, protein ( Aventis ) , Vincristine sulfate , DZ - 3358 (Daiichi ) , kinase C inhibitor, protein kinase C inhibitors, microalgal, FR - 182877 (Fujisawa , also known as WS - 9885B ) , GS - 164 protein tyrosine phosphatase inhibitors , purine nucleoside ( Takeda ), GS - 198 ( Takeda ), KAR - 2 (Hungarian Academy of phosphorylase inhibitors, purpurins, pyrazoloacridine, pyri - Sciences ), BSF - 223651 (BASF , also known as ILX -651 and doxylated hemoglobin polyoxyethylerie conjugate , raf 15 LU -223651 ) , SAH - 49960 (Lilly /Novartis ), SDZ- 268970 antagonists , raltitrexed , ramosetron , ras farnesyl protein (Lilly /Novartis ) , AM - 97 ( Armad /Kyowa Hakko ) , AM - 132 transferase inhibitors , ras inhibitors , ras -GAP inhibitor, ( Armad ) , AM - 138 ( Armad /Kyowa Hakko ), IDN - 5005 ( In retelliptine demethylated , rhenium Re 186 etidronate , dena ), Cryptophycin 52 ( also known as LY -355703 ), rhizoxin , ribozymes, RII retinamide , rogletimide, rohi- AC - 7739 ( Ajinomoto , also known as AVE - 8063A and tukine, romurtide, roquinimex , rubiginone B1 , ruboxyl, 20 CS -39 . HCI ) , AC - 7700 ( Ajinomoto , also known as AVE safingol, saintopin , SarCNU , sarcophytol A , sargramostim , 8062 , AVE - 8062A , CS - 39 - L -Ser .HC1 , and RPR - 258062A ) , Sdi 1 mimetics, semustine , senescence derived inhibitor 1 , Vitilevuamide , Tubulysin A , Canadensol , Centaureidin ( also sense oligonucleotides, signal transduction inhibitors , signal known as NSC - 106969) , T -138067 ( Tularik , also known as transduction modulators , single chain antigen - binding pro T -67 , TL - 138067 and TI- 138067 ) , COBRA - 1 (Parker tein , sizofiran , sobuzoxane , sodium borocaptate , sodium 25 Hughes Institute , also known as DDE - 261 and WHI- 261 ) , phenylacetate , solverol, somatomedin binding protein , son H10 (Kansas State University ) , H16 (Kansas State Univer ermin , sparfosic acid , spicamycin D , spiromustine, spleno sity ), Oncocidin A1 ( also known as BTO - 956 and DIME ) , pentin , spongistatin 1 , squalamine, stem cell inhibitor, stem DDE -313 (Parker Hughes Institute ), Fijianolide B , Lauli cell division inhibitors , stipiamide , stromelysin inhibitors , malide , SPA - 2 (Parker Hughes Institute ) , SPA - 1 ( Parker sulfinosine , superactive vasoactive intestinal peptide antago - 30 Hughes Institute , also known as SPIKET- P ), 3 - IAABU nist, suradista , suramin , swainsonine, synthetic gly - (Cytoskeleton /Mt . Sinai School of Medicine , also known as cosaminoglycans , tallimustine, tamoxifen methiodide , tau - MF - 569) , Narcosine ( also known as NSC - 5366 ), Nascapine, romustine , tazarotene , tecogalan sodium , tegafur, D - 24851 (Asta Medica ) , A - 105972 (Abbott ) , Hemiasterlin , tellurapyrylium , telomerase inhibitors , temoporfin , temozo - 3 -BAABU ( Cytoskeleton /Mt . Sinai School of Medicine , lomide , teniposide , tetrachlorodecaoxide , tetrazomine , thali - 35 also known as MF - 191 ) , TMPN ( Arizona State University ), blastine, thiocoraline, thrombopoietin , thrombopoietin Vanadocene acetylacetonate, T - 138026 ( Tularik ) , Monsa mimetic , thymalfasin , thymopoietin receptor agonist, thy - trol, Inanocine ( also known as NSC -698666 ) , 3 - 1AABE motrinan , thyroid stimulating hormone , tin ethyl etiopurpu - (Cytoskeleton /Mt . Sinai School of Medicine ) , A - 204197 rin , tirapazamine , titanocene bichloride, topsentin , tore - ( Abbott ), T -607 ( Tuiarik , also known as T - 900607 ) , RPR mifene, totipotent stem cell factor, translation inhibitors, 40 115781 (Aventis ), Eleutherobins ( such as Desmeth tretinoin , triacetyluridine , triciribine , trimetrexate , triptore - yleleutherobin , Desaetyleleutherobin , Isoeleutherobin A , lin , tropisetron , turosteride , tyrosine kinase inhibitors , tyr- and Z - Eleutherobin ) , Caribaeoside , Caribaeolin , Halichon phostins, UBC inhibitors , ubenimex , urogenital sinus - de drin B , D -64131 (Asta Medica ), D -68144 ( Asta Medica ), rived growth inhibitory factor, urokinase receptor Diazonamide A , A - 293620 ( Abbott ), NPI- 2350 (Nereus ), antagonists , vapreotide , variolin B , vector system , erythro - 45 Taccalonolide A , TUB - 245 (Aventis ), A - 259754 ( Abbott ) , cyte gene therapy , velaresol, veramine , verdins, verteporfin , Diozostatin , ( - ) - Phenylahistin (also known as NSCL vinorelbine , vinxaltine , vitaxin , vorozole , zanoterone , zeni - 96F037 ) , D -68838 ( Asta Medica ) , D - 68836 ( Asta Medica ) , platin , zilascorb , zinostatin stimalamer , mechloroethamine, Myoseverin B , D - 43411 ( Zentaris , also known as D - 81862 ) , cyclophosphamide , chlorambucil, busulfan , carmustine , A - 289099 ( Abbott ) , A - 318315 ( Abbott ) , HTI- 286 ( also lomusitne , decarbazine , methotrexate , cytarabine , mercap - 50 known as SPA - 110 , trifluoroacetate salt ) (Wyeth ) , D - 82317 topurine , thioguanine, pentostatin , mechloroethamine , (Zentaris ) , D - 82318 ( Zentaris ) , SC - 12983 (NCI ) , Resvera cyclophosphamide, chlorambucil, meiphalan , ethylenimine, statin phosphate sodium , BPR -OY - 007 (National Health methylmelamine, hexamethlymelamine , thiotepa, busulfan , Research Institutes ), and SSR - 250411 (Sanofi ) . carmustine , lomusitne, semustine , streptozocin , decarba In some embodiments , a therapeutic agent is an anti zine , fluorouracil , floxouridine , cytarabine , mercaptopurine , 55 inflammatory agent. In some embodiments , a therapeutic thioguanine , pentostatin , erbulozole (also known as agent is an anti - TNF agent, an IL - 1 receptor antagonist, an R -55104 ) , Dolastatin 10 (also known as DLS - 10 and NSC IL - 2 receptor antagonist , a cytotoxic agent, an immuno 376128 ), Mivobulin isethionate ( also known as CI- 980 ) , modulatory agent, an antibiotic , a T - cell co - stimulatory Vincristine, NSC -639829 , Discodermolide (also known as blocker, a B cell depleting agent, an immunosuppressive NVP -XX - A - 296 ) , ABT -751 ( Abbott , also known as 60 agent, an alkylating agent, an anti -metabolite , a plant alka E - 7010 ) , Altorhyrtins (such as Altorhyrtin A and Altorhyrtin loid , a terpenoids , a topoisomerase inhibitor, an antitumour C ) , Spongistatins ( such as Spongistatin 1 , Spongistatin 2 , antibiotic , an antibody , a hormonal therapy , an anti - diabetes Spongistatin 3 , Spongistatin 4 , Spongistatin 5 , Spongistatin agent, a leukotriene inhibitor , or combinations thereof. In 6 , Spongistatin 7 , Spongistatin 8 , and Spongistatin 9 ) , some embodiments , a therapeutic agent is selected from : Cemadotin hydrochloride ( also known as LU - 103793 and 65 alefacept, efalizumab , methotrexate , acitretin , isotretinoin , NSC - D - 669356 ) , Epothilones (such as Epothilone A , Epoth - hydroxyurea , mycophenolate mofetil , sulfasalazine, 6 - Thio ilone B , Epothilone C ( also known as desoxyepothilone A or guanine, Dovonex , Taclonex , betamethasone , tazarotene , US 9 ,840 , 537 B2 123 124 hydroxychloroquine, etanercept, adalimumab , infliximab , acetonide, fluocinonide , fluocortin , fluocortolone , fluo abatacept, rituximab , tratuzumab , Anti- CD45 monoclonal rometholone, fluperolone, fluprednidene , fluticasone , for antibody AHN - 12 (NCI ) , Iodine - 131 Anti -B1 Antibody mocortal, formoterol, halcinonide, halometasone , hydrocor ( Corixa Corp .) , anti -CD66 monoclonal antibody BW 250 / tisone , hydrocortisone aceponate , hydrocortisone buteprate , 183 (NCI , Southampton General Hospital) , anti -CD45 5 hydrocortisone butyrate , loteprednol, medrysone, mepred monoclonal antibody (NCI , Baylor College of Medicine ), nisone , methylprednisolone ,methylprednisolone aceponate , antibody anti- anb3 integrin (NCI ) , BIW - 8962 ( Bio Wa Inc . ) , mometasone furoate , paramethasone , prednicarbate , pred Antibody BC8 (NCI ) , antibody muJ591 (NCI ) , indium In nisone , rimexolone, tixocortol, triamcinolone, ulobetasol, 111 monoclonal antibody MN - 14 (NCI ) , yttrium Y 90 Pioglitazone , Rosiglitazone, Glimepiride, Glyburide , Chlo monoclonal antibody MN - 14 (NCI ) , F105 Monoclonal Anti - 10 rpropamide , Glipizide , Tolbutamide , Tolazamide , Glu body (NIAID ) , Monoclonal Antibody RAV12 (Raven Bio cophage, Metformin , (glyburide +metformin ) , Rosiglita technologies) , CAT - 192 (Human Anti - TGF -Betal Monoclo zone+ metformin , (Rosiglitazone + glimepiride ) , Exenatide, nal Antibody, Genzyme) , antibody 3F8 (NCI ) , 177Lu- J591 Insulin , Sitagliptin , (glipizide and metformin ), Repaglinide, (Weill Medical College of Cornell University ) , TB - 403 Acarbose , Nateglinide , Orlistat, cisplatin ; carboplatin ; oxa (Biolnvent International AB ) , anakinra , azathioprine , cyclo - 15 liplatin ; mechlorethamine; cyclophosphamide ; chlorambu phosphamide , cyclosporine A , leflunomide , d -penicillamine , amitriptyline , or nortriptyline , chlorambucil , nitrogen mus cil ; vincristine ; vinblastine ; vinorelbine ; vindesine ; mercap tard , prasterone , LJP 394 (abetimus sodium ), LW 1082 (La topurine ; fludarabine ; pentostatin ; cladribine ; 5 - fluorouracil Jolla Pharmaceutical) , eculizumab , belibumab , rhuCD40L (5FU ) ; floxuridine (FUDR ); cytosine arabinoside; (NIAID ) , epratuzumab , sirolimus , tacrolimus, pimecroli trimethoprim ; pyrimethamine ; pemetrexed ; paclitaxel; doc mus , thalidomide, antithymocyte globulin -equine ( Atgam , 20 etaxel ; etoposide ; teniposide ; irinotecan ; topotecan ; amsa Pharmacia Upjohn ) , antithymocyte globulin -rabbit ( Thymo crine ; etoposide ; etoposide phosphate ; teniposide ; dactino globulin , Genzyme) , Muromonab -CD3 (FDA Office of mycin , doxorubicin ; daunorubicin ; valrubicine ; idarubicine ; Orphan Products Development ), basiliximab , daclizumab , epirubicin ; bleomycin ; plicamycin ; mitomycin ; finasteride ; riluzole , cladribine, natalizumab , interferon beta - 1b , inter goserelin ; aminoglutethimide ; anastrozole ; letrozole ; voro feron beta - la , tizanidine, baclofen , mesalazine, asacol , pen - 25 zole ; exemestane ; 4 -androstene - 3 ,6 , 17 - trione (“ 6 -OXO ” ; tasa , mesalamine , balsalazide , olsalazine , 6 -mercaptopurine , 1 , 4 , 6 - androstatrien - 3 , 17 - dione ( ATD ); formestane ; testolac AIN457 ( Anti IL - 17 Monoclonal Antibody , Novartis ) , the tone ; fadrozole ; A - 81834 ( 3 -( 3 - ( 1 , 1 -dimethylethylthio - 5 ophylline, D2E7 ( a human anti - TNF mAb from Knoll Phar ( quinoline - 2 - ylmethoxy ) - 1 - ( 4 - chloromethylphenyl) indole maceuticals ) , Mepolizumab (Anti - IL - 5 antibody, SB 2 -yl ) - 2 , 2 - dimethylpropionaldehyde oxime - O - 2 - acetic acid ; 240563 ), Canakinumab ( Anti- IL - 1 Beta Antibody, NIAMS) , 30 AME103 ( Amira ); AME803 ( Amira ); atreleuton ; BAY -x Anti -IL - 2 Receptor Antibody (Daclizumab , NHLBI) , CNTO 1005 ( (R ) - ( + ) -alpha - cyclopentyl- 4 - ( 2 - quinolinylmethoxy ) 328 ( Anti IL -6 Monoclonal Antibody, Centocor ), ACZ885 Benzeneacetic acid ) ; CJ- 13610 ( 4 - ( 3 - ( 4 - ( 2 -Methyl - imida ( fully human anti - interleukin - 1beta monoclonal antibody, zol- 1 -yl ) -phenylsulfanyl ) -phenyl ) - tetrahydro -pyran -4 Novartis ), CNTO 1275 (Fully Human Anti - IL - 12 Monoclo carboxylic acid amide ); DG -031 (DeCode ); DG -051 nal Antibody, Centocor ), ( 3 S ) - N -hydroxy -4 - { { 4 - [ (4 -hy - z (DeCode ); MK886 ( 1 - [ ( 4 - chlorophenyl) methyl ] 3 - [ ( 1 , 1 - di droxy - 2 -butynyl ) oxy ] phenyl} sulfonyl ) - 2 , 2 - dimethyl - 3 35 methylethyl) thio ]- a ,a -dimethyl -5 - (1 -methylethyl ) - 1H - in thiomorpholinecarboxamide ( apratastat ) , golimumab dole - 2 - propanoic acid , sodium salt ) ; MK591 ( 3 - ( 1 - 4 [ ( 4 (CNTO 148 ), Onercept, BG9924 ( Biogen Idec ), Certoli chlorophenyl) methyl ]- 3 -[ (t - butylthio )- 5 - ( 2 - quinoly) zumab Pegol (CDP870 , UCB Pharma ), AZD9056 ( Astra methoxy ) - 1H - indole - 2 ] -, dimethylpropanoic acid ) ; Zeneca ), AZD5069 ( AstraZeneca ), AZD9668 ( AstraZen RP64966 ( [ 4 - [ 5 - ( 3 -Phenyl - propyl ) thiophen - 2 -yl ] butoxy ] eca ), AZD7928 (AstraZeneca ), AZD2914 (AstraZeneca ), 40 acetic acid ); SA6541 (( R ) - S -[ [4 - ( dimethylamino ) phenyl] AZD6067 (AstraZeneca ) , AZD3342 ( AstraZeneca ), methyl] - N - (3 -mercapto - 2methyl- 1 -oxopropyl - L -cysteine ) ; AZD8309 ( AstraZeneca ) ,) , [( 1R ) - 3 -methyl - 1 -( { (2S ) - 3 -phe SC - 56938 ( ethyl- 1 - [ 2 - [ 4 - ( phenylmethyl) phenoxy ] ethyl) - 4 nyl- 2 - [ ( pyrazin - 2 - ylcarbonyl) amino ] propanoyl } amino ) bu piperidine - carboxylate ) ; VIA - 2291 (Via Pharmaceuticals ) ; tyl] boronic acid (Bortezomib ) , AMG -714 , ( Anti - IL 15 WY - 47 , 288 ( 2 - [ ( 1 - naphthalenyloxy )methyl ] quinoline ) ; Human Monoclonal Antibody , Amgen ) , ABT- 874 ( Anti 4545 216zileuton ; ZD - 2138 (6 - ( ( 3 - fluoro - 5 - ( tetrahydro - 4 -methoxy IL - 12 monoclonal antibody , Abbott Labs ), MRA ( Tocili 2H -pyran - 4yl) phenoxy )methyl ) - 1 -methyl - 2 ( 1H ) - quinloli zumab , an Anti IL - 6 Receptor Monoclonal Antibody, Chugai none ); doxycycline; or combinations thereof. Pharmaceutical) , CAT- 354 (a human anti- interleukin - 13 Starting Materials monoclonal antibody , Cambridge Antibody Technology , Disclosed herein , in certain embodiments , are molecules MedImmune ), aspirin , salicylic acid , gentisic acid , choline 50 of Formula 11 , having the structure : magnesium salicylate , choline salicylate , choline magne sium salicylate , choline salicylate, magnesium salicylate , A1- X , - B . ; Formula II sodium salicylate , diflunisal , carprofen , fenoprofen , feno profen calcium , flurobiprofen , ibuprofen , ketoprofen , nabu tone , ketolorac , ketorolac tromethamine, naproxen , oxapro X , is a cleavable linker ; zin , diclofenac , etodolac , indomethacin , sulindac , tolmetin0 -, 55 is a peptide with a sequence comprising 5 to 9 acidic meclofenamate , meclofenamate sodium , mefenamic acid , amino acids and having a first reactive amino acid piroxicam , meloxicam , celecoxib , rofecoxib , valdecoxib , moiety ca ; parecoxib , etoricoxib , lumiracoxib , CS -502 (Sankyo ), JTE B , is a peptide with a sequence comprising 7 to 9 basic 522 ( Japan Tobacco Inc. ) , L - 745 , 337 ( Almirall ) , NS398 amino acids and having a second reactive amino acid ( Sigma) , betamethasone (Celestone ), prednisoneon (DeltaDolto - 6060 moiety CB ; and sone ) , alclometasone. aldosterone , amcinonide. beclometa - A1 - X1 -B1 has a third reactive amino acid moiety Cmon A , sone , betamethasone , budesonide, ciclesonide, clobetasol, or X?; and clobetasone , clocortolone , cloprednol, cortisone , cortivazol, wherein CA is capable of reacting with a first cargo moiety deflazacort , deoxycorticosterone , desonide , desoximeta - comprising DA, CB is capable of reacting with a second cargo sone , desoxycortone, dexamethasone , diflorasone , diflucor- 65 moiety comprising DB , and cm is capable of reacting with a tolone , difluprednate , fluclorolone , fludrocortisone , macromolecular carrier comprising M to form a molecule of fludroxycortide , flumetasone, flunisolide , fluocinolone Formula I . US 9 , 840 ,537 B2 125 126 In some embodiments , the c A , CR, and cy have functional wherein o represent 5 - ( amino - 3 -oxapentanoyl ) ; F (4 -Ac ) rep groups that are orthogonally reactive. In some embodiments , resent para - acetyl - ( L ) - phenylalanine ; and C (Me ) represents CA , CB , and cy are each independently selected from a S -methyl - (L )- cysteine . naturally occurring amino acid or a non -naturally - occurring In some embodiments , the molecule further comprises a amino acid . In some embodiments , CA , CR , and cw are each 5 polyethylene glycol (PEG ) polymer. In some embodiments , independently selected from a D amino acid , a L amino acid , the PEG polymer is covalently linked to the molecule at the an a -amino acid , a ß - amino acid , or a y -amino acid . In some F (4 - Ac ) subunit. In some embodiments , the molecule com embodiments , C4 , CB , and cy are each independently selected prises groups that can be orthogonally reacted . In some from any amino acid having a free thiol group , any amino embodiments , the groups that can be orthogonally reacted acid having a N - terminal amine group , and any amino acid 10 are chosen from : an amine , thiol and an acetyl phenylala with a side chain capable of forming an oxime or hydrazone nine . In some embodiments , the molecule comprises an bond upon reaction with a hydroxylamine or hydrazine amine, a thiol , and an acetyl phenylalanine . group . In some embodiments , CA , CB , and cy are each In some embodiments , the PEG polymer has an average independently selected from D - cysteine , D - glutamate , molecular weight of 500 daltons. In some embodiments , the lysine , and para - 4 - acetyl L - phenylalanine . In some embodi- 15 PEG polymer has an average molecular weight of 2 , 000 ments , CB is any amino acid having a free thiol group . In daltons. In some embodiments, the PEG polymer has an some embodiments , Cp is D -cysteine . In some embodiments , average molecular weight of 5 , 000 daltons. In some embodi CA is any amino acid having a N -terminal amine group . In ments , the PEG polymer has an average molecular weight of some embodiments , c , is D - glutamate . In some embodi- 10 , 000 daltons . In some embodiments , the PEG polymer has ments, c , is lysine. In some embodiments , cv is any amino 20 an average molecular weight of 20 ,000 daltons . In some acid with a side chain capable of forming an oxime or embodiments , the PEG polymer has an average molecular hydrazone bond upon reaction with a hydroxylamine or weight of 40 , 000 daltons . Disclosed herein , in certain hydrazine group . In some embodiments , Cy is para - 4 -acetyl embodiments , is the use of the molecule in the synthesis of L - phenylalanine . a molecule according to Formula I . As used herein , “ orthogonally reactive” means a plurality 25 Disclosed herein , in certain embodiments , is a molecule of groups can be attached to a molecule via a sequence of having the amino acid sequence : reactions that do not cross react enabling specific attachment ( D -Glu ) 5- 0 -Pro - Leu -Glys -Cys (me ) -Ala -Gly - ( D - Arg ) s of each group in the presence of the others . In some ( D - Cys )- [ PEG (36 ) ] embodiments , the three groups (DA , DR, and Dw ) are able to wherein all glutamates and arginines are D -amino acids; o be attached to A1- X - B , via CA, CB , and cm using a sequence 30 represents 5 - ( amino - 3 - oxapentanoyl) ; C (me ) represents of 3 independent reactions that do not cross react so that S -methyl - ( L ) -cysteine ; and PEG ( K ) represents a -amino - w each group is attached to only one site on A - X - B . amide poly ( ethylene glycol ) with an average three thousand Disclosed herein , in certain embodiments , is a molecule Dalton molecular weight. In some embodiments , the mol having the amino acid sequence: ecule further comprises a fluorescent moiety . Disclosed (D -Glu ) , F (4 - Ac) - o- Pro - Leu -Gly -Cys ( Me ) - Ala -Gly herein , in certain embodiments , is the use of the molecule in ( D - Arg ) : - ( D - Cys ) the synthesis of a molecule according to Formula I . US 9 ,840 , 537 B2 127 128

NH2 HS SH

N HN HNCNH, = HN HN HÀNH H

= NH HN HNCNH, 'NH HNCNH, HN HN HNNHHNVNHHANNHHN,NH UOVO H?N

: HN NH HN HNCNH, HN H?N jyTNT NH HN O N NH HNCNH, HN_NH HN my

ZI PeptideP-2 " Peptide-1P

öt N HN OH to noto

H OOH HN noto

N HOO noto LeeLivein TZ HOGO.HO hoto OOHOOH H2N US 9 ,840 , 537 B2 129 130

"SH SH

? Ö NH NHINH HNCNH, HN. HN NH HNHN. HNNHHN-NH NH HNCNH, SNH'NH HNCNH, HNHN SNH HNNHHNQNHH?N,NH NH HN NH HNCNH, HN CNH NH HN.

NH HNCNH, HN HNNH HN

PeptideP-3 PeptideP-4 -continued

o ???? ??? ???? ??? OH ???? ??? ???? OOH ???? ???? US 9 ,840 , 537 B2 131 132

NH2 HS

NH2 SH O NHHN HNCNH, HN

IZ HN H?NNHI HN HN HNCNH, HNNHHÀNHH?NNH HN IZ NHNH H?NCNH HN HNNH2 HN HNCNH, HN HN H?NCNH HN O NH“HN HNCNH, HN

IZ NH HN(NH HN HNNH

NH PeptideP-5 -continued PeptideP-6

" ÖNH NHO ?Y OOH OH OH HOGO 01OH OH

HOO 0oH OOH OOH US 9 ,840 , 537 B2 133 134

NH2 THN

H OH HOGO ???? .ii OOH HN. ????

'NH NH HN*NH,HNCNHHN?NH |HN?NHHN?NH

HN iì

ì PeptideP-8 -continued ?YNTINTUNTYNYNTYNYvozNH PeptideP-7 NH ÜliONUN HNHN. HN(NH egrunde *NH HN HNCNH,HN?NH 'NH'NHSNH NH HN(NH HN OH NH OOHOH H?NCNH HNHN

0OH Mw=2,000 US 9 ,840 , 537 B2 135 136

NH NH2 MNH2 0 OH ???? TYNY".Try 000Mw=3, ???? OOH SH ???? NH NH N HN. ANH H?N ANHNH HANVNH HN HNCNH,HNNH NH NH HNVNH HN IZ HN PeptideP-9 HN continued- -CNH HNVNH PeptideP-10

)

NHHN. HNCNH, HN

HN. HNCNH, HNNHHANHHNNH HN NHHN HNCNH, HN tition

NH HNCNH, ??? HN iTYTTTTTTTTTT04OH ??? 04OH compeMw=5,000 ?,?? DELL US 9 ,840 , 537 B2 137 138

NH2 NH2 SH HS.

NH IZ HN. HNCNH, NH 0 H?N

NH? NH HNCNH, HN. H?N

NH HNCNH, HNNH NH NH HNCNH, HN. HNNH NH

Inn PeptideP-12 -continued hetopenbare PeptideP-11 NHÀ

ZT OH HOO HOO OOH HO

O OnNH H2N US 9 ,840 , 537 B2 139 140

HN SHSH HS

N IZ NHHN HNNH, "NH HN HNNH,

NH HN HNCNH, N NH HN. HN H?N H2NNHH2NNH HN *NH HN HNCNH, HN. HNNH HN H2NNHHUNNH N HNCNH, HN NH HNCNH, HN H2NNH HNHN IZ

PeptideP-13 PeptideP-14 -continued OHN IZ NH· Juliusini HO OH OHHO

0 OH HOVO yoHOOH HOOHOGO NHNH2 OOH N HOVO s US 9 ,840 , 537 B2 141 142

NH2 SSHSH SH NH © ?? NH IZ HNNH, HN. SNH H?N NH HN. . H?NNH NH HNCNH, SNH'NH IZ SNH HNCNH,HNNH H?NNH HNHN 'NHHN*NH,HNNHHNCNH NH NH HNCNH, HN(NH HNHN NH NH HNNH,HN.NHHENNHHANNH HNHNHNHNHNHN. NH NH H?N N NH HN NH IZ HNCNH, HANNH HN. SNH ÜYENTANTYNYNTYNYNTYNH, HN eufugiatnungingin OH H?N HNHN OH HN HN(NH, NH HN | PeptideP-15 PeptideP-16 -continued PeptideP-17 .NH

o HN-NH2 HN

IZ HNNH2 HN om HO0 OH OYOHOOH NIH odom HO0 N OH OYOH OOH OHH HO0 odon OYOH IZ oohooh cuiry OOHOH manyyearsthelimited HO. Nihlilmilelih HO0 Oy,OH US 9 , 840 , 537 B2 143 144 EXAMPLES mobile phase consisted of a water ( 0 .05 % TFA )( solvent A ) /acetonitrile (0 .05 % TFA )( solvent B ) gradient. Materials and Methods Centrifugation was carried out at 4° C . with an Eppendorf HPLC - grade acetonitrile was purchased from Fisher Sci centrifuge 5810R or a Beckman Microfugeg® 18 . entific (Phillipsburg , Pa . ). Purified water was collected 5 through Milli - Q water purification system (Millipore , Bed Exemplary materials for synthesis of the selective deliv ford , Mass . ) . 3 -Maleimidopropionic acid - Pfp ester was pur ery molecules disclosed herein include , but are not limited chased from Molecular Biosciences (Boulder , Colo . ). PBS to , any of peptides P - 1 , P -2 , P - 3 , P -4 , P -5 , P - 6 , P -7 , P -8 , P - 9 , EDTA buffer was purchased from Teknova (Hollister , P - 10 , P - 11, P12 , P - 13 , P - 14 , P - 15, P - 16 , and P - 17 . Calif .) . Trifluoroacetic acid ( TFA ) , Dimethylformamide 10 The above starting materials are summarized below : (DMF ) and N -methylmorpholine (NMM ) were supplied by Sigma- Aldrich (Milwaukee , Wis . ) . A -Mercaptoethyl - w methoxy , poly -oxyethylene (Mw 2 ,000 , 5, 000 , 20 ,000 and Peptide Sequences 40 ,000 ) [mPEG ( 2K ) -SH , mPEG (5K ) -SH , mPEG ( 20KUN )) - SH SH , 15 Peptide P - 1 eeeeeeeeeOPLGC ( Me) AGrrrrrrrrrc mPEG ( 40K ) -SH ] and a - aminoxyl- w -methoxy , polyoxyeth ylene (Mw 2, 000 , 5, 000 , 20 ,000 and 40 ,000 ) [mPEG (2K ) Peptide P - 2 eeeeeoPLGC (Me ) AGrrrrrrrrc ONH , , MPEG ( 5K ) -ONH2 , mPEG ( 20K ) -ONH2 , mPEG Peptide P - 3 eeeeeF (4 - Ac )OPLGC (Me ) AGrrrrrrrrc (40K ) -ONH2 ] were purchased from NOF America Corporation ( Irvine , Calif .) . mPEG ( 1K ) - NHNH , was pur- 20 Peptide P - 4 eeeeeeeeeF ( 4- Ae ) OPLGC (Me ) AGrrrrrrrrrc chased from Nanocs (New York ). IRDye 800CW maleimide (Mal - IRDye ) and IRDye 750 succinimidyl ester were sup Peptide P - 5 (Ac ) eeeeeOPLGC (Me ) AGrrrrrrrrck plied by Li- Cor Biosciences (Lincoln , Nebr. ) . Lyophilized Peptide P - 6 eeeeeOPLGC (Me ) AGOF (4 - Ac ) rrrrrrrrc peptides P1- P17 were prepared using standard resin based Peptide P - 7 eeeeeeeeeOPLGC (Me ) AGrrrrRRRRRCOF (4 -Ae ) peptide coupling methods. 25 LC -MS analysis was carried out on an Agilent 1200 SL Peptide P - 8 [MPEG ( 2K ) ] crrrrrrrrPLGC (Me ) AGoeeeeek series in combination with AB SCIEX API 3200 , equipped with CTC PAL autosampler operating at 4° C ., a vacuum Peptide P - 9 [mPEG (5K ) ]crrrrrrrrPLGC (Me ) AGoeeeeek degasser , binary pump, UV - VIS detector, associated Analyst Peptide P - 10 eeeeeoPLGC (Me ) AGrrrrrrrrc [PEG (36 ) ] 1 . 5 analytical software and a Phenomenex column (Kinetex 3 Abbreviations : Standard i letter amino acid abbreviations were used in all the 2 . 6u C18 100A , 100x2. 1 mm ) or a Waters 2695 separation sequences . Lowercase characters indicated D - amino acids . All module equipped with a Waters 2487 dual à absorbance peptides were amidated at C - terminus . O : 5 - ( amino - 3 - oxapentanoyl ) ; F ( 4 - Ac ) : para - acetyl - ( L ) - phenyl detector in combination with Finnigan LCQ Deca XP mass alanine ; C (Me ) : S -methyl - ( L ) - cysteine . spectrometer . The equipment is associated with Xcalibur PEG ( 3K ) : a - amino - w - amide poly (ethylene glycol ) with an aver aged three thousand Daltons molecular weight ; analytical software and a Peeke Scientific column ( Titan 200 MPEG ( 2k ) : a - carboxy - w -methoxy poly ( ethylene glycol) with an averaged two thousand Daltons molecular weight ; 5 um , C18 -MC , 50x2 . 1 mm ) . MPEG ( 5k ) : a - carboxy - 0 -methoxy poly ( ethylene glycol ) with an Preparation HPLC were carried out on an Agilent system averaged five thousand Daltons molecular weight . ( Agilent 1200 series ) and a Thermo Scientific column (Hy AC : acetyl . persil Gold C18 , 5u , 250x10 mm ), or a Waters Delta Prep 10 preparative HPLC System and a Varian column (F75L , C18 , 15u , 1200 g ) , or a Waters PrepLC System equipped with a Example 1 Waters 2487 dual Nabsorbance detector , Fraction Collector III, Masslynx software and a Thermo Scientific column (Hypersil Gold C18 , 5u , 250x10 mm ) or a Phenomenex column ( luna, C18 ( 2 ) , 5u , 100A AX 150x30 mm ) . The Synthesis of SDM - 2 from Peptide P -1 US 9 ,840 , 537 B2 145 146

ASO3H SO3H

14HN0| HNVOPfpNMM,DMF20h HNHNHNHN N enhoeonsonyou ÖONHHOHOHOH NMM,DMF1h MalCW800-IRDye HÖ–HÖ

P-1 VN' CHALI

HO-H ??0 ??0

NXNNN ??0 O ??0 OOHOH iN ?????? HOHNAN ??0

HOS Na HOS SO3H HNNYOE HOS yolyang poco N HN,HN,HN| moreand OE 0 HNNHHN,NH H YN H?????*???? UH IHNNYANINEN CNHNHANHNH TZ COOHHNTÖiöü3ìö3À? II L HN, HOSNH CHNNHCHÁNH HN?NHH?NH IT H U LILILILILNILNINY

N H 0 O

? 20h7.4,PBSMPEGSH|PH(40K)- SDM-2 -continued NUHOH=0

5 II

H H119118119118HHT5116151561551565FO NYNY HHà6?2| OOHOH OH HOOHOYO

Hoo HOOHO N

65H2

Mw=40,000 toyou US 9 , 840 , 537 B2 149 150 Synthesis of Intermediate 5 To a solution of peptide P - 1 ( 8 mg, 2 . 1 umol) in DMF ( 0 . 8 mL ) at room temperature in the dark were added IRDye 800CW maleimide ( 2 mg, 1 . 7 umol) and N -methylmorpho line ( 10 UL , 91 umol ) with stirring . The reaction was 5 followed by LC -MS and usually completed in 1 h . The mixture was directly used in the next step without further purification . To the reaction mixture above was added 3 -maleimido propionic acid -Pfp ester ( 2 mg, 6 . 0 umol) . The resulting 10 mixture was stirred at room temperature in the dark for 20 h . Purification by RP - HPLC afforded intermediate 5 ( 2 . 1 mg, 22 % for two steps) . Calculated : [ M + 3H ] 3 + (C187H290N5 , 06486 ) m / z = 1526 . Found ESI: [ M + 3H ] 3 + (C187H290N5906486 ) m /z = 1526 . 15 Synthesis of Selective Delivery Molecule SDM -2 The mixture of intermediate 5 ( 1 . 5 mg , 0 . 27 umol) and mPEG (40K ) -SH ( 10 mg, 0 .25 umol) in PBS - EDTA buffer ( 0 .5 mL , 137 mM NaCl, 7 mM Na2HPO4, 3 mM KC1, 1 .4 mM K3PO4, 4 mM EDTA , pH 7 . 4 ) was stirred at room 20 temperature in the dark for 20 h . Purification by RP -HPLC afforded selective delivery molecule SDM - 2 ( 7 . 0 mg, 61 % ) . Selective delivery molecules SDM - 1 , SDM - 3 , SDM - 4 , and SDM - 5 were prepared analogously to SDM - 2 from peptide P - 1 . 25 Example 2 Synthesis of SDM - 6 from Peptide P - 2 US 9 ,840 , 537 B2 151 152

SO3H YNYNH2 SH SH

"NH

O NH 03S YNH OHOOHHOy HN*NH,HN?NHHNCNH haat,suremakeway HNNHHN?NHHN*NH NH NH 03 NH UH H O 1 HN*NH,HN?NH HNVNHH?N,NHNHI H 'NH

? O = Jin ZI HNHN anyor MM,DMF5h 9

P-2 0oCNH-02 ? opinios Cy5-Mal NMM,DMF1h OHOHOH de

JOOHN ?????????? oohOOHOH LH Ho?0 ??? o????? ???0 H2NY US 9 ,840 , 537 B2 153 154

SO3H MSO3H

0 HN plantaladeunaperasHNE OR 0

-S 0

1 NH HN 0 ?NH'NH

OH 0 HN*NH,HNNHHN?NH

H HN_NHHNNHHNqNHHÀNH HN 1 OB HNNHH?N,NH H?NH,HNCNH IZ 'NH HGHOO HN 1

| HNHNHNHN N O = SDM-6 UHH .111 -continued (8 IZ03 mPEG(40K)-SHPH7.4,PBS20h | - ZI 7 hu 0 O =

N N O = H |0obNHH.

- ZI O = OONHHNO O ???? HOHni HO OH ???

) 0OH

??0 ??? IZ 03 ?????? ?? vyrorecotropinsime OHOH 0 0 Mw=40,000 H otot US 9 , 840 , 537 B2 155 156 Synthesis of Intermediate 7 To a solution of peptide P - 2 (378 . 5 mg, 0 . 1 mmol) in DMF (25 mL ) at room temperature in the dark were added Cy5 maleimide (87 mg, 0 .09 mmol) and N -methylmorpho line ( 350 UL , 3 . 2 mmol) with stirring. The reaction was 5 followed by LC -MS and completed in 1 h . The mixture was directly used in the next step without further purification . To the reaction mixture above was added 3 -maleimido propionic acid - Pfp ester ( 50 mg, 0 . 15 mmol) . The resulting mixture was stirred at room temperature in the dark for 5 h . 10 Purification by RP -HPLC afforded intermediate 7 (108 mg, 27 % for two steps ). Calculated : [M + 2H ] 2+ (C143H235N5104494 ) m / z = 1780 . Found ESI: [ M + 2H ]2 + (C148H235N5104484 ) m /z = 1780 . Synthesis of Selective Delivery Molecule SDM -6 15 The mixture of intermediate 7 ( 95 mg, 21. 2 umol) and mPEG (40K ) - SH ( 0 . 9 g , 22 .5 umol ) in PBS - EDTA buffer ( 40 mL , 137 mM NaCl, 7 mM Na2HPO4, 3 mM KC1, 1 .4 mM K3PO4 , 4 mM EDTA , pH 7 . 4 ) was stirred at room tempera ture in the dark for 20 h . Purification by RP -HPLC afforded 20 selective delivery molecule SDM - 6 ( 0 .85 g , 90 % ) . Selective delivery molecules SDM - 7 and SDM - 8 were prepared analogously to SDM - 6 from peptide P - 2 .

Example 3 25 Synthesis of SDM -25 from Peptide P - 3 US 9 ,840 , 537 B2 157 158

HOS

.0 NH2

H OzS. H ? . .HN HN CNH HN. 0 TANINYOHLNHS H = O ?? : IZ NH |HN, NH 0 (HN;NHCHÁNH, (HNNHHNENHCHÁNH H = 0 H?NNH,NHI NO ?Hx65H . ,. IZ HN. HN?NHH?NH 0 NH H HOH NHA! Os ' za HN. '' ZE AzNH OK HN. Oz IZ HNHNHNHN 8 NMM,DMF1h IZ NMM,DMF36h O = OH= Cy7-NHS Cy5-Mal in OR P-3 = O IZ 9010HHN6 oOHNHLo H

O = ??0

H?OS SOH

038 O. THNYNOH S HN ?HNLNLNLNYSOHO- NH HN NH HNNHHÀNHHN,NHH?N CHN;NHCHÁNHHNNH( HN^NHHNXNH |HN,.HNNHCHÁNH( NYNYN HN NYYNY NH

N HN HNOoOH HNHNHNHN, NH .??????HHN?? OHOH HNHNHNHN H IZ

. 220mManiline,24H OF SDM-25 JpH3.0,1MGlycine IZ -continued 000*7=MW NETNI O MPEG(2K)-ONH2P5 ofotvo

HO?o ???? notohoto ??-?? HOO honete?-????? HOCO ???? Hosemenaliparazoals resultanangel.com US 9 , 840 ,537 B2 161 162 Synthesis of Intermediate 8 intermediate 9 ( 28 . 1 mg, 25 % ) and intermediate 8 (63 mg) . To a solution of peptide P - 3 (200 mg, 49 .6 umol) in DMF Calculated : [M + 3H ]3 + (C18H282N5305 , S . ) m / z = 1421. ( 5 mL ) at room temperature in the dark were added Cy5 Found ESI : [ M + 3H ]3 + (C187H282N5305 . S . ) m / z = 1421. maleimide (60 mg, 65 . 6 umol) and N -methylmorpholine ( 80 Synthesis of Selective Delivery Molecule SDM - 25 ul , 0 .73 mmol) with stirring . The reaction was followed by 5 The mixture of intermediate 9 (28 . 1 mg 5 . 4 umol) and LC -MS and completed in 1 h . Ether (40 mL ) was added to MPEG ( 2K ) -ONH , ( 17 mg. 7 . 6 umol) in glycine buffer ( 4 the mixture . The precipitate was collected after centrifuge , mL, 0 . 1 M , 20 mM aniline , pH 3 . 0 ) and acetonitrile (0 . 8 mL ) washed with ether (40 mLx2 ) and purified by HPLC to was stirred at room temperature in the dark for 24 h . After afford intermediate 8 ( 141 mg, 61 % ) . the reaction was complete , acetophenone ( 10 UL , 86 umol) Calculated : ( M + 3H ] * * (C152H242N5104394 ) m / z = 1200 . 10 was added . The mixture was stirred at room temperature for Found ESI: [ M + 3H ] 3 + (C152H242N51043S4 ) m / z = 1200 . 2 h . Purification by RP -HPLC afforded selective delivery Synthesis of Intermediate 9 To a solution of intermediate 8 ( 101 mg, 21 . 8 umol) in molecule SDM - 25 (25 mg, 63 % ) . DMF ( 10 mL ) at room temperature were added Cy7 car Selective delivery molecules SDM - 9, SDM -10 , SDM -22 , boxylic acid , succinimidyl ester ( 40 mg, 41. 1 umol) and 15 SDM - 23 , SDM - 24 , SDM - 26 , SDM - 27 , SDM - 29 and SDM N -methylmorpholine ( 0 . 2 mL , 1 . 8 mmol) . The resulting 31 were prepared analogously to SDM - 25 from peptide P - 3 . mixture was stirred at room temperature in the dark for 36 h . Ether ( 35 mL ) was added to the mixture. The precipitate Example 4 was collected after centrifuge and washed with ether (40 mLx2 ). Purification of the mixture by RP -HPLC afforded Synthesis of SDM - 15 from Peptide P - 4 US 9 ,840 , 537 B2 191 164

SO3H

SO3H O3Sy S Z IHO NN ?? 'NH HN*NH, HS. "'SH HN,NHH?NI. IZ

03S N: HN,HN,HN HOH OHONÜNNINNNH NN LH N OE HO 0 NINAINTUNENINH, HNNH,HN*NH H HN*NH, TZ 'NH TN. 'NH 12NLNANOTE ] HNNHH?N,NH HNNHHÀNHH?NNHNHA OE HN, ?? N 20mManiline,24h HN, N. OE - 1 N O GlycineM10.,3PHONH2K)-mPEG( OHOONY N 12 NUN 0HN 11 Z HN OE - OE -

O Cy5-Mal NMM,DMF1h Cy7-NHS NMM,DMF48h P-4 HNINN© ON oohOOH OH 3020HOOHOHOqohou ?????????N?( ??? OOH OHOOH OOHOH NANNY 0 H2N'NONNYYNEWYE?Ö HOHOHOHOHO H OOHOSOHOLOH OHOOHOHOI" conyTotaandeof HO H2NNYN HNIN US 9 ,840 , 537 B2 165165 166

SO3H

0740

HN?NH,HNNH* 'NH HN,HN NNNNNNH2 Mw=2,HNNHH?NNHHN 07"YOHOHONONIN INLINZI

IZ 0OHOLOHOOHP (HO??? ??????????? ?????????? SO3H NNT.N werkenaan US 9 , 840 , 537 B2 167 168 Synthesis of Intermediate 11 To a solution of peptide P - 4 ( 30 mg, 6 .2 umol ) in DMF ( 2 mL ) at room temperature in the dark were added Cy5 maleimide ( 7. 5 mg, 8. 2 umol) and N -methylmorpholine ( 15 uL , 0 . 14 mmol) with stirring . The reaction was followed by 5 LC -MS and completed in 1 h . The mixture was purified by HPLC to afford intermediate 11 ( 19 . 7 mg, 59 % ) . Calculated : [ M + 3H ] 3 + ( C , H , N5 , 056S _ ) m / z = 1424 . Found ESI: [ M + 3H ] 3 + (C178H22N59056S4 ) m / z = 1424 . Synthesis of Intermediate 12 To a solution of intermediate 11 ( 15 mg, 2 . 8 umol) in 10 DMF ( 1. 5 mL ) at room temperature were added Cy7 car boxylic acid , succinimidyl ester ( 4 mg, 4 . 3 umol) and N -methylmorpholine ( 10 UL , 91 umol) . The resulting mix ture above was stirred at room temperature in the dark for 48 h . Purification by RP -HPLC afforded intermediate 12 ( 5 . 0 15 mg, 30 % ) . Calculated : [ M + 3H ] 3 + (C213Hz22N6 , 0 . S ) m / z= 1645 . Found ESI: [ M + 3H ]3 + (C213H322N6106396 ) m / z = 1645. Synthesis of Selective Delivery Molecule SDM - 15 The mixture of intermediate 12 ( 1 . 1 mg , 0 . 18 umol) and 20 mPEG ( 2K ) -ONH , ( 1 mg, 0 . 5 umol) in glycine buffer ( 1 mL , 0 . 1 M , 20 mM aniline , pH 3 . 0 ) and acetonitrile ( 0 . 2 mL ) was stirred at room temperature in the dark for 1 day . Purification by RP -HPLC afforded selective delivery molecule SDM - 15 ( 0 . 6 mg, 42 % ) . Selective delivery molecules SDM - 11, SDM -12 , SDM 13 , SDM - 14 and SDM - 28 were prepared analogously to SDM - 15 from intermediate 11 . Example 5 30 Synthesis of SDM - 16 from Peptide P - 5 US 9 ,840 , 537 B2 169 170

SO3. SO3H v no

NH2 HN

NH2 SSHSH NH2

N H?NNHI NH

NH*?? HNCNH,HN?NH HNVNHH?N,NH SNH'NH'NH HNCNH, HN- H?NNH, NHNH

NH OPfpNMM,DMF5h YNTYNTYNYINTYNYTNYYNT 19

NMM,DMF1h EZ Cy5-Mal P-5 hiphopanemas N

?? ?????? HO0 ?????? ???????? HO0 o?? US 9 ,840 , 537 B2 171 172

$03 SO2 SO3 SOH

+ N protanto 000Mw=40,Mw=40,000 vo IZ NH2

0 HN O

NH NH H?NNHNH?HNA HN. HN.

NHNH IZ NH HN. HN. O HN 'NHANH HNCNH, H HN?NH,HNCNH

. NH H2NNH 0 HN. HN. H?NNH

? SDM-16 20 NH -continued HN. 0 ANH ????? MPEG(2K)-SHpH7.4,PBS20h HN NH iTNTYTTINTININTIT 14 0 Or 0oCNHH ÖONHH

??? ???? ???? OOH ??? ??? ???? 0OH ?,?? ?,??