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United States Patent ( 10) Patent No US010328026B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 328 , 026 B2 Thaxton et al. (45 ) Date of Patent: * Jun . 25 , 2019 ( 54 ) SYNTHETIC NANOSTRUCTURES (58 ) Field of Classification Search INCLUDING NUCLEIC ACIDS AND /OR CPC .. .. .. .. A61K 9 / 127 OTHER ENTITIES See application file for complete search history . (71 ) Applicant: Northwestern University, Evanston , IL (56 ) References Cited (US ) U . S . PATENT DOCUMENTS (72 ) Inventors : C . Shad Thaxton , Chicago , IL (US ) ; 5 ,472 , 881 A 12 / 1995 Beebe et al. Chad A . Mirkin , Wilmette , IL ( US) ; 5 , 814 ,666 A 9 / 1998 Green et al . Kaylin M . McMahon , Chicago , IL 5 , 955 , 589 A 9 / 1999 Cook et al. (US ) ; Sushant Tripathy , Evanston , IL 6 , 274 , 337 B1 8 / 2001 Parce et al. (US ) ; Raja Kannan Mutharasan , 6 , 361, 944 B1 3 / 2002 Mirkin et al. 6 ,506 , 564 B1 1 / 2003 Mirkin et al. Chicago , IL ( US ) ; David M . Leander , 6 ,677 , 153 B2 1 / 2004 Iversen St. Louis , MO (US ) ; Andrea Luthi, 7 ,691 , 414 B2 4 / 2010 Sligar et al. Evanston , IL (US ) 7 , 951 ,453 B25 / 2011 Debertret et al . 8 ,323 ,686 B2 * 12/ 2012 Mirkin .. A61K 9 / 1275 424 / 450 ( 73 ) Assignee : Northwestern University, Evanston , IL 8 ,933 ,046 B2 1 / 2015 Machuy et al . (US ) 9 , 216 , 155 B2 8 /2015 Thaxton et al. 9 , 532 , 948 B2 1 / 2017 Mirkin et al. ( * ) Notice: Subject to any disclaimer , the term of this 9 ,693 , 957 B2 7 / 2017 Lin et al. patent is extended or adjusted under 35 2003 /0147966 AL 8 / 2003 Franzen et al . U . S . C . 154 (b ) by 3 days . 2004 /0038891 A1 2 /2004 Bisgaier et al . This patent is subject to a terminal dis (Continued ) claimer. FOREIGN PATENT DOCUMENTS (21 ) Appl. No. : 14/ 963, 881 CN 1474831 A 2 / 2004 CN 102036652 A 4 / 2011 ( 22) Filed : Dec . 9 , 2015 (Continued ) (65 ) Prior Publication Data OTHER PUBLICATIONS US 2016 / 0184226 A1 Jun . 30 , 2016 Wolfrum et al. (Nature Biotechnology . Oct . 2007 ; 25 ( 10 ) : 1149 1157 ) . * Related U . S . Application Data Kim et al . (Molecular Pharmaceutics . 2008 ; 5 ( 4 ) : 622 -631 ). * Continuation of application No . 14 / 215, 569, filed on Thaxton et al. ( J . Am . Chem . Soc . 2009 ; 131 : 1384 - 1385 , published (60 ) on web Jan . 9 , 2009 ) . * Mar . 17 , 2014 , now Pat. No. 9 , 216 , 155 , which is a International Search Report and Written Opinion for PCT/ US2013 / division of application No . 13 /522 ,827 , filed as 027431 dated Jun . 13 , 2013 . application No. PCT /US2011 / 021753 on Jan . 19 , International Preliminary Report on Patentability dated Sep . 4 , 2014 2011 , now abandoned . for PCT /US2013 / 027431 International Preliminary Report on Patentability dated Feb . 25 , (60 ) Provisional application No . 61/ 424 , 904 , filed on Dec . 2016 for PCT/ US2014 /050963 . 20 , 2010 , provisional application No. 61 / 365 , 987 , filed on Jul. 20 , 2010 , provisional application No . ( Continued ) 61/ 296 , 373 , filed on Jan . 19 , 2010 . Primary Examiner — Scott Long ( 74 ) Attorney , Agent, or Firm — Wolf, Greenfield & (51 ) Int. Cl. Sacks, P . C . A61K 9 / 127 ( 2006 .01 ) A61K 31/ 7088 ( 2006 .01 ) ( 57 ) ABSTRACT B82Y 5700 ( 2011 . 01) Articles , compositions, kits , and methods relating to nano C12N 15 / 87 ( 2006 . 01) structures , including synthetic nanostructures, are provided . A61K 9 /51 ( 2006 . 01 ) Certain embodiments described herein include structures A61K 47 /54 ( 2017 . 01 ) having a core -shell type arrangement ; for instance , a nano A61K 47 /69 ( 2017 .01 ) structure core may be surrounded by a shell including a C12N 15 / 11 ( 2006 .01 ) material , such as a lipid bilayer , and may include other ( 52 ) U . S . CI. components such as oligonucleotides. In some embodi CPC . .. .. .. A61K 9 / 127 ( 2013 . 01 ) ; A61K 9 / 1271 ments , the structures, when introduced into a subject , can be ( 2013 .01 ) ; A61K 9 /5115 ( 2013 .01 ) ; A61K used to deliver nucleic acids and / or can regulate gene 9 /5123 (2013 .01 ) ; A61K 31/ 7088 ( 2013 .01 ) ; expression . Accordingly , the structures described herein A61K 47 /544 ( 2017 .08 ) ; A61K 47 /554 may be used to diagnose , prevent, treat or manage certain ( 2017 .08 ) ; A61K 47 /6917 ( 2017 . 08 ) ; A61K diseases or bodily conditions. In some cases, the structures 4776923 (2017 .08 ) ; B82Y 5 / 00 ( 2013 .01 ) ; are both a therapeutic agent and a diagnostic agent. C12N 15 / 87 ( 2013 .01 ) ; CI2N 15 / 111 ( 2013 . 01 ) ; C12N 2310 / 113 ( 2013 .01 ) ; C12N 20 Claims, 21 Drawing Sheets 2310 / 3515 ( 2013 .01 ) ; CI2N 2320 / 32 ( 2013 .01 ) Specification includes a Sequence Listing . US 10 ,328 ,026 B2 Page 2 References Cited WO WO 2010 /017152 2 /2010 ( 56 ) WO WO 2010 /017154 2 /2010 U . S . PATENT DOCUMENTS WO WO 2010 /091293 A1 8 / 2010 WO WO 2010 / 120420 10 / 2010 2004 /0053384 AL 3 / 2004 Sligar et al . WO WO 2011 /017456 A2 2 / 2011 2004 / 0158051 A18 / 2004 Ozkan et al . WO WO 2011 /017690 A2 2 / 2011 2005 / 0130167 A1 6 / 2005 Bao et al. Wo WO 2011 /053940 A2 5 / 2011 2006 / 0083781 A14 / 2006 Shastri et al . wo WO 2011/ 079290 A1 6 / 2011 2006 / 0292174 A1 12 / 2006 De Los Rios et al. wo WO 2012 /022948 A1 2 / 2012 2007 /0218501 A1 9 / 2007 Fogelman et al . WO WO 2012 / 068470 A2 5 / 2012 2007 /0243136 A1 10 / 2007 Fisher et al . WO WO 2014 /025795 A1 2 / 2014 2007 /0249555 Al 10 /2007 Barbaras et al . WO WO 2015 / 195628 A2 12 / 2015 2007 / 0298257 A 12 / 2007 Ludwig et al . WO WO 2017 /011662 AL 1 / 2017 2008 /0181928 AL 7 / 2008 Hakimi-Mehr et al . WO WO 2017 / 035278 A1 3 / 2017 2008 / 0194463 Al 8 / 2008 Weller et al . WO WO 2017 / 193087 A1 11 /2017 2008 / 0274454 AL 11/ 2008 Mirkin et al . WO WO 2018 /053368 A1 3 / 2018 2008 /0306016 Al 12 / 2008 Mirkin et al . 2008 / 0311182 A1 12 / 2008 Ferrari et al . 2009/ 0018028 A1 1 / 2009 Lindsay et al . OTHER PUBLICATIONS 2009 / 0209629 AL 8 / 2009 Mirkin et al. 2009 /0317802 Al 12 / 2009 Bhatia et al. International Search Report and Written Opinion dated Feb . 25 , 2009 / 0324706 A1 * 12 / 2009 Mirkin . A61K 9 / 1275 2016 for PCT/ US2015 /062431 . 424 /450 International Preliminary Report on Patentability dated Jun . 8 , 2017 2010 / 0136682 A1 6 / 2010 Mirkin et al . for PCT/ US2015 / 062431 . 2010 /0184844 Al 7 / 2010 Mirkin et al. International Search Report and Written Opinion dated Apr. 11 , 2010 /0233141 A1 9 / 2010 Polach et al. 2010 / 0233270 A1 9 / 2010 Mirkin et al . 2017 for PCT /US2016 /067243 . 2011/ 0052680 A1 3 / 2011 Hendrickson International Search Report and Written Opinion dated Jun . 19 , 2011/ 0059156 A9 3 / 2011 Mirkin et al . 2017 for PCT/US2017 /021293 . 2011 / 0111974 A1 5 / 2011 Mirkin et al . Aurasense Therapeutics, NIH grant, “ Topically -delivered Target 2012 /0149843 Al 6 / 2012 Chien et al . Gene Suppression of Immune Activation in Psoriasis — David 2012 /0244230 A1 9 / 2012 Mirkin et al. Giljohann ” , Accessed on Aug . 2 , 2017 from http : / / grantome. com / 2013 /0034599 A1 2 / 2013 Thaxton et al . 2013 /0089614 Al 4 / 2013 Zhang et al. grant/ NIH /R41 - AR066438 -01 Accessible online on Feb . 21, 2016 2013 / 0101512 Al 4 / 2013 Mirkin et al. as verified through Wayback Machine . X Aims 1 - 3 . 2013 /0195759 Al 8 / 2013 Mirkin et al. Boudreault et al . , Nanoscale tools to selectively destroy cancer cells. 2013 / 0196951 A1 8 / 2013 Schoenfisch et al. Chem Commun . May 14 , 2008 ; ( 18 ) : 2118 - 20 . doi: 10 . 1039 / 2013 / 0295129 A1 11/ 2013 Irvine et al . b800528a . Epub Apr. 7 , 2008 . 2014 /0005258 A1 1 / 2014 Mirkin et al . Cho et al . , Targeted delivery of siRNA - generating DNA nanocas 2014 /0065425 A1 3 / 2014 Bogdanov settes using multifunctional nanoparticles . Small . Jun . 10 , 2014 /0294927 Al 10 / 2014 Thaxton et al . 2013 ; 9 ( 11 ) :1964 -73 . doi : 10 . 1002/ sm11. 201201973 . Epub Jan . 6 , 2015 / 0064255 Al 3 / 2015 Thaxton et al . 2013 . 2015 /0086985 AL 3 / 2015 Giljohann et al . Houot et al. , T -cell modulation combined with intratumoral CpG 2015 /0111790 A1 4 / 2015 Ategeka et al . cures lymphoma in a mouse model without the need for chemo 2016 / 0194642 Al 7 / 2016 Gryaznov et al . therapy . Blood . Apr. 9 , 2009 ; 113 ( 15 ) : 3546 -52 . doi: 10 . 1182 /blood 2016 /0274134 AL 9 / 2016 Mutharasan et al . 2008 - 07 - 170274 . Epub Oct . 21 , 2008 . 2016 /0310425 A1 10 / 2016 Mirkin et al . Kandimalla et al . , Secondary structures in CpG oligonucleotides affect immunostimulatory activity . Biochem Biophys Res Commun . FOREIGN PATENT DOCUMENTS Jul. 11 , 2003 ;306 ( 4 ): 948 -53 . EP 1 889 911 A2 2 / 2008 Khmelinskaia et al ., Effect of anchor positioning on binding and EP 2399608 AL 12 / 2011 diffusion of elongated 3D DNA nanostructures on lipid membranes . JP 2011 - 507807 A 3 / 2011 J . Phys. D : Appl. Phys Apr. 13, 2016 : 49 ( 19 ) : 194001 . WO WO 92 / 21330 12 / 1992 Kong et al. , Cationic lipid -coated gold nanoparticles as efficient and WO WO 93 / 21528 A1 10 / 1993 non - cytotoxic intracellular siRNA delivery vehicles. Pharm Res. WO WO 1998 /004740 A1 2 / 1998 Feb . 2012 ; 29 ( 2 ) : 362 - 74 . doi: 10 . 1007 /s11095 -011 -0554 - y . Epub WO WO 2000 /020645 4 / 2000 Aug . 13 , 2011. WO WO 2001 /003709 A11 / 2001 Lee IH , Kwon HK , An S , Kim D , Kim S , Yu MK , Lee JH , Lee TS , WO WO 2003 /008539 A2 1 / 2003 WO WO 2006 / 110350 A2 10 / 2006 Im SH , Jon S . Imageable antigen -presenting gold nanoparticle WO WO 2006 / 110350 A3 10 / 2006 vaccines for effective cancer immunotherapy in vivo . Angew Chem WO WO 2006 / 128121 A2 11 / 2006 Int Ed Engl .
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