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Us 8980907 B2 US008980907B2 (12) United States Patent (10) Patent No.: US 8,980,907 B2 Baker, Jr. et al. (45) Date of Patent: Mar. 17, 2015 (54) DENDRIMER CONJUGATES 4,892,935 A 1/1990 Yoshida et al. 4.914,021 A 4, 1990 Toth (71) Applicant: E" of the try is of 4,921,7894,918,164 A 4,5/1990 1990 SalemHellstrom et al. et al. ichigan, Ann Arbor, MI (US) 4,921,790 A 5/1990 O’Brien 4,939,240 A 7, 1990 Chu et al. (72) Inventors: James R. Baker, Jr., Ann Arbor, MI 4.946,778 A 8, 1990 Ladner et al. (US); Xue-min Cheng, Ann Arbor, MI 4,963.484. A 10/1990 Kufe (US); Abraham F. L. Van Der Spek 4,965,128 A 10, 1990 Greidanus Ann Arbor,s MI (US);O - O Baohua Mark s 5,053.4895,041,516 A 10/19918, 1991 KifeFrechet et al. Huang, Ann Arbor, MI (US); Thommey 5,110,911. A 5/1992 Samuel et al. P. Thomas, Dexter, MI (US) 5,270,163 A 12/1993 Gold et al. 5,338,532 A 8, 1994 Tomalia et al. (73) Assignee: The Regents of the University of 3: A g 3: R etd 1 Michigan,O O Ann Arbor, MI (US) 5,393,795- w A 2/1995 HedstrandSa etca. al. 5,393,797 A 2f1995 Hedstrand et al. (*) Notice: Subject to any disclaimer, the term of this 5,475,096 A 12/1995 E. s a patent is extended or adjusted under 35 5,512,443 A 4/1996 Schlom et al. U.S.C. 154(b) by 0 days. 5,527,524. A 6/1996 Tomalia et al. (Continued) (21) Appl. No.: 14/107,817 FOREIGN PATENT DOCUMENTS (22) Filed: Dec. 16, 2013 CA 2187921 11, 1995 (65) Prior Publication Data CA 2386998 4/2001 US 2014/0128327 A1 May 8, 2014 (Continued) OTHER PUBLICATIONS Related U.S. Application Data (63) Continuation of application No. 12/570977, filed on Maini, et al., “Infliximab (chimeric anti-tumour necrosis factor Sep 30, 2009 s- s monoclonal antibody) versus placebo in rheumatoid arthritis patients p. 3U, receiving concomitant methotrexate: a randomised phase III trial.” (60) Provisional application No. 61/101.461, filed on Sep. Lancet (1999) vol. 354, pp. 1932-1939. 30, 2008. Chandrasekar, Durairaj, et al., “The development of folate-PAMAM dendrimer conjugates for targeted delivery of anti-arthritic drugs and (51) Int. Cl. their pharmacokinetics and biodistribution in arthritic rats.” A 6LX3/553 (2006.01) Biomaterials (2007) vol. 28, pp. 504-512. A6 IK3I/485 (2006.01) Mullen, Douglas G., “A Quantitative Assessment of Nanoparticle— A 6LX3/5377 (2006.01) Ligand Distributions: Implications for Targeted Drug and Imaging CO7D 489/02 (2006.015 Delivery in Dendrimer Conjugates.” ACS Nano (2010), 4(2), pp. CO7D 413/06 (2006.01) 657-670. inued A6 IK 47/48 (2006.01) (Continued) (52) U.S. Cl. CPC ......... A61K (2013.0);47/483 (2013.01); A61K31/485 A61K47/48207 (2013.01) Primary Examiner - Anoop Singh USPC .......... 514/282, 514/237.2, 424/78.3:546/46 Assistant Examiner - Anna Falkowitz (58) Field of Classification Search (74) Attorney, Agent, or Firm — Casimir Jones S.C. USPC .................. 514/282,237.2: 424/78.3:546/46 See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention relates to novel therapeutic and diag U.S. PATENT DOCUMENTS nostic dendrimers. In particular, the present invention is directed to dendrimer-linker conjugates, methods of synthe 4,161,948 A 7, 1979 Bichon sizing the same, compositions comprising the conjugates, as 4,507,466 A 3, 1985 Tomalia et al. well as systems and methods utilizing the conjugates (e.g., in 4,558,120 A 12/1985 Tomalia et al. diagnostic and/or therapeutic settings (e.g., for the delivery of 4,568,737 A 2, 1986 Tomalia et al. 4,587,329 A 5, 1986 Tomalia et al. therapeutics, imaging, and/or targeting agents (e.g., in disease 4,631,337 A 12/1986 Tomalia et al. (e.g., cancer) diagnosis and/or therapy, pain therapy, etc.)). 4,694,064 A 9, 1987 Tomalia et al. Accordingly, dendrimer-linker conjugates of the present 4,708,930 A 1 1/1987 Kortright et al. invention may further comprise one or more components for 4,713,975 A 12/1987 Tomalia et al. targeting, imaging, sensing, and/or providing a therapeutic or 4,737,550 A 4, 1988 Tomalia et al. 4,743,543 A 5/1988 Kortright diagnostic material and/or monitoring response to therapy. 4,827,945 A 5, 1989 Groman 4,857,599 A 8, 1989 Tomalia et al. 4,871,779 A 10, 1989 Killat et al. 5 Claims, 50 Drawing Sheets US 8,980.907 B2 Page 2 (56) References Cited 2010, O15885.0 A1 6/2010 Baker, Jr. 2010, 0160299 A1 6/2010 Baker, Jr. U.S. PATENT DOCUMENTS 2010, 0183749 A1 7/2010 Brey 5,545,530 8, 1996 Satomura et al. FOREIGN PATENT DOCUMENTS 5,560,929 10, 1996 Hedstrand et al. 5,631,329 5, 1997 Yin et al. CN 10 12678O3 9, 2008 5,661,025 8, 1997 Szoka et al. EP OO997.58 10, 1984 5,674,192 10, 1997 Sahatian EP O27118O 6, 1988 5,693,014 12, 1997 Abele et al. EP 1941861 T 2008 5,693,763 12, 1997 Codington et al. JP 2002-265495 9, 2002 5,714,166 2, 1998 Tomalia et al. WO 88.01178 2, 1988 5,733,303 3, 1998 Israel et al. WO 88.0118O 2, 1988 5,755,722 5, 1998 Barry et al. WO 90/O2545 3, 1990 5,773,527 6, 1998 Tomalia et al. WO 95/24221 9, 1995 5,792,105 8, 1998 Lin WO 95/28641 10, 1995 5,795,582 8, 1998 Wright WO 9707398 2, 1997 5,800,391 9, 1998 Kontos WO 97,38134 10, 1997 5,800,508 9, 1998 Goicoechea et al. WO 98.33941 8, 1998 5,800,519 9, 1998 Sandock WO 99.02651 1, 1999 5,808,005 9, 1998 Codington et al. WO 99.07724 2, 1999 5,843,089 12, 1998 Sahatian WO 996.1662 2, 1999 5,851,228 12, 1998 Pinheiro WO 99.10362 3, 1999 5,855,866 1, 1999 Thorpe WO 99.5865.6 11, 1999 5,855,881 1, 1999 Loike et al. WO OOf 16807 3, 2000 5,857,998 1, 1999 Barry WO O1/87348 11, 2001 5,861,319 1, 1999 Lin et al. WO O102861 11, 2001 5,866,561 2, 1999 Ungs WO O3,OO3975 1, 2003 5,868,719 2, 1999 Tsukernik WO 03/011 115 2, 2003 5,876.445 3, 1999 Andersen WO O3,055935 T 2003 5,892,019 4, 1999 Schlom WO 2006/033766 3, 2006 5,892,020 4, 1999 Mezes WO 2007/01 1967 1, 2007 5,898,005 4, 1999 Singh WO 2007O12001 1, 2007 5,902,863 5, 1999 Dvornic et al. WO 2007/034750 3, 2007 5,908.413 6, 1999 Lange WO 2007/080114 7/2007 5,913,894 6, 1999 Schmitt WO 2008/0O8483 1, 2008 5,922,887 7, 1999 Dondio et al. WO 2011002852 1, 2011 5,933,145 8, 1999 Meek WO 2011028334 3, 2011 5,935,114 8, 1999 Jang WO 2011/059609 5, 2011 6,051.429 4, 2000 Hawley-Nelson et al. WO 2011053618 5, 2011 6,054,444 4, 2000 Jackson WO 2011 O72290 6, 2011 6,267.987 T/2001 Park et al. 6,312,679 11, 2001 Tomalia et al. OTHER PUBLICATIONS 6,471.968 10, 2002 Baker et al. Mullen, et al., “Design, synthesis, and biological functionality of a 6,485,718 11, 2002 Parthasarathy dendrimer-based modular drug delivery platform. Bioconjugate 6,585,956 T/2003 Malik et al. 6,869,772 3, 2005 Lichtman et al. Chemistry, vol. 22, No. 4, pp. 679-689 (Mar. 22, 2011). 7,078.461 T/2006 Tomalia Frechet, Jean M.J., et al., “Reversed-phase high-performance liquid 7,097.856 8, 2006 Frechet chromatography of functionalized dendritic macromolecules,” Jour 7,208,486 4, 2007 Burnett nal of Chromatography A, 667 (1994), pp. 284-289. 7,261,875 8, 2007 Li Opsteen, et al., “Modular synthesis of block copolymers via cycload 7,368,512 5/2008 Newkome dition of terminal azide and alkyne functionalized polymers'. 7,459,145 12, 2008 Bao Chemical Communicaitons, vol. 1, pp. 57-59 (2005). 7,745,229 6, 2010 Wang Yim, et al., “Versatile conjugation of octreotide to dendrimers by 2001/0031498 10, 2001 Leclercq cycloaddition (“Click”) chemistry to yield high-affinity mullivalent 2002fO165179 11, 2002 Baker, Jr. 2003/0129158 T/2003 Matthews et al. .......... 424/78.17 cyclic peptide dendrimers.” Bioconjugate Chemistry, vol. 20, No. 7. 2003/O18O250 9, 2003 Chauhan et al. pp. 1323-1331 (2009). 2004.0109842 6, 2004 Baker, Jr. Huang, B., et al., “Copper-free click conjugation of methotrexate to 2004/O120979 6, 2004 Roessler et al. a PAMAM dendrimer platform'. Tetrahedron Letters, E-pub, Dec. 2005/0214247 9, 2005 Shaunak 10, 2010, v. 52, pp. 141 1-1414. 2006/0057211 3, 2006 Chorny Dijk, M.V., et al., “Synthesis and Applications of Biomedical and 2007/0020620 1/2007 Finn Pharmaceutical Polymers via Click Chemistry Methodologies.” 2007/004 1934 2, 2007 William et al. .............. 424/78.3 Bioconjugate Chemistry, Nov. 2009, v. 20, No. 11, pp. 2011-2016. 2007/O122348 5/2007 Kaiko et al. ................. 424, 10.1 Nimmo, C.M. et al., “Regenerative Biomaterials that “Click: Simple, 2007/0298OO6 12, 2007 Tomalia et al.
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