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(12) Patent Application Publication (10) Pub. No.: US 2014/0220346A1 Heller Et Al US 20140220346A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0220346A1 Heller et al. (43) Pub. Date: Aug. 7, 2014 (54) MODULAR POLYMER HYDROGEL (22) Filed: Dec. 4, 2013 NANOPARTICLES AND METHODS OF THER MANUFACTURE Related U.S. Application Data (60) Provisional application No. 61/733,366, filed on Dec. (71) Applicants: Memorial Sloan-Kettering Cancer 4, 2012. Center, New York, NY (US); Massachusetts Institute of Technology, Publication Classification Cambridge, MA (US) (51) Int. Cl. (72) Inventors: Daniel A. Heller, New York, NY (US); A647/48 (2006.01) Jasmine Wallas, New York, NY (US); A614.9/00 (2006.01) Yair Levi, Cambridge, MA (US); (52) U.S. Cl. George W. Pratt, Waban, MA (US); CPC ......... A61K 47/4823 (2013.01); A61K 49/0054 Daniel G. Anderson, Sudbury, MA (2013.01); A61K 49/0073 (2013.01) (US); Robert Langer, Newton, MA USPC .............................. 428/402:536/51:536/112 (US) (57) ABSTRACT (73) Assignees: Memorial Sloan-Kettering Cancer In certain embodiments, a nano-sized vehicle (e.g., a nanogel Center, New York, NY (US); comprising nanoparticles) is provided herein for drug deliv Massachusetts Institute of Technology, ery with tunable biodistribution, low toxicity, and degradabil Cambridge, MA (US) ity, and with demonstrated targeting to bone. The composi tion is useful, for example, in the treatment of bone disease, particularly bone metastases from cancers such as breast, (21) Appl. No.: 14/097,212 prostate, or lung cancer. Patent Application Publication Aug. 7, 2014 Sheet 1 of 36 US 2014/0220346 A1 N Patent Application Publication Aug. 7, 2014 Sheet 2 of 36 US 2014/0220346 A1 8],'04- Patent Application Publication Aug. 7, 2014 Sheet 3 of 36 US 2014/0220346 A1 SS S 3. 8. SO 2 5. DAETER (nm) F.G. 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Š Patent Application Publication Aug. 7, 2014 Sheet 30 of 36 US 2014/0220346 A1 ear ear s Patent Application Publication Aug. 7, 2014 Sheet 31 of 36 US 2014/0220346 A1 Patent Application Publication Aug. 7, 2014 Sheet 32 of 36 US 2014/0220346 A1 s SON,NS: Patent Application Publication Aug. 7, 2014 Sheet 33 of 36 US 2014/0220346 A1 SSONNS: S388th Patent Application Publication Aug. 7, 2014 Sheet 34 of 36 US 2014/0220346 A1 a r me s s {X} wom ill a. --- & Patent Application Publication Aug. 7, 2014 Sheet 35 of 36 US 2014/0220346 A1 Patent Application Publication Aug. 7, 2014 Sheet 36 of 36 US 2014/0220346 A1 ASS; SASSAYSATER ANGS AK RAS. ea epG2 NANOGS > 3 > 8 x is Bis. NANOGELS 2 : 0. St. > 8 US 2014/0220346 A1 Aug. 7, 2014 MODULAR POLYMER HYDROGEL ization (Van Thienen et al., Macromol. 2005). Biodistribution NANOPARTICLES AND METHODS OF of nanogels appears to be modulated in part by the attachment THEIR MANUFACTURE of Surface ligands, similar to behavior of other nanoparticle types. For instance, the functionalization of poly(2-N,N-(di CROSS REFERENCE ethylamino)ethyl methacrylate) nanogels with polyethylene 0001. This application claims the benefit under 35 U.S.C. glycol (PEG) results in a shift of distribution from the liver S119(e) of U.S. Provisional Application No. 61/733,366 filed and spleen towards the lungs and kidneys (Tamura et al., Acta Biomater 2011). Dec. 4, 2012. 0007 Nanogels incorporating dextran have shown prom GOVERNMENT SUPPORT iseas delivery vehicles (Van Thienen et al., Macromol. 2005). However, there has been little in vivo work relating to nano 0002 This invention was made with government support gels incorporating dextran that would be applicable to their under Grant No. RO1 DEO16516 and RO1 EBOOO244 use as delivery vehicles, and no such work has been shown in awarded by NIH. The government has certain rights in this bone tissue. There remains a need for vehicles for delivery of invention. drugs and other substances to bone tissue. TECHNICAL FIELD SUMMARY OF THE INVENTION 0003. This invention relates generally to nanogels and 0008. In certain embodiments, a nano-sized vehicle (e.g., methods of their manufacture. More particularly, in certain a nanogel comprising nanoparticles) is provided herein for embodiments, nanogels for targeted tissue localization are drug delivery with tunable biodistribution, low toxicity, and described herein. degradability, and with demonstrated targeting to bone. The composition is useful, for example, in the treatment of bone BACKGROUND disease, particularly bone metastases from cancers such as 0004 Bone diseases, such as osteoporosis, metabolic dis breast, prostate, or lung cancer. eases, and metastatic cancers, are common, but systems 0009. In one aspect, the invention is directed to a nanogel capable of targeting therapeutics to the bone remain limited for targeted tissue localization (e.g., for preferential localiza (Wang et al., Adv. Drug Del. Rev. 2005; and Zhang et al., tion in?on bone, bone marrow, liver, and/or lymph nodes), the Chem. Soc. Rev. 2007). Nanogels porous nanoscale hydro nanogel comprising residual (e.g., free click-able) functional gel networks, are a class of nanomaterials with tunable groups of at least one type (e.g., unreacted groups for Subse chemical properties that facilitate targeting and delivery to quent conjugation). In some embodiments the nanogel com specific tissues. They are intrinsically porous and can be prises a targeting ligand. In some embodiments, the targeting loaded with Small drugs or macromolecules by physical ligand is a bisphosphonate for localization in bone. In some entrapment, covalent conjugation or controlled self-assembly embodiments, the residual (e.g., free click-able) functional (Kabanov et al., Angew Chem. Int. Edit. 2009: Naeye et al., groups are of one or more types comprising one or more of the Biomat. 2011; Raemdonck et al., Soft Mat. 2009; Zhan et al., following: alkyne, azide, thiol (Sulfydryl), alkene, acrylate, Biomacro. 2011, 12,3612: Oh et al., Prog. Polym. Sci 2008: oxime, maliemide, NHS (N-hydroxysuccinimide), amine Vinogradov et al., Adv. Drug Del. Rev. 2002). (primary amine, secondary amine, tertiary amine, and/or 0005. The high concentration of the mineral hydroxyapa quarternary ammonium), phenyl, benzyl, hydroxyl, carbonyl, tite (HA) in bone represents a target for selective delivery. aldehyde, carbonate, carboxylate, carboxyl, ester, methoxy, Calcium ions in HA are chelated by the bisphosphonate (BP) hydroperoxy, peroxy, ether, meiacetal, meiketal, acetal, ketal, group, which is structurally analogous to endogenous inor orthoester, orthocarbonate ester, amide, carboxyamide, imine ganic phosphate (Lawson et al., Biomed. Mater. Res. BAppl. (primary ketimine, secondary ketamine, primary aldimine, Biomater: 2010). Systemic administration of BPs leads to secondary aldimine), imide, azo (diimide), cyanate (cyanate deposition of these molecules on bone tissues with minimal or isocyanate), nitrate, nitrile, isonitrile, nitrite (nitroSooxy accumulation at other sites (Deligny et al., Nucl. Med. Biol. group), nitro, nitroso, pyridyl, Sulfide, disulfide, Sulfinyl, Sul 1990). Bisphosphonates are used to treat osteoporosis, meta fonyl, Sulfino, Sulfo, thiocyanate, isothiocyanate, carono bolic diseases, and they may be useful for the targeting of thioyl, thione, thial, phosphine, phosphono, phosphate, phos radio-pharmaceuticals, estrogen, corticoids, anti-inflamma phodiester, borono, boronate, bornino, borinate, halo, fluoro, tory agents, and proteins (Wang et al., Adv.
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