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WO 2017/106630 Al 22 June 2017 (22.06.2017) W P O P C T

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WO 2017/106630 Al 22 June 2017 (22.06.2017) W P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/106630 Al 22 June 2017 (22.06.2017) W P O P C T (51) International Patent Classification: (74) Agent: RESNICK, David, S.; Nixon Peabody LLP, 100 A61K 47/60 (2017.01) Summer Street, Boston, MA 021 10-213 1 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 16/067 149 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, 16 December 2016 (16. 12.2016) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (26) Publication Language: English MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (30) Priority Data: NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, 62/269,438 18 December 201 5 (18. 12.2015) US RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (71) Applicants: THE GENERAL HOSPITAL CORPORA¬ ZA, ZM, ZW. TION [US/US]; 55 Fruit Street, Boston, MA 021 14 (US). XTUIT PHARMACEUTICALS, INC. [US/US]; 1000 (84) Designated States (unless otherwise indicated, for every Winter Street, Suite 3350, Waltham, MA 02451 (US). kind of regional protection available): ARIPO (BW, GH, MASSACHUSETTS INSTITUTE OF TECHNOLOGY GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, [US/US]; 77 Massachusetts Avenue, Cambridge, MA TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 02139 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors: BLUME-JENSEN, Peter; 35 1 Dudley Road, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Newton, MA 02459 (US). CHICKERING, Donald, E., SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Ill; 3 Holly Way, Framingham, MA 01701 (US). KO- GW, KM, ML, MR, NE, SN, TD, TG). PESKY, Paul, W.; 7 Mason Street, Lexington, MA 02421 Declarations under Rule 4.17 : (US). REITER, Lawrence, A.; 32 West Mystic Ave., Mystic, CT 06355 (US). CRANE, Alan; 25 Quidnic Road, — as to applicant's entitlement to apply for and be granted a Newton, MA 02468 (US). LANGER, Robert, S.; 98 patent (Rule 4.1 7(H)) Montvale Rd., Newton, MA 02459 (US). TONG, Rong; — as to the applicant's entitlement to claim the priority of the 100 Memorial Drive, Apt. 8-20B, Cambridge, MA 02142- earlier application (Rule 4.1 7(in)) 1331 (US). JAIN, Rakesh, K.; 14 Squirrel Road, Wells- ley, MA 0248 1 (US). CHAUHAN, Vikash, Pal, Singh; 5 Published: Peabody Terrace, Apt. 32, Boston, MA 02138 (US). IN- — with international search report (Art. 21(3)) CIO, Joao; c/o The General Hospital Corporation, 55 Fruit Street, Boston, MA 021 14 (US). FUKUMURA, Dai; 28 — before the expiration of the time limit for amending the Nightingale Path, Newton, MA 02459 (US). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (54) Title: POLYACETAL POLYMERS, CONJUGATES, PARTICLES AND USES THEREOF FIG. 1A o o (57) Abstract: Provided herein are polymers, pH-sensitive polymers and/or linkers; conjugates comprising said polymers and/or linkers, optionally, coupled to one or more agents and/or targeting moieties; and particles (e.g., nanoparticles comprising the afore- said polymers, linkers and/or conjugates), which can be used to enhance the delivery and/or efficacy of one or more agents in a sub - Je POLYACETALPOLYMERS, CONJUGATES, PARTICLES AND USES THEREOF RELATED APPLICATIONS This application claims benefit under 35 S § 119(e) of U.S. Provisional Application Number 62/269,438 filed December 18, 2015, the contents of which are incorporated herein by reference in their entirety. GOVERNMENT SUPPORT This invention was made with Government support under Grant No. CA80124-15 awarded by the National Institutes of Health. The Government has certain rights in the invention. TECHNICAL FIELD The present invention generally relates to particles, such as nanoparticles, the polymers of which the particles are comprised, as well as to compositions thereof The present invention also generally relates to methods of using the compositions provided for delivery of agents, such as one or more pharmaceutical agents (e.g., one or more drugs). BACKGROUND Advances in biomedical research have led to the introduction of several novel systemically administered molecular and nanotherapeutic agents in both preclinical and clinical settings (Jones, D . (2007) Nat Rev Drug Discov 6, 174-175; Moghimi, S. M . etal. (2005) Faseb J. 19, 311-330). While these new agents act on unique targets that afford greater specificity to target cells, e.g., tumor ceils, or improved pharmacodynamic properties, their effectiveness suffers from limitations in their deliver}' owing to the properties of the target microenvironment (Jain, R . K . (1998) Nat Med 4, 655-657; Sanhai, W. R . etal. (2008) Nal Nanotechnol 3, 242-244, Chauhan, V et al. (201 ) Annu Rev Che Biomol Eng. 2(1):28 -98) . Limited approaches are currently available to overcome the deliver)' barriers for drags. Thus, the need exists for identifying new agents and formulations that enhance the delivery, distribution, and/or efficacy of therapeutic agents, including nanotherapeutics (e.g., lipid- or polymeric nanoparticles and viruses), protein and nucleic acid drugs, targeted therapies, immune therapies (e.g., immune checkpoint blockers, vaccines and/or immune cells), and small molecule chemotherapeutic agents. SUMMARY The present invention discloses, at least in part, pH-sensitive and/or polyacetal polymers and/or linkers; conjugates comprising said polymers and/or linkers, optionally, coupled to one or more agents and/or targeting moieties; and particles (e.g., nanoparticles comprising the aforesaid polymers, linkers and/or conjugates), collectively referred to herein as "compositions," which can be used to enhance the delivery and/or efficacy of one or more agents in a subject. Without wishing to be bound by theory, the compositions disclosed herein may improve the efficiency of an agent, e.g., a therapeutic and/or diagnostic agent. In one embodiment, the compositions can result in one or more of: (i) increasing the localization and/or delivery of the agent to a target cell or tissue (e.g., a cancer or a fibrotic cell or tissue; or a liver cell or tissue); (ii) selectively penetrating into a fibrotic tissue (e.g., a desmopiastic tumor or a fibrotic tissue chosen from liver, kidney, lung or bone marrow (e.g., myelofibrotic bone marrow)); (iii) selectively penetrating into a diseased blood vessel (e.g., a leaky tumor vessel); (iv) exhibiting increased pH-sensitivity and/or enhanced agent release in a hypoxic microenvironment, e.g., in a tumor or a fibrotic tissue (e.g., fibrotic or cirrhotic liver, or a tissue having renal fibrosis, pulmonary fibrosis or myelofibrosis); (v) increasing the selective delivery and/or release of the agent to the tumor or fibrotic tissue, or (vi) increasing the half- life of the agent. In some embodiments, by selectively targeting an agent to a ceil or tissue in need (e.g., a cancer or a fibrotic tissue), the composition described herein can comprise an agent at a concentration that would otherwise produce an adverse effect when administered systemically as a free form (e.g., no coupled to pH-sensitive and/or polyacetal polymer or particle as described herein). Certain embodiments disclosed herein provide compositions and methods for treating or preventing a disorder. In some embodiments, the disorder is a fibrotic disorder. In some embodiments, the disorder is a cancer disorder (e.g., a desmopiastic tumor or metastatic lesion). In some embodiments, the disorder is a liver disease or disorder. These embodiments comprise administering to a subject a particle, e.g., a pH-sensitive and/or polyacetal particle described herein, as a single agent or as a combination with one or more therapeutic agents. The compositions disclosed herein can result in a higher amount of released agent at a target site (e.g., in a hypoxic tumor), while having minimal or no effect at other non-target sites (e.g., in intact and/or healthy blood vessels and/or normal or healthy tissues). In one embodiment, the agent delivered or released is a therapeutic and/or diagnostic agent (e.g., an Anti-hypertensive and/or Collagen Modifying Agent (AHCM) (e.g., an angiotensin receptor blocker (ARB ) as described herein). Alternatively, or in combination, the agent delivered or released is an anti-cancer therapeutic agent and/or a liver therapeutic agent. Thus, provided herein are compositions and methods for improving the delivery and/or efficacy of a therapy (e.g., a cancer, anti-fibrotic, or a liver therapy), ranging in size from a ceil (e.g., an immune cell) or a large nanotherapeutic (e.g., lipid- or polymeric nanoparticles and viruses), protein and nucleic acid drugs, to low molecular weight chemotherapeutics and/or oxygen radicals. Polymers In one aspect, the invention features a pH-sensitive polymer, e.g., a polymer comprising a polyacetal poiymer (e.g., a polyacetal polymer of Formula (I), Formula (I-a), or Formula (IV) described herein). In some embodiments, the average molecular weight of the poiymer (e.g., a polyacetal polymer as described herein) used in a particle (e.g., a micelle or a nanoparticle as described herein) is from about 2 kDa to about 200 kDa, (e.g., from about 2.5 kDa to about 75 kDa, from about 5 kDa about 150 kDa, from about 10 kDa to about 125 kDa, from about 12.5 kDa to about 100 kDa, from about 15 kDa to about 90 kDa, from about 17.5 kDa to about about 80 kDa, from about 20 kDa to about 70 kDa, from about 22.5 kDa to about 60 kDa, or from about 25 kDa to about 50 kDa).
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