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WO 2017/031084 Al 23 February 2017 (23.02.2017) P O P C T

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WO 2017/031084 Al 23 February 2017 (23.02.2017) 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 2017/031084 Al 23 February 2017 (23.02.2017) P O P C T (51) International Patent Classification: (72) Inventors: LAM, Kit S.; c/o The Regents of the Univer A61K 9/14 (2006.01) C08L 29/04 (2006.01) sity of California, 1111 Franklin St., 12th Floor, Oakland, A61K 9/51 (2006.01) California 94607 (US). LI, Yuanpei; c/o The Regents of the University of California, 1111 Franklin St., 12th Floor, (21) International Application Number: Oakland, California 94607 (US). XIAO, Kai; c/o The Re PCT/US20 16/047097 gents of the University of California, 1111 Franklin St., (22) International Filing Date: 12th Floor, Oakland, California 94607 (US). FENG, 15 August 2016 (15.08.2016) Caihong; c/o The Regents of the University of California, 1111 Franklin St., 12th Floor, Oakland, California 94607 (25) Filing Language: English (US). (26) Publication Language: English (74) Agents: PRESLEY, Andrew D. et al; KILPATRICK (30) Priority Data: TOWNSEND & STOCKTON LLP, Mailstop: IP Docket 62/205,402 14 August 2015 (14.08.2015) US ing - 22, 1100 Peachtree Street, Suite 2800, Atlanta, Geor gia 30309 (US). (71) Applicant: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA [US/US]; 1111 Franklin Street, 12th (81) Designated States (unless otherwise indicated, for every Floor, Oakland, California 94607 (US). kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, 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, ZA, ZM, ZW. [Continued on nextpage] (54) Title: POLY(VINYL ALCOHOL) NANOCARRIERS (57) Abstract: The present invention provides a Fig. 6A nanoparticle including at least one polyvinyl al cohol) (PVA) having a molecular weight of from PBS DOX 4 mg/kg about 10 kDa to about 200 kDa, substituted with BTZ 0.8 mg/kg DOX-DCMs 4 mg/kg one or more moieties selected from: a therapeutic 10 agent having a boronic acid moiety, wherein the BTZ-PVA 0.8 rrng/kg BTZ 0.8mg/kg + DOX 4mg kg therapeutic agent is covalently linked to the PVA BTZ-PVA .2 m I /kg BTZ-PVA 0.8mg/kg + via a boronate ester bond; a crosslinking group DOX-DC s 4mg/kg having a disulfide moiety, wherein the crosslink ing group is covalently linked to the PVA, and a o porphyrin, wherein the porphyrin is covalently > linked to the PVA. Use of the nanoparticles for tumor detection and the treatment of diseases, in cluding methods for photodynamic therapy and photofhermal therapy, are also described. > a w o 2017/031084 Ai II II II I III IIII II llll I Mil l Hill II I II (84) Designated States (unless otherwise indicated, for every SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, kind of regional protection available): ARIPO (BW, GH, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Published: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, — with international search report (Art. 21(3)) DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, POLYVINYL ALCOHOL) N NOCARRIERS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] Tl e present application claims priority to U.S. Provisional Pat. Appl. No. 62/205,402, filed on August 14, 2 , which application is incorporated herein by reference in its entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] Tlie present invention was made with government support from the National Institutes of Health under Grant Nos. 3R01CA115483 and R01EB012569. The United States government has certain rights to the invention. BACKGROUND OF THE INVENTION [0003] Nanotechnology is an emerging field that has shown promise for the development of novel diagnostic, imaging, and therapeutic agents for a variety of diseases, including cancer. The nanomaterials used for drag delivery include solid nanoparticles, liposomes, dendrimers, polymeric micelles, water soluble polymers, and protein aggregates. Nanoparticles offer several distinct advantages for these drugs, such as improved solubility, prolonged in vivo circulation time and preferential accumulation at tumor sites due to the enhanced permeability and retention exhibited by many tumor tissues. Tl e optimal particle size of nanoparticles for passive tumor targeting has been reported to range from 0 to 00 nm. The enhanced accumulation of drags in tumor tissue can result in increased therapeutic efficacy as well as a decrease in side effects. In order to successfully develop an effective nanotherapeutic, an agent must be associated with a suitable carrier (such as a nanoparticle) in a manner that does not inhibit its therapeutic or diagnostic activity. If the carrier is to include targeting groups that direct the drag to a desired location in a subject, such as a tumor, the targeting groups must also be linked to the carrier in a way that does not interfere with their ability to interact with the target. The identification and combination of drugs, carriers, and targeting agents to provide effective nanotherapeutics remains a challenge. Versatile platforms for efficiently combining these various components and testing the combinations are still needed. The present invention addresses this and other needs. BRIEF SUMMARY OF THE- INVENTION [00Θ4] In one embodiment, the present invention provides a nanoparticle including at least one poly(vinyl alcohol) (PVA) having a molecular weight of from about kDa to about 200 kDa, substituted with one or more moieties selected from: a therapeutic agent having a boronic acid moiety, wherein the therapeutic agent is covalently linked to the PVA via a boronate ester bond; a crosslinking group having a disulfide moiety, wherein the crosslinking group is covalently linked to the PVA, and a porphyrin, wherein the porphyrin is covalently linked to the PVA. [0005] In some embodiments, the PVA has a structure according to formula I : wherein: each R is independently selected from H and a moiety according to formula la: wherein L is a linking moiety and R is a therapeutic moiety, or any two adjacent R moieties are taken together with the oxygen atoms to which they are bound to form a moiety according to Formula b: wherein R is a therapeutic moiety, provided that at least one R is H and at least one R is other than H ; each R2 is independently selected from -OH, a cellular targeting moiety, and an imaging moiety, or any two adjacent R2 moieties are taken together to form a cellular targeting moiety or an imaging moiety; subscript x is an integer of from about 1to about 1200, and subscript y is an integer of from 0 to about 3800, wherein the sum of x and y is an integer of from about 200 to about 5000, and the x and y repeating units are randomly distributed in the PVA. In some embodiments, the PVA has a structure according to formula II: wherein each R is independently selected from H and a moiety ~L -R , wherein LJ is a linking moiety and R is the disulfide moiety, provided that at least one R' is H and at least two R are the moiety - . - each R2 is independently selected from -OH, a cellular targeting moiety, and an imaging moiety, or any two adjacent R2 moieties are taken together to form a cellular targeting moiety or an imaging moiety; subscript w is an integer of from about 2 to about 1200, and subscript y is an integer of from 0 to about 3800, wherein the sum of w and y is an integer of from about 200 to about 5000, and the w and y repeating units are randomly distributed in the PVA. In some embodiments, the PVA has a structure according to formula III: wherein each R4 is independently selected from H and a moiety -L -R a, wherein L4 is a Sinking moiety and R a is the porphyrin, provided that at least one R4 is H and at least one 4 is the moiety -L -R ; each R is independently selected from -OH, a cellular targeting moiety, and an imaging moiety, or any two adjacent R2 moieties are taken together to form a cellular targeting moiety or an imaging moiety; subscript z is an integer of from about i to about 1200, and subscript y is an integer of from 0 to about 3800, wherein the sum of z and y is an integer of from about 200 to about 5000, and the z and y repeating units are randomly distributed in the PVA. [0008] In some embodiments, the invention provides a method for treating a disease including administering a therapeutically effective am ount of a nanoparticie of the invention to a subject in need thereof. [0009] In some embodiments, the invention provides a method of treating a disease via photodynamic or photothermal therapy including administering to a subject in need thereof a therapeutically effective amount of a nanoparticie of the invention, wherein the nanoparticie has a porphyrin, and exposing the subject to radiation, thereby treating the disease via photodynamic or photothermal therapy [0010] n further embodiments, the invention provides a method of detecting a tumor in a subject including administering to the subject an effective amount of a nanoparticie of the invention and detecting the nanoparticie via fluorescence imaging, magnetic resonance imaging, or positron emission tomography.
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