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WO 2016/130546 Al 18 August 2016 (18.08.2016) 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 2016/130546 Al 18 August 2016 (18.08.2016) P O P C T (51) International Patent Classification: (72) Inventors: HELLER, Daniel A.; 116 1 York Avenue, Apt. A61K 47/48 (2006.01) A61K 9/16 (2006.01) 3G, New York, NY 10065 (US). SHAMAY, Yosef; c/o A61K 31/00 (2006.01) Memorial Sloan Kettering Cancer Center, 1275 York Av enue, New York, NY 10065 (US). (21) International Application Number: PCT/US2016/017153 (74) Agents: HAULBROOK, William, R. et al; Choate, Hall & Stewart LLP, Two International Place, Boston, MA (22) International Filing Date: 021 10 (US). 9 February 2016 (09.02.2016) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 62/1 14,507 10 February 2015 (10.02.2015) US HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (71) Applicant: MEMORIAL SLOAN KETTERING CAN¬ KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, CER CENTER [US/US]; 1275 York Avenue, New York, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, NY 10065 (US). 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: DYE-STABILIZED NANOPARTICLES AND METHODS OF THEIR MANUFACTURE AND THERAPEUTIC USE (57) Abstract: Described herein are nanoparticles which are largely made of VALDECOXIB CELECOXIE (e.g., 90 wt.%) hydrophobic drugs and are stabilized by water soluble dyes. The EIGENVALUE: 4.714 EIGENVALUE: 7.726 nanoparticles can range in size from 30 nm to 150 nm and have highly negative surface charge (e.g., -55mV). These nanoparticles are highly soluble in water, stable for days in PBS buffer and can be easily lyophilzed and reconstituted in water. Using quantitative self-assembly prediction calculations, topochemical molecular descriptors were identified and validated as highly predictive indicat ors of nano-assembly, nanoparticle size, and drug loading. The resulting nano - particles selectively targeted kinase inhibitors to caveolin- 1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeut ic effects while avoiding pERK inhibition in healthy skin. The nanoparticles ex hibited remarkable anti-tumor efficacy in vitro and in vivo in models of hepato cellular carcinoma. o FIG. 1 8 o w o 2016 130 46 Ai Iinn iiiiiii 1mil i mil il i 1ill urn i mil imil i mill m i i i (84) Designated States (unless otherwise indicated, for every Declarations under Rule 4.17: kind of regional protection available): ARIPO (BW, GH, — as to applicant's entitlement to apply for and be granted GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, apatent (Rule 4.1 7(H)) TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, — as to the applicant's entitlement to claim the priority of DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, the earlier application (Rule 4.l 7(iii)) LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, Published: SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, DYE-STABILIZED NANOPARTICLES AND METHODS OF THEIR MANUFACTURE AND THERAPEUTIC USE Cross Reference to Related Application [0001] This application claims the benefit of U.S. Application Serial No. 62/1 14,507 filed on February 10, 2015, the disclosure of which is hereby incorporated by reference in its entirety. Government Support [0002] This invention was made with government support under grant number DP2- HD075698 awarded by the National Institutes of Health (NIH), grant number P30 CA008748 awarded by the National Cancer Institute (NCI), and grant number TG-MCB-130013 awarded by the National Science Foundation (NSF). The government has certain rights in this invention. Field of the Invention [0003] This invention relates generally to nanoparticles and methods of their manufacture and therapeutic use. In particular embodiments, the invention relates to dye-stabilized nanoparticles for the treatment of cancer and other diseases. Background [0004] Many FDA approved and non-approved small molecule drugs suffer from poor water solubility, rapid clearance and relatively low concentration at site of disease. In cancer patients, systemically-delivered chemotherapy is often highly toxic, limiting the dose. In addition, potentially therapeutic new molecules are often too toxic to deliver using conventional routes, preventing their further development. Even as new molecularly targeted therapies are increasingly reaching the clinic, it is apparent that even such drugs often exhibit serious side- effects due to off-target responses. The use of nanotechnology to treat advanced cancers promises the reduction of toxic side-effects and improved efficacy (Lammers et al., Journal of controlled release, 161 .2 (2012): 175-187). Nanoparticle therapeutics currently in the clinic attenuate some of the side-effects of chemotherapies. For instance, the liposomal drug doxorubicin reduces the cardiotoxicity of the encapsulated doxorubicin (Tacar et al., Journal of pharmacy andpharmacology, 65.2 (2013): 157-1 70). Paclitaxel reduces the incidence of neutropenia (Gradishar, Expert opinion on pharmacotherapy, (2006): 1041-1053 ). Most nanoparticulate formulations use macromolecule scaffolds or lipid bilayers (Lammers et al., Britishjournal of cancer, (2008): 392-397). [0005] Cyanine dyes are well known in the art to track therapeutic delivery. However, cyanine dyes at concentrations above 0.5% in water are known to self-assemble into aggregates and form chromatic liquid crystals, thereby limiting the efficacy of the therapeutic (Harrison et al., Journal of physical chemistry, 100.6 (1996): 2310-2321; Wurthner et al., Angewandte Chemie International Edition, 50. 15 (20 ) : 3376-3410). Hydrophobic interactions, along with weak attractions between aromatic rings of molecules (π - π interactions) cause molecular stacking. Because this stacking can occur with any number of molecules, aggregation can begin at any concentration, and many chromatic liquid crystals do not appear to exhibit the equivalent of a critical micelle concentration. Such aggregation is called isodesmic because it occurs at all concentrations. However, the aggregates formed at low concentrations are not large enough to align, and, at larger concentrations, aggregate size increases into supra-molecular assemblies. [0006] A limitation of targeted nanoparticle drug carrier design is that complex synthetic schemes are often required, resulting in low loadings and higher barriers to clinical translation. The synthesis of nanoscale drug delivery vehicles is highly dependent on drug chemistry, and synthetic strategies seldom benefit from a priori information. This can also result in processes that are often unpredictable and based on trial-and-error methods. Moreover, low drug loadings and encapsulation efficiencies are common in most types of nanoparticle formulations, including liposomes, polymer micelles, and protein-based nanoparticles. [0007] Crossing the vascular endothelial barriers remains a major challenge for developing efficient, targeted nanoparticle drug delivery systems for cancer therapy. Recently, caveolae-mediated targeting has been proposed as a strategy to facilitate endothelial penetration at tumor sites. Caveolae are specialized plasmalemmal vesicles which traffic material into and across the cell. Caveolin-mediated tumor targeting has been demonstrated using specific antibodies targeting caveolin-1. Interestingly, highly sulfated aromatic polymers can bind to caveolin through electrostatic and hydrophobic interactions. [0008] Although caveolin-mediated tumor targeting might be advantageous because it does not require complex molecular recognition moieties such as antibodies, no methods exist that are able to develop a drug delivery strategy incorporating this chemistry as development of targeted nanoparticle drug carriers often requires complex synthetic schemes involving both supramolecular self-assembly and chemical modification. These processes are generally difficult to predict, execute, and control. [0009] To improve materials properties in disparate fields, computational methods have been developed to guide synthetic strategies. For example, in drug carrier design, quantitative structure-property relationship (QSPR) calculations have been used to find molecular descriptors which correlate with in vivo performance, and molecular dynamics simulations have been used to understand nanoparticle supramolecular chemistry. However, these quantitative approaches have not yet enabled appreciable predictive power to facilitate the synthesis of drug carrier nanomaterials. [0010] There exists a need for an easily tracked therapeutic platform that can encapsulate many classes of hydrophobic drugs at high concentrations, provide high anti-tumor efficacy, and provide predictability and control. Summary of invention [0011] Described herein is a targeted drug delivery system which is accurately and quantitatively predicted to self-assemble into nanoparticles based on the molecular structures of precursor molecules that are the drugs themselves.
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