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Cancer Cell Targeting Using Nanoparticles

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Cancer Cell Targeting Using Nanoparticles (19) & (11) EP 2 436 376 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 04.04.2012 Bulletin 2012/14 A61K 9/14 (2006.01) B82B 1/00 (2006.01) A61P 35/00 (2006.01) A61K 9/51 (2006.01) (2006.01) (2006.01) (21) Application number: 11186037.5 A61K 31/337 A61K 9/48 (22) Date of filing: 31.03.2008 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Zale, Stephen E. HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Cambridge, MA 02142 (US) RO SE SI SK TR • Ali, Mir Mikkaram Designated Extension States: Woburn, MA 01801 (US) AL BA MK RS (74) Representative: Harris, Jennifer Lucy et al (30) Priority: 28.09.2007 US 976197 P Kilburn & Strode LLP 20 Red Lion Street (62) Document number(s) of the earlier application(s) in London WC1R 4PJ (GB) accordance with Art. 76 EPC: 08744752.0 / 2 136 788 Remarks: •This application was filed on 20-10-2011 as a (71) Applicant: Bind Biosciences, Inc. divisional application to the application mentioned Cambridge, MA 02139 (US) under INID code 62. •Claims filed after the date of receipt of the divisional application (Rule 68(4) EPC). (54) Cancer cell targeting using nanoparticles (57) The present invention generally relates to poly- having highly controlled properties, which can be formed mersand macromolecules, inparticular, to polymersuse- by mixing together two or more macromolecules in dif- ful in particles such as nanoparticles. One aspect of the ferent ratios. One or more of the macromolecules may invention is directed to a method of developing nanopar- be a polymeric conjugate of a moiety to a biocompatible ticles with desired properties. In one set of embodiments, polymer. In some cases, the nanoparticle may contain a the method includes producing libraries of nanoparticles drug. Other aspects of the invention are directed to meth- ods using nanoparticle libraries. EP 2 436 376 A1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 436 376 A1 2 EP 2 436 376 A1 Description RELATED APPLICATIONS 5 [0001] This application claims priority to U.S. Provisional Application No. 60/976,197, Attorney Docket No. BBZ-014-1, filed September 28, 2007, titled "CANCER CELL TARGETING USING NANOPARTICLES;" and International Application No. PCT/US2007/007927, Attorney Docket No. BBZ-005PC, filed March 30, 2007, titled "SYSTEM FOR TARGETED DELIVERY OF THERAPEUTIC AGENTS," all of which are incorporated herein by reference in their entirety. Additionally, the contents of anypatents, patent applications, and references cited throughout this specificationare hereby incorporated 10 by reference in their entireties. FIELD OF INVENTION [0002] The present invention generally relates to pharmaceutical compositions comprising target-specific stealth na- 15 noparticles useful in the treatment of cancer. BACKGROUND [0003] The delivery of a drug to a patient with controlled-release of the active ingredient has been an active area of 20 research for decades and has been fueled by the many recent developments in polymer science. In addition, controlled release polymer systems can be designed to provide a drug level in the optimum range over a longer period of time than other drug delivery methods, thus increasing the efficacy of the drug and minimizing problems with patient compliance. [0004] Biodegradable particles have been developed as sustained release vehicles used in the administration of small molecule drugs, proteins and peptide drugs, and nucleic acids. The drugs are typically encapsulated in a polymer matrix 25 which is biodegradable and biocompatible. As the polymer is degraded and/or as the drug diffuses out of the polymer, the drug is released into the body. [0005] Targeting controlled release polymer systems (e.g., targeted to a particular tissue or cell type or targeted to a specific diseased tissue but not normal tissue) is desirable because it reduces the amount of a drug present in tissues of the body that are not targeted. This is particularly important when treating a condition such as cancer where it is 30 desirable that a cytotoxic dose of the drug is delivered to cancer cells without killing the surrounding non-cancerous tissue. Effective drug targeting should reduce the undesirable and sometimes life threatening side effects common in anticancer therapy. In addition, targeting may allow drugs to reach certain tissues they would otherwise be unable to reach without a targeted nanoparticle. [0006] Accordingly, a need exists to develop delivery systems which can deliver therapeutic levels of drug to treat 35 diseases such as cancer, while also reducing patient side effects. SUMMARY OF THE INVENTION [0007] There remains a need for compositions useful in the treatment or prevention or amelioration of one or more 40 symptoms of cancer, particularly cancers that express prostate specific membrane antigen (PSMA), including, but not limited to, prostate cancer, non-small cell lung cancer, colorectal carcinoma, and glioblastoma, and solid tumors ex- pressing PSMA in the tumor neovasculature. In one aspect, the invention provides a pharmaceutical composition com- prising a plurality of target-specific stealth nanoparticles that comprise a therapeutic agent; wherein said nanoparticles contain targeting moieties attached thereto, wherein the targeting moiety is a low-molecular weight PSMA ligand. 45 [0008] In one embodiment of the pharmaceutical composition of the invention, the nanoparticle has an amount of targeting moiety effective for the treatment of prostate cancer in a subject in need thereof. In another embodiment, the nanoparticle has an amount of targeting moiety effective for the treatment of solid tumors expressing PSMA in the tumor neovasculature in a subject in need thereof. In yet another embodiment, the low-molecular weight PSMA ligand has a Ki of between 0.5nM and 10nM. 50 [0009] In one embodiment of the pharmaceutical composition of the invention, the nanoparticle has an amount of therapeutic agent effective for the treatment of prostate cancer in a subject in need thereof. In another embodiment, the nanoparticle has an amount of therapeutic agent effective for the treatment of solid tumors expressing PSMA in the tumor neovasculature in a subject in need thereof. [0010] In another embodiment of the target-specific stealth nanoparticles of the invention, the low-molecular weight 55 PSMA ligand has a molecular weight of less than 1000 g/mol. In particular embodiments, the low-molecular weight PSMA ligand is selected from the group consisting of compounds I, II, III and IV. In other embodiments, the low- molecular weight PSMA ligand is 3 EP 2 436 376 A1 5 10 and enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. [0011] In other embodiments of the target-specific stealth nanoparticles of the invention, the nanoparticle comprises a polymeric matrix. In one embodiment, the polymeric matrix comprises two or more polymers. In another embodiment, the polymeric matrix comprises polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly (orthoesters), polycyanoacrylates, polyvinyl al- 15 cohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polysty- renes, or polyamines, or combinations thereof. In still another embodiment, the polymeric matrix comprises one or more polyesters, polyanhydrides, polyethers, polyurethanes, polymethacrylates, polyacrylates or polycyanoacrylates. In an- other embodiment, at least one polymer is a polyalkylene glycol. In still another embodiment, the polyalkylene glycol is polyethylene glycol. In yet another embodiment, at least one polymer is a polyester. In another embodiment, the polyester 20 is selected from the group consisting of PLGA, PLA, PGA, and polycaprolactones. In still another embodiment, the polyester is PLGA or PLA. In yet another embodiment, the polymeric matrix comprises a copolymer of two or more polymers. In another embodiment, the copolymer is a copolymer of a polyalkylene glycol and a polyester. In still another embodiment, the copolymer is a copolymer of PLGA or PLA and PEG. In yet another embodiment, the polymeric matrix comprises PLGA or PLA and a copolymer of PLGA or PLA and PEG. 25 [0012] In another embodiment, the polymeric matrix comprises a lipid-terminated polyalkylene glycol and a polyester. In another embodiment of the pharmaceutical composition of the invention, the polymeric matrix comprises lipid-termi- nated PEG and PLGA. In one embodiment, the lipid is of the Formula V. In a particular embodiment, the lipid is 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and salts thereof, e.g., the sodium salt. [0013] In another embodiment of the pharmaceutical composition of the invention, a portion of the polymer matrix is 30 covalently bound to the low-molecular weight PSMA ligand. In another embodiment, the polymer matrix is covalently bound to the low-molecular weight PSMA ligand via the free terminus of PEG. In still another embodiment, the polymer matrix is covalently bound to the low-molecular weight PSMA ligand via a carboxyl group at the free terminus of PEG. In yet another embodiment, the polymer matrix is covalently bound to the low-molecular weight PSMA ligand via a maleimide functional group at the free terminus of PEG. 35 [0014] In another embodiment of the pharmaceutical composition of the invention, the nanoparticle has a ratio of ligand-bound polymer to non- functionalizedpolymer
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