Claims for Patent: 10,369,113

Summary for Patent: 10,369,113

Title:	Prostate specific membrane antigen (PSMA) targeted nanoparticles for therapy of prostate cancer
Abstract:	The invention provides a nanoparticle composition that is decorated with a urea-based small-molecule peptidomimetic inhibitor of prostate specific membrane antigen (PSMA), which is expressed by almost all solid tumors. This strategy takes advantage of both the avidity of the functionalized nanoparticle for binding to PSMA and the ability of the nanoparticle to be retained for longer periods of time in the tumor due to enhanced leakage via EPR into the tumor interstitium and poor clearance due to underdeveloped or non-existent lymphatics within the tumor.
Inventor(s):	Chandran; Sachin S. (Highland Park, NJ), Ray; Sangeeta (Ellicott City, MD), Pomper; Martin G. (Baltimore, MD), Denmeade; Samuel R. (Ellicott City, MD), Mease; Ronnie C. (Fairfax, VA)
Assignee:	The Johns Hopkins University (Baltimore, MD)
Application Number:	15/209,352
Patent Claims:	1. A nanoparticle composition of formula I: (X).sub.m--(Y).sub.n--Z (I); wherein X is an organic small molecule PSMA inhibitor having a formula: ##STR00010## wherein: R.sub.1 is optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O or N; optionally substituted arylene, optionally substituted arylalkylene, optionally substituted heteroarylene, optionally substituted heterocyclic, or optionally substituted carbocyclic; R.sub.2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted alkylcarboxy, or optionally substituted carbocyclic; R' and R'' are each independently --OR.sub.4, --SR.sub.4, --SOR.sub.4, --SO.sub.2R.sub.4, N(R.sub.3)S(O).sub.2--R.sub.4, --N(R.sub.3)(SO.sub.2)NR.sub.3R.sub.4, --NR.sub.3R.sub.4, --C(O)--O--R.sub.4, --C(O)R.sub.4, --C(O)NR.sub.3R.sub.4, or --N(R.sub.3)C(O)R.sub.4; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; Y is an organic linker having a formula ##STR00011## wherein A is O, S, NH, N(alkyl) or N(aryl); and R.sub.A is --(CH.sub.2).sub.r-Q-; Q is CO, C(O)O, C(O)NH, C(O)NR.sub.B, OCO, OC(O)O, OC(O)NH, OC(O)NR.sub.B, NHCO, NHC(O)O, NHC(O)NH, NHC(O)NR.sub.B, NR.sub.BCO, NR.sub.BC(O)O, NR.sub.BC(O)NH, NR.sub.BC(O)NR.sub.B, CS, C(S)O, C(S)NH, C(S)NR.sub.B, OCS, OC(S)O, OC(S)NH, OC(S)NR.sub.B, NHCS, NHC(S)O, NHC(S)NH, NHC(S)NR.sub.B, NR.sub.BCS, NR.sub.BC(S)O, NR.sub.BC(S)NH, NR.sub.BC(S)NR.sub.B; each R.sub.B is independently optionally substituted alkyl or optionally substituted aryl; and r is 3-20; Z is a nanoparticle comprising a biologically active agent and a fluorescein; m is 1-1000 and n is 1-1000. 2. The composition of claim 1, wherein Z is a nanoparticle comprising Poly-lactide-b-ethylene glycol-b-lactide (PLA-PEG-PLA), polylactide (PLA), polyglycolide, polylactide-polyglycolide, poly(lactide-co-glycolide), polyethylene glycol-co-lactide (PEG-PLA), poly(lactic-co-glycolic acid), polyhydroxybutyric acid, polyhydroxyvaleric acid, polycaprolactone, polyesteramide, polycyanoacrylate, poly(amino acids), polycarbonate, polyanhydride, poly alkylcyanoacrylate, polyethylene glycol (PEG), polysialic acid, polylactic (polylactide), polyglycolic acid (polyglycolide), apolylactic-polyglycolic acid, polyvinyl alcohol, polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxyethyloxazoline, polyhydroxypropyloxazoline, polyaspartamide, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, polyvinylmethylether, polyhydroxyethyl acrylate, derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose, methoxypolyethylene glycol, avidin, biotin; or combinations thereof; or wherein Z is a nanoparticle comprising Poly-lactide-b-ethylene glycol-b-lactide (PLA-PEG-PLA), polylactide (PLA), polyglycolide, polylactide-polyglycolide, poly(lactide-co-glycolide), polyethylene glycol-co-lactide (PEG-PLA), or combinations thereof; or wherein Z comprises one or more polymers, wherein the one or more polymers have an average molecular weight from about 2,000 Da to about 5,000 Da; or wherein the nanoparticle has a diameter ranging from about 1 nm to about 500 nm; or wherein the biologically active agent is selected from a nucleic acid, a polynucleotide, an amino acid, a peptide a protein, a polypeptide, a carbohydrate, a lipid, a glycoprotein, a glycan, a lipoprotein, and a small molecule; or wherein the biologically active agent is a known pharmaceutical; or wherein the biologically active agent is selected from an anti-AIDS agent, anti-cancer agent, antibiotic, antioxidants, immunosuppressant, anti-viral agent, enzyme inhibitor, protease inhibitor, reverse transcriptase inhibitor, fusion inhibitor, neurotoxin, opiod, hypnotic, anti-histamine, lubricant, tranquilizer, anti-convulsant, muscle relaxant, anti-Parkinson agent, anti-spasmodic, muscle contractant, channel blocker, miotic, anti-cholinergic, anti-glaucoma agent, anti-parasite, anti-protozoal, modulator of cell-extracellular matrix interaction, cell growth inhibitor, anti-adhesion agent, vasodilating agent, inhibitor of DNA, inhibitor of RNA, inhibitor of protein synthesis, inhibitors of apoptotic genes, modulators of transcription factors, anti-hypertensive, analgesic, anti-pyretic, steroidal anti-inflammatory agent, non steroidal anti-inflammatory agent, anti-angiogenic, anti-secretory, anticoagulant, antithrombotic agent, local anesthetic, ophthalmic, prostaglandin, anti-depressant, anti-psychotic, anti-emetic, antiproliferative, antimigration, antiangiogenic, antithrombotic, anti-inflammatory, antiphlogistic, cytostatic, cytotoxic, anticoagulative, antibacterial, antiviral and/or antimycotic agent and an imaging agent; or wherein the biologically active agent is selected from actinomycin D, ametantrone, 9-Aminocamptothecin, aminoglutethimide, amsacrine, anastrozole, antagonists of purine and pyrimidine bases, anthracycline, aromatase inhibitors, asparaginase, antiestrogens, bendamustine, bexarotene, biolimus A9, bleomycin, buserelin, busulfan, calicheamicins, camptothecin, camptothecin derivatives, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, alkylating cytostatics, dacarbazine, dactinomycin, daunorubicin, 5'-deoxy-5-fluorouridine, docetaxel, doxorubicin (adriamycin), doxorubicin lipo, epirubicin, estramustine, etoposide, exemestane, fludarabine, fluorouracil, folic acid antagonists, formestane, gemcitabine, glucocorticoids, goserelin, hormones and hormone antagonists, hycamtin, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, letrozole, leuprorelin, lomustine, maytansinoids, melphalan, mercaptopurine, methotrexate, miltefosine, mitomycins, mitopodozide, antimitotic agents, mitoxantrone, nimustine, oxaliplatin, oxazaphosphorines, paclitaxel, pentostatin, podophyllotoxin derivatives, procarbazine, rapamycin, rhodomycin D, tamoxifen, temozolomide, teniposide, testolactone, thiotepa, thioguanine, topoisomerase inhibitors, topotecan, treosulfan, tretinoin, triptorelin, trofosfamides, vinca alkaloids, vinblastine, vincristine, vindesine, vinorelbine, cytostatically active antibiotics, chlorethamine, cyclophosphamide, trofosfamide, ifosfamide, melphalan, chlorambucil, busulfan, thiotepa, carmustine, lomustine, dacarbazine, procarbazine, temozolomide, treosulfan, estramustine, nimustine, daunorubicin, doxorubicin (adriamycin), dactinomycin, mitomycin C, bleomycin, epirubicin (4-epi-adriamycin), idarubicin, mitoxantrone, amsacrine, actinomycin D, methotrexate, 5-fluorouracil, 6-thioguanin, 6-mercaptopurine, fludarabine, cladribine, pentostatin, gemcitabine, cytarabine, azathioprine, raltitrexed, capecitabine, cytosine arabinoside, thioguanine, mercaptopurine, vincristine, vinblastine, vindesine, etoposide, alkaloids, podophyllotoxins, cisplatin, carboplatin, oxaliplatin, vincristine, vinblastine, vindesine, vinorelbine, paclitaxel, etoposide, teniposide, camptothecin, topotecan, irinotecan, hydroxycarbamide (hydroxyurea), imatinib, miltefosine, amsacrine, topotecan (inhibitor of topoisomerase-I), pentostatin, bexarotene, biolimus A9, rapamycin (sirolimus), rhodomycin D, ametantrone, bendamustine, oxazaphosphorine, 5'-deoxy-5-fluorouridine, 9-aminocamptothecin, podophyllotoxin derivatives, mitopodozide, vinca alkaloids, calicheamicins, maytansinoids, tretinoin, asparaginase, trastuzumab, alemtuzumab) and rituximab, glucocorticoids, prednisone, estrogens, fosfestrol, estramustine, LHRH, buserelin, goserelin, leuprorelin, triptorelin, flutamide, cyproterone acetate, tamoxifen, toremifen, aminoglutethimide, formestane, exemestane, letrozole, anastrozole, Cu/Zn SOD, glutathione, anti-apoptotic polypeptides; or wherein the biologically active agent is docetaxel. 3. The composition of claim 2, wherein R' and R'' are each independently --OR.sub.4; wherein each R.sub.4 is independently H, methyl, or ethyl; wherein R.sub.1 is a side chain of a naturally occurring amino acid; or wherein R.sub.1 is optionally substituted alkylene, containing 0, 1, 2, or 3 heteroatoms selected from O, or N; optionally substituted arylalkylene, or optionally substituted heterocyclic; wherein R.sub.2 is optionally substituted alkyl, containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; or optionally substituted arylalkyl; or wherein R.sub.2 is a side chain of a naturally occurring amino acid; or wherein R.sub.1 is (CH.sub.2).sub.p--O--Y, (CH.sub.2).sub.p--SO--Y, (CH.sub.2).sub.p--SO.sub.2--Y, (CH.sub.2).sub.p--N(R.sub.3)S(O).sub.2--Y, (CH.sub.2).sub.p--N(R.sub.3)(SO.sub.2)NR.sub.3--Y, (CH.sub.2).sub.p--NR.sub.3--Y, (CH.sub.2).sub.p--C(O)--O--Y, (CH.sub.2).sub.p--C(O)--Y, (CH.sub.2).sub.p--C(O)NR.sub.3--Y, or (CH.sub.2).sub.p--N(R.sub.3)C(O)--Y; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; and p is 1-6; or wherein R.sub.1 is (CH.sub.2).sub.p--O--Y, (CH.sub.2).sub.p--NR.sub.3--Y, (CH.sub.2).sub.p--C(O)--O--Y, (CH.sub.2).sub.p--C(O)--Y, (CH.sub.2).sub.p--C(O)NR.sub.3--Y, or (CH.sub.2).sub.p--N(R.sub.3)C(O)--Y; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; and p is 3-6; or wherein R.sub.1 is (CH.sub.2).sub.p--NR.sub.3--Y; wherein R.sub.2 is (CH.sub.2).sub.p--OR.sub.4, (CH.sub.2).sub.p--SR.sub.4, (CH.sub.2).sub.p--SOR.sub.4, (CH.sub.2).sub.p--SO.sub.2R.sub.4, (CH.sub.2).sub.p--N(R.sub.3)S(O).sub.2--R.sub.4, (CH.sub.2).sub.p--N(R.sub.3)(SO.sub.2)NR.sub.3R.sub.4, (CH.sub.2).sub.p--NR.sub.3R.sub.4, (CH.sub.2).sub.p--C(O)--O--R.sub.4, (CH.sub.2).sub.p--C(O)R.sub.4, (CH.sub.2).sub.p--C(O)NR.sub.3R.sub.4, or (CH.sub.2).sub.p--N(R.sub.3)C(O)R.sub.4; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; and p is 1-6; or wherein R.sub.2 is (CH.sub.2).sub.p--OR.sub.4, (CH.sub.2).sub.p--C(O)--O--R.sub.4, (CH.sub.2).sub.p--C(O)R.sub.4, (CH.sub.2).sub.p--C(O)NR.sub.3R.sub.4, or (CH.sub.2).sub.p--N(R.sub.3)C(O)R.sub.4; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; and p is 1-3; or wherein R.sub.2 is (CH.sub.2).sub.p--C(O)--O--R.sub.4; or wherein A is C.dbd.O; or wherein R.sub.A is (CH.sub.2).sub.r-Q-Z, (CH.sub.2O).sub.r-Q-Z, (CH.sub.2NH).sub.r-Q-Z, (CH.sub.2NR.sub.B).sub.r-Q-Z, or combinations thereof, wherein Q is CO, C(O)O, C(O)NH, C(O)NR.sub.B, OCO, OC(O)O, OC(O)NH, OC(O)NR.sub.B, NHCO, NHC(O)O, NHC(O)NH, NHC(O)NR.sub.B, NR.sub.BCO, NR.sub.BC(O)O, NR.sub.BC(O)NH, NR.sub.BC(O)NR.sub.B, CS, C(S)O, C(S)NH, C(S)NR.sub.B, OCS, OC(S)O, OC(S)NH, OC(S)NR.sub.B, NHCS, NHC(S)O, NHC(S)NH, NHC(S)NR.sub.B, NR.sub.BCS, NR.sub.BC(S)O, NR.sub.BC(S)NH, NR.sub.BC(S)NR.sub.B; each R.sub.B is independently optionally substituted alkyl or optionally substituted aryl; and r is 3-20; or wherein Q is C(O)O, NHC(S)NH, or NHC(O)NH. 4. The composition of claim 1, of formula III: ##STR00012## wherein, R.sub.1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted carbocyclic; R.sub.2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted alkylcarboxy, or optionally substituted carbocyclic; R' and R'' are each independently --OR.sub.4, --SR.sub.4, --SOR.sub.4, --SO.sub.2R.sub.4, --N(R.sub.3)S(O).sub.2--R.sub.4, --N(R.sub.3)(SO.sub.2)NR.sub.3R.sub.4, --NR.sub.3R.sub.4, --C(O)--O--R.sub.4, --C(O)R.sub.4, --C(O)NR.sub.3R.sub.4, or --N(R.sub.3)C(O)R.sub.4; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; A is O, S, NH, N(alkyl) or N(aryl); and R.sub.A is optionally substituted alkylene, optionally substituted alkenylene or optionally substituted alkynylene, each containing heteroatoms selected from O, S, or N; Z is a nanoparticle comprising a biologically active agent; and q is 1-1000; or a pharmaceutically acceptable salt thereof. 5. The composition of claim 4, wherein R' and R'' are each independently --OR.sub.4; and each R.sub.4 is independently H, methyl, or ethyl; wherein R.sub.1 is optionally substituted alkylene, containing 0, 1, 2, or 3 heteroatoms selected from O, or N; optionally substituted arylalkylene, or optionally substituted heterocyclic; or wherein R.sub.1 is (CH.sub.2).sub.p--O--, (CH.sub.2).sub.p--NR.sub.3--, (CH.sub.2).sub.p--C(O)--O--, (CH.sub.2).sub.p--C(O)--, (CH.sub.2).sub.p--C(O)NR.sub.3--, or (CH.sub.2).sub.p--N(R.sub.3)C(O)--; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; and p is 3-6; or wherein R.sub.1 is (CH.sub.2).sub.p--NR.sub.3--; wherein R.sub.2 is optionally substituted alkyl, containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; or optionally substituted arylalkyl; or wherein R.sub.2 is (CH.sub.2).sub.p--OR.sub.4, (CH.sub.2).sub.p--C(O)--O--R.sub.4, (CH.sub.2).sub.p--C(O)R.sub.4, (CH.sub.2).sub.p--C(O)NR.sub.3R.sub.4, or (CH.sub.2).sub.p--N(R.sub.3)C(O)R.sub.4; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; and p is 1-3; or wherein R.sub.2 is (CH.sub.2).sub.p--C(O)--O--R.sub.4; or wherein A is C.dbd.O; R.sub.A is (CH.sub.2).sub.r-Q-, (CH.sub.2O).sub.r-Q-, (CH.sub.2NH).sub.r-Q-, (CH.sub.2NR.sub.B).sub.r-Q-, or combinations thereof, wherein Q is CO, C(O)O, C(O)NH, C(O)NR.sub.B, OCO, OC(O)O, OC(O)NH, OC(O)NR.sub.B, NHCO, NHC(O)O, NHC(O)NH, NHC(O)NR.sub.B, NR.sub.BCO, NR.sub.BC(O)O, NR.sub.BC(O)NH, NR.sub.BC(O)NR.sub.B, CS, C(S)O, C(S)NH, C(S)NR.sub.B, OCS, OC(S)O, OC(S)NH, OC(S)NR.sub.B, NHCS, NHC(S)O, NHC(S)NH, NHC(S)NR.sub.B, NR.sub.BCS, NR.sub.BC(S)O, NR.sub.BC(S)NH, NR.sub.BC(S)NR.sub.B; each R.sub.B is independently optionally substituted alkyl or optionally substituted aryl; and r is 3-20; or wherein Q is C(O)O, NHC(S)NH, or NHC(O)NH; or wherein Z is a nanoparticle comprising Poly-lactide-b-ethylene glycol-b-lactide (PLA-PEG-PLA), polylactide (PLA), polyglycolide, polylactide-polyglycolide, poly(lactide-co-glycolide), polyethylene glycol-co-lactide (PEG-PLA), or combinations thereof. 6. The composition of claim 1, of formula IV: ##STR00013## wherein, R' and R'' are each independently --OR.sub.4, --SR.sub.4, --SOR.sub.4, --SO.sub.2R.sub.4, --N(R.sub.3)S(O).sub.2--R.sub.4, --N(R.sub.3)(SO.sub.2)NR.sub.3R.sub.4, --NR.sub.3R.sub.4, --C(O)--O--R.sub.4, --C(O)R.sub.4, --C(O)NR.sub.3R.sub.4, or --N(R.sub.3)C(O)R.sub.4; R.sub.3 and R.sub.4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; R.sub.A is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing heteroatoms selected from O, S, or N; Z is a nanoparticle comprising a biologically active agent; n is 1-4; p is 1-3; and q is 1-1000; or a pharmaceutically acceptable salt thereof. 7. The composition of claim 6, wherein R' and R'' are each independently --OR.sub.4; and each R.sub.4 is independently H, methyl, or ethyl; or wherein R.sub.A is (CH.sub.2).sub.r-Q-, (CH.sub.2O).sub.r-Q-, (CH.sub.2NH).sub.r-Q-, (CH.sub.2NR.sub.B).sub.r-Q-, or combinations thereof, wherein Q is CO, C(O)O, C(O)NH, C(O)NR.sub.B, OCO, OC(O)O, OC(O)NH, OC(O)NR.sub.B, NHCO, NHC(O)O, NHC(O)NH, NHC(O)NR.sub.B, NR.sub.BCO, NR.sub.BC(O)O, NR.sub.BC(O)NH, NR.sub.BC(O)NR.sub.B, CS, C(S)O, C(S)NH, C(S)NR.sub.B, OCS, OC(S)O, OC(S)NH, OC(S)NR.sub.B, NHCS, NHC(S)O, NHC(S)NH, NHC(S)NR.sub.B, NR.sub.BCS, NR.sub.BC(S)O, NR.sub.BC(S)NH, NR.sub.BC(S)NR.sub.B; each R.sub.B is independently optionally substituted alkyl or optionally substituted aryl; and r is 3-20; or wherein Q is C(O)O, NHC(S)NH, or NHC(O)NH; or wherein Z is a nanoparticle comprising Poly-lactide-b-ethylene glycol-b-lactide (PLA-PEG-PLA), polylactide (PLA), polyglycolide, polylactide-polyglycolide, poly(lactide-co-glycolide), polyethylene glycol-co-lactide (PEG-PLA), or combinations thereof. 8. A kit comprising a nanoparticle composition of claim 1, and instructions for use in treating cancer. 9. A pharmaceutical composition comprising a nanoparticle composition of claim 1, and a pharmaceutically suitable excipient. 10. A method of synthesizing the nanoparticle composition of claim 1, comprising the steps of: a) reacting a compound of formula A: ##STR00014## wherein, R.sub.1 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted carbocyclic; R.sub.2 is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted carbocyclic; R' and R'' are each independently --OR.sub.4, --SR.sub.4, --SOR.sub.4, --SO.sub.2R.sub.4, --N(R.sub.3)S(O).sub.2--R.sub.4, --N(R.sub.3)(SO.sub.2)NR.sub.3R.sub.4, --NR.sub.3R.sub.4, --C(O)--O--R.sub.4, --C(O)R.sub.4, --C(O)NR.sub.3R.sub.4, or --N(R.sub.3)C(O)R.sub.4; R.sub.3 and R4 are each independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; or optionally substituted carbocyclic; with a compound of formula B: ##STR00015## wherein A is O, S, NH, N(alkyl) or N(aryl); R.sub.A is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing heteroatoms selected from O, S, or N; and each LG is independently a leaving group; and each LG is independently a leaving group; and b) reacting the product of step a) with a nanoparticle comprising a biologically active agent to form the nanoparticle composition of claim 1. 11. A method comprising administering the nanoparticle composition of claim 1 to a subject, wherein the subject optionally has a disease or disorder. 12. The method of claim 11, wherein the disease is cancer or a proliferation disease. 13. The method of claim 12, wherein the disease is prostate cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, epithelial cancers, esophageal cancer, gastrointestinal cancers, gall bladder cancer, gynecological cancers, kidney cancer, laryngeal cancer, liver cancer, lung cancer, nose cancer, ovarian cancer, pancreatic cancer, rectum cancer, Schneeberg lung cancer, skin cancer, squamus cell and/or basal cell cancers, stomach cancer, testicular cancer, throat cancer, tongue cancer, urethral cancer, uterine cancer, vaginal cancer, cancer of the large intestine, cancer of the small intestine, cancer in the area of the mouth and on the lip, brain tumors (gliomas), connective tissue tumor, Ewing tumors, eye tumors, germ cell tumor, hypophysis tumor, osteolytic tumors and osteoblastic tumors, soft tissue tumors, urological tumors, Wilm's tumor, tumors of the small intestine, tumors of ear, nose and throat, head and neck tumors (tumors situated in the region of the neck, nose and ears), tumor of the eyelid, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), adenocarcinomas, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytomas, basal cell carcinoma, brain metastases, breast carcinoma, bronchial carcinoma, Burkitt's lymphoma, Canine B-Cell Lymphoma, carcinoids, choroidal melanoma, chronic myelogenous leukemia (CML), colorectal carcinoma, colon carcinoma, craniopharyngiomas, corpus carcinoma, CUP syndrome, endometrial carcinoma, ependymoma, epithelial call-derived neoplasia (epithelial carcinoma), esophageal carcinoma, gall carcinomas, glioblastomas, hairy cell leukemia, head and neck squamous cell carcinoma, hematological neoplasias, hepatocellular carcinoma, Hodgkin's disease, Kaposi's sarcoma, liver metastases, leukemia, lymphomas, malignant lymphoma (Hodgkin/Non-Hodgkin), malignant melanoma, malignant neoplasma, malignomas of the gastrointestinal tract, medulloblastomas, melanoma, meningiomas, mycosis fungoides, myelomas, neurinoma, neuroblastoma, Non-Hodgkin's lymphomas, non-small cell bronchial carcinoma, oligodendroglioma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, papillary renal carcinoma, penile carcinoma, plasmacytoma, prostate carcinoma, rectal carcinoma, renal cell carcinoma, retinoblastoma, squamous cell carcinoma of the head and the neck, soft tissue sarcoma, spinocellular carcinoma, T-cell lymphoma (Mycosis fungoides), thymoma, thyroid carcinoma, tube carcinoma, urothelial carcinoma, vulvar carcinoma, wart appearance, and solid tumors; or wherein the disease is cancer, wherein the cancer comprises a neovasculature expressing PSMA; or wherein the disease is prostate cancer, renal cell carcinoma, glioblastoma, colon cancer, gastric cancer, bladder cancer, pancreatic cancer, sarcoma, melanoma, skin cancer and lung cancer; or wherein the disease is inflammation, arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, systemic lupus erthematosus (SLE), skin-related conditions, psoriasis, eczema, burns, dermatitis, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, complications associated with hypertension and/or heart failure, vascular organ damage, restenosis, cardiomyopathy, stroke, ischemic stroke, hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia, brain ischemia, ischemia resulting from cardiac/coronary bypass, neurodegenerative disorders, liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, pneumonia, herpes virus, myalgias due to infection, influenza, autoimmune disease, graft vs. host reaction and allograft rejections, treatment of bone resorption diseases, osteoporosis, multiple sclerosis, angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders having an inflammatory or apoptotic component, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy. 14. The method of claim 11, wherein the subject is administered an additional therapeutic agent. 15. The method of claim 14, wherein the nanoparticle composition and the additional therapeutic agent are administered simultaneously or sequentially. 16. The method of claim 11, wherein the subject is a human, rat, mouse, cat, dog, horse, sheep, cow, monkey, avian, or amphibian. 17. The method of claim 11, wherein the subject is a human. 18. The method of claim 11, wherein the nanoparticle composition has an IC.sub.50 value ranging from about 0.1 to about 200 nM. 19. The method of claim 17, wherein the nanoparticle composition has an IC.sub.50 value ranging from about 0.5 to about 125 nM.

Details for Patent 10,369,113

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2027-11-30
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2027-11-30
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2027-11-30
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2027-11-30
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2027-11-30