Prostate specific membrane antigen (PSMA) targeted nanoparticles for therapy of prostate cancer

Patent metadata

Field	Value
Publication number	US-10369113-B2
Application number	US-201615209352-A
Country	US
Kind code	B2
Filing date	Jul 13, 2016
Priority date	Nov 30, 2007
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

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.

First claim

What is claimed is:

1. A nanoparticle composition of formula I:
(X) m —(Y) n —Z  (I);

wherein
X is an organic small molecule PSMA inhibitor having a formula:

wherein:
R 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 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 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , N(R 3 )S(O) 2 —R 4 , —N(R 3 )(SO 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)—O—R 4 , —C(O)R 4 , —C(O)NR 3 R 4 , or —N(R 3 )C(O)R 4 ;
R 3 and R 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

wherein A is O, S, NH, N(alkyl) or N(aryl); and
R A is —(CH 2 ) r -Q-;
Q is CO, C(O)O, C(O)NH, C(O)NR B , OCO, OC(O)O, OC(O)NH, OC(O)NR B , NHCO, NHC(O)O, NHC(O)NH, NHC(O)NR B , NR B CO, NR B C(O)O, NR B C(O)NH, NR B C(O)NR B , CS, C(S)O, C(S)NH, C(S)NR B , OCS, OC(S)O, OC(S)NH, OC(S)NR B , NHCS, NHC(S)O, NHC(S)NH, NHC(S)NR B , NR B CS, NR B C(S)O, NR B C(S)NH, NR B C(S)NR B ;
each R 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,

Assignees

• Univ Johns Hopkins

Inventors

• Chandran Sachin S
• Ray Sangeeta
• Pomper Martin G
• Denmeade Samuel R
• Mease Ronnie C

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title