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.

1 . A nanoparticle composition comprising,
 a) a prostate specific membrane antigen (PSMA) inhibitor;   b) a linker,   c) a biologically active agent; and   d) a nanoparticle.   
     
     
         2 . The composition of  claim 1 , wherein the PSMA inhibitor is attached to a linker. 
     
     
         3 . The composition of  claim 1 , wherein the biologically active agent is encapsulated in the nanoparticle. 
     
     
         4 . The composition of  claim 1 , wherein the linker is attached to the nanoparticle. 
     
     
         5 . A nanoparticle composition of formula I:
   (X) m (Y) n —Z  (I);
   wherein   X is an organic small molecule PSMA inhibitor;   Y is an organic linker;   Z is a nanoparticle comprising a biologically active agent;   m is 1-1000 and   n is 1-1000.   
     
     
         6 . The composition of  claim 5 , wherein X is a compound of formula II, 
       
         
           
           
               
               
           
         
         wherein, 
         R 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 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; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 - 18 . (canceled) 
     
     
         19 . The composition of  claim 5 , wherein Y is 
       
         
           
           
               
               
           
         
         wherein 
         A is O, S, NH, N(alkyl) or N(aryl); and 
         R A  is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing heteroatoms selected from O, S, or N. 
       
     
     
         20 - 30 . (canceled) 
     
     
         31 . The composition of  claim 5 , 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. 
     
     
         32 - 33 . (canceled) 
     
     
         34 . The composition of  claim 5 , of formula III: 
       
         
           
           
               
               
           
         
         wherein, 
         R 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 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; 
         A is O, S, NH, N(alkyl) or N(aryl); and 
         R 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; and 
         q is 1-1000; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 - 44 . (canceled) 
     
     
         45 . The composition of  claim 5 , of formula IV: 
       
         
           
           
               
               
           
         
         wherein, 
         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; 
         R 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; and 
         q is 1-1000; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 - 49 . (canceled) 
     
     
         50 . A method for treating or preventing a disease or disorder in a subject, the method comprising the step of administering to the subject a nanoparticle composition of  claim 1 , such that the administration of the nanoparticle composition is effective to treat or prevent said disease or disorder. 
     
     
         51 . The method of  claim 50 , wherein the disease is cancer or a proliferation disease. 
     
     
         52 . The method of  claim 51 , wherein the disease is cancer, tumor or carcinoma. 
     
     
         53 . The method of  claim 52 , 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. 
     
     
         54 - 62 . (canceled) 
     
     
         63 . A kit comprising a nanoparticle composition of  claim 1 , and instructions for use in treating cancer. 
     
     
         64 . A pharmaceutical composition comprising a nanoparticle composition of  claim 1 , and a pharmaceutically suitable excipient. 
     
     
         65 . A method of synthesizing a compound of formula II in  claim 5 , comprising the steps of:
 a) reacting a compound of formula A:   
       
         
           
           
               
               
           
         
         wherein, 
         R 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 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 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; 
         with a compound of formula B: 
       
       
         
           
           
               
               
           
         
         wherein 
         A is O, S, NH, N(alkyl) or N(aryl); 
         R 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 
         b) reacting the product of step a) with a nanoparticle comprising a biologically active agent to form a composition of formula II. 
       
     
     
         66 . A method for treating or preventing a disease or disorder in a subject, the method comprising the step of administering to the subject a nanoparticle composition of  claim 5 , such that the administration of the nanoparticle composition is effective to treat or prevent said disease or disorder. 
     
     
         67 . A kit comprising a nanoparticle composition of  claim 5 , and instructions for use in treating cancer. 
     
     
         68 . A pharmaceutical composition comprising a nanoparticle composition of  claim 5 , and a pharmaceutically suitable excipient.