Polymeric systems for the delivery of anticancer drugs

Abstract

The present invention relates to compositions for the treatment of cancerous tissues in warm-blooded animals containing one or two anticancer agents attached to polymeric carriers having monomer units derived from one or more of N-(2-carboxypropyl)methacrylamide (2-CPMA), N-(3-carboxypropyl)methacrylamide (3-CPMA), N-(2-aminopropyl)methacrylamide (2-APMA) and/or N-(3-aminopropyl)methacrylamide (3-APMA) are also included. Anticancer agents in compositions can be attached to said polymeric carrier by side-chains which can be susceptible to hydrolysis by lysosomal enzymes intracellularly. Compositions can also include a targeting ligand attached to the polymeric carrier, optionally through a second linker.

1 - 20 . (canceled) 
     
     
         21 . A therapeutic composition comprising
 a first polymer carrier comprises
 (a) a first monomer selected from the group consisting of N-(3-aminopropyl)methacrylamide (3-APMA), and N-(2-aminopropyl)methacrylamide (2-APMA), and their combination; and 
 (b) optionally a second monomer; and 
   a first anticancer agent attached to the first polymer carrier, optionally through a first linker; and   a targeting ligand attached to the first polymer carrier, optionally through a second linker,   wherein the targeting ligand is selected from the group consisting of RGDfK (arginine-glycine-aspartic acid-D-phenylalanine-lysine oligopeptide), EPPT1 (YCAREPPTRTFAYWG, that is, tyrosine-cysteine-alanine-arginine-glutamic acid-proline-proline-threonine-arginine-threonine-phenylalanine-alanine-tyrosine-tryptophane-glycineoligopeptide), and folate.   
     
     
         22 . The composition of  claim 21 , wherein the first anticancer agent is attached to the first polymer carrier through the first linker, wherein the first anticancer agent is selected from the group consisting of docetaxel, gemcitabine, cisplatin, and their combination. 
     
     
         23 . The composition of  claim 21 , wherein the first polymer carrier further comprises a second monomer selected from the group consisting of N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-carboxypropyl) methacrylamide (2-CPMA), N-(3-carboxypropyl)methacrylamide (3-CPMA), an acrylamide, a methacrylamide, an acrylate, and a methacrylate. 
     
     
         24 . The composition of  claim 21 , further comprising an additional anticancer agent attached to the first polymer carrier, optionally through a linker, wherein the additional anticancer agent is different than the first anticancer agent, and wherein the additional anticancer agent is attached to the first monomer or if a second monomer is present, the additional anticancer agent is attached to the first monomer or the second monomer. 
     
     
         25 . The composition of  claim 21 , wherein the targeting ligand is attached to the first monomer or, if a second monomer is present, the targeting ligand is attached to the first monomer or the second monomer. 
     
     
         26 . The composition of  claim 21 , further comprising
 a second polymer carrier; and   a second anticancer agent attached to the second polymer carrier, optionally through a linker;   wherein the second polymer carrier comprises a second monomer selected from the group consisting of N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-carboxypropyl) methacrylamide (2-CPMA), N-(3-carboxypropyl)methacrylamide (3-CPMA), N-(3-aminopropyl)methacrylamide (3-APMA), and N-(2-aminopropyl)methacrylamide (2-APMA), and combinations, and   wherein the second anticancer agent is selected from the group consisting of docetaxel, gemcitabine, cisplatin, and their combination.   
     
     
         27 . The composition of  claim 21 , wherein said first polymer carrier comprises (a) between about 5.0 and about 99.7 mol % of underivatized monomer units, (b) between about 0.2 and about 20.0 mol % of derivatized monomer units attached to the first anticancer agent; and (c) between about 0 and about 94.8 mol % of derivatized monomer units attached to a targeting ligand. 
     
     
         28 . The composition of  claim 27 , wherein said first polymer carrier comprises between about 0.1 and about 94.8 mol % of derivatized monomer units attached to the targeting ligand. 
     
     
         29 . The composition of  claim 21  having one or more linkers, wherein each of the one or more linkers is susceptible to cleavage by lysosomal enzymes. 
     
     
         30 . The composition of  claim 29 , wherein the linker is selected from the group consisting of oligopeptide sequences, oligosaccharide sequences and structures similar to those in nucleic acids. 
     
     
         31 . The composition of  claim 30 , wherein the linker is an oligopeptide sequence selected from the group consisting of Gly-Gly, Gly-Phe-Gly, Gly-Phe-Phe, Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Ala-Val-Ala, Gly-Phe-Leu-Gly (SEQ ID NO: 1), Gly-Phe-Phe-Leu (SEQ ID NO: 2), Gly-Leu-Leu-Gly (SEQ ID NO: 3), Gly-Phe-Tyr-Ala (SEQ ID NO: 4), Gly-Phe-Gly-Phe (SEQ ID NO: 5), Ala-Gly-Val-Phe (SEQ ID NO: 6), Gly-Phe-Phe-Gly (SEQ ID NO: 7), Gly-Phe-Leu-Gly-Phe (SEQ ID NO: 8), or Gly-Gly-Phe-Leu-Gly-Phe (SEQ ID NO: 9). 
     
     
         32 . The composition of  claim 31 , wherein the oligopeptide sequence is Gly-Phe-Leu-Gly (SEQ ID NO: 1). 
     
     
         33 . A pharmaceutical composition comprising the composition of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         34 . A method of treating a cancer or neoplastic disease comprising administering a therapeutically effective amount of a composition according to  claim 21 . 
     
     
         35 . The method of  claim 34 , wherein the cancer or neoplastic disease is selected from the group consisting of carcinomas, carcinomas of solid tissues, squamous cell carcinomas, adenocarcinomas, sarcomas, gliomas, high grade gliomas, blastomas, neuroblastomas, plasmacytomas, histiocytomas, melanomas, adenomas, hypoxic tumours, myelomas, metastatic cancers, cervical dysplasias, anal dysplasias, severe dysplasias, hyperplasias, atypical hyperplasias, and neoplasias. 
     
     
         36 . A method of making a therapeutic composition comprising:
 reacting a first polymer carrier with a first anticancer agent, optionally through a linker, to produce a first conjugated drug monomer, wherein the first polymer carrier comprises a first monomer selected from the group consisting of N-(3-aminopropyl)methacrylamide (3-APMA), and N-(2-aminopropyl)methacrylamide (2-APMA), and their combination;   polymerizing the first conjugated drug monomers to form a polymer drug conjugate; and   adding a targeting ligand to the polymer drug conjugate, wherein the targeting ligand is selected from the group consisting of RGDfK (arginine-glycine-aspartic acid-D-phenylalanine-lysine oligopeptide), EPPT1 (YCAREPPTRTFAYWG, that is, tyrosine-cysteine-alanine-arginine-glutamic acid-proline-proline-threonine-arginine-threonine-phenylalanine-alanine-tyrosine-tryptophane-glycineoligopeptide), and folate.   
     
     
         37 . The method of  claim 36 , further comprising
 coupling the linker with the first anticancer agent,   wherein the linker is selected from the group consisting of oligopeptide sequences, oligosaccharide sequences and structures similar to those in nucleic acids, and wherein the linker is coupled to the first monomer molecule and   wherein the first anticancer agent is selected from the group consisting of docetaxel, gemcitabine, cisplatin, and their combination.   
     
     
         38 . The method of  claim 36 , wherein the first polymer carrier further comprises a second monomer selected from the group consisting of N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-carboxypropyl) methacrylamide (2-CPMA), N-(3-carboxypropyl)methacrylamide (3-CPMA), an acrylamide, a methacrylamide, an acrylate, and a methacrylate. 
     
     
         39 . The method of  claim 36 , further comprising
 reacting a second anticancer agent with the first polymer carrier, optionally through a linker, wherein the additional anticancer agent is different than the first anticancer agent, and wherein the additional anticancer agent is attached to the first monomer or if a second monomer is present, the additional anticancer agent is attached to the first monomer or the second monomer.   
     
     
         40 . The method of  claim 36 , further comprising
 polymerizing a second conjugated drug monomer with the first conjugated drug monomer to form the polymer drug conjugate,   wherein the second conjugated drug monomer comprises a second monomer selected from the group consisting of N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-carboxypropyl) methacrylamide (2-CPMA), N-(3-carboxypropyl)methacrylamide (3-CPMA), N-(3-aminopropyl)methacrylamide (3-APMA), and N-(2-aminopropyl)methacrylamide (2-APMA), and combinations, and   wherein the second anticancer agent is selected from the group consisting of docetaxel, gemcitabine, cisplatin, and their combination.