Poly(amino acid) targeting moieties

Abstract

The present invention generally relates to polymers and macromolecules, in particular, to polymers useful in particles such as nanoparticles. One aspect of the invention is directed to a method of developing nanoparticles with desired properties. In one set of embodiments, the method includes producing libraries of nanoparticles having highly controlled properties, which can be formed by mixing together two or more macromolecules in different ratios. One or more of the macromolecules may be a polymeric conjugate of a moiety to a biocompatible polymer. In some cases, the nanoparticle may contain a drug. Other aspects of the invention are directed to methods using nanoparticle libraries.

1 . A controlled-release system, comprising
 a plurality of target-specific stealth nanoparticles;   wherein said nanoparticles contain targeting moieties attached thereto, wherein the targeting moiety is a poly(amino acid) that targets the basement membrane of a blood vessel.   
     
     
         2 . The controlled-release system of  claim 1 , wherein the nanoparticle has an amount of targeting moiety effective for the treatment of vulnerable plaque in a subject in need thereof. 
     
     
         3 . The controlled-release system of  claim 1 , wherein the nanoparticle has an amount of targeting moiety effective for the treatment of restenosis. 
     
     
         4 . The controlled-release system of  claim 1 , wherein the nanoparticle has an amount of targeting moiety effective for the treatment of cancer in a subject in need thereof. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The controlled-release system of  claim 1 , wherein the poly(amino acid) comprises natural amino acids, unnatural amino acids, modified amino acids, or protected amino acids. 
     
     
         8 . The controlled-release system of  claim 1 , wherein the poly(amino acid) is selected from the group consisting of a protein, peptidomimetic, affibody or peptide. 
     
     
         9 . The controlled-release system of  claim 1 , wherein the poly(amino acid) binds to the basement membrane of a blood vessel. 
     
     
         10 . The controlled-release system of  claim 1 , wherein the poly(amino acid) binds to collagen. 
     
     
         11 . The controlled-release system of  claim 1 , wherein the poly(amino acid) binds to collagen IV. 
     
     
         12 . (canceled) 
     
     
         13 . The controlled-release system of  claim 8 , wherein the peptide comprises a sequence selected from the group consisting of AKERC, CREKA, ARYLQKLN and AXYLZZLN, wherein X and Z are variable amino acids. 
     
     
         14 . The controlled-release system of  claim 1 , wherein the nanoparticle comprises a polymeric matrix. 
     
     
         15 . The controlled-release system of  claim 14 , wherein the polymeric matrix comprises two or more polymers. 
     
     
         16 . The controlled-release system of  claim 13 , wherein the polymeric matrix comprises polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, dextran or polyamines, or combinations thereof. 
     
     
         17 - 19 . (canceled) 
     
     
         20 . The controlled-release system of  claim 14 , wherein at least one polymer is a polyester. 
     
     
         21 . The controlled-release system of  claim 20 , wherein the polyester is selected from the group consisting of PLGA, PLA, PGA, and polycaprolactones. 
     
     
         22 . The controlled-release system of  claim 20 , wherein the polyester is PLGA or PLA. 
     
     
         23 . The controlled-release system of  claim 14 , wherein the polymeric matrix comprises a copolymer of two or more polymers. 
     
     
         24 . The controlled-release system of  claim 23 , wherein the copolymer is a copolymer of a polyalkylene glycol and a polyester. 
     
     
         25 . The controlled-release system of  claim 24 , wherein the copolymer is a copolymer of PLGA and PEG. 
     
     
         26 . The controlled-release system of  claim 24 , wherein the polymeric matrix comprises PLGA and a copolymer of PLGA and PEG. 
     
     
         27 . (canceled) 
     
     
         28 . The controlled-release system of  claim 14 , wherein the polymeric matrix comprises lipid-terminated PEG and PLGA. 
     
     
         29 - 34 . (canceled) 
     
     
         35 . The controlled-release system of  claim 14 , wherein the nanoparticle has a ratio of ligand-bound polymer to non-functionalized polymer effective for the treatment of cancer. 
     
     
         36 . The controlled-release system of  claim 14 , wherein the nanoparticle has a ratio of ligand-bound polymer to non-functionalized polymer effective for the treatment of a vulnerable plaque. 
     
     
         37 . The controlled-release system of  claim 14 , wherein the polymers of the polymer matrix have a molecular weight effective for the treatment of cancer. 
     
     
         38 . The controlled-release system of  claim 14 , wherein the polymers of the polymer matrix have a molecular weight effective for the treatment of vulnerable plaque. 
     
     
         39 - 42 . (canceled) 
     
     
         43 . The controlled-release system of  claim 1 , wherein the nanoparticle further comprises a therapeutic agent. 
     
     
         44 - 45 . (canceled) 
     
     
         46 . The controlled-release system of  claim 43 , wherein the therapeutic agent is selected from the group consisting of mitoxantrone and docetaxel. 
     
     
         47 . The controlled-release system of  claim 43 , wherein the therapeutic agent is selected from the group consisting of VEGF, fibroblast growth factors, monocyte chemoatractant protein 1 (MCP-1), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta), DEL-1, insulin like growth factors (IGF), placental growth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1 (PG-E1), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (THF-alpha), granulocyte stimulating growth factor (G-CSF), granulocyte macrophage colony-stimulating growth factor (GM-CSF), angiogenin, follistatin, and proliferin, PR39, PR11, nicotine, hydroxy-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, statins, niacin, bile acid resins, fibrates, antioxidants, extracellular matrix synthesis promoters, inhibitors of plaque inflammation and extracellular degradation, and estradiol. 
     
     
         48 . The controlled-release system of  claim 43 , wherein the therapeutic agent is selected from the group consisting of everolimus, paclitaxel, zotarolimus, pioglitazone, BO-653, rosiglitazone, sirolimus, dexamethasone, rapamycin, tacrolimus, biophosphonates, estrogen, angiopeptin, statin, PDGF inhibitors, ROCK inhibitors, MMP inhibitors, 2-CdA, zotarolimus and dexamethasone. 
     
     
         49 . A method of treating breast cancer in a subject in need thereof, comprising administering to the subject an effective amount of the controlled-release system of  claim 1 . 
     
     
         50 - 54 . (canceled) 
     
     
         55 . A method of treating vulnerable plaque in a subject in need thereof, comprising administering to the subject an effective amount of the controlled-release system of  claim 1 . 
     
     
         56 . A method of treating restenosis in a subject in need thereof, comprising administering to the subject an effective amount of the controlled-release system of  claim 1 . 
     
     
         57 . The method of  claim 55 , wherein the controlled-release system is locally administered to a designated region of the blood vessel where the vulnerable plaque occurs. 
     
     
         58 . The method of  claim 55 , wherein the controlled-release system is administered via a medical device. 
     
     
         59 . The method of  claim 58 , wherein the medical device is a drug eluding stent, needle catheter, or stent graft. 
     
     
         60 - 62 . (canceled) 
     
     
         63 . A method of preparing a stealth nanoparticle, wherein the nanoparticle has a ratio of ligand-bound polymer to non-functionalized polymer effective for the treatment of a disease, comprising:
 providing a therapeutic agent;   providing a first polymer;   providing a poly(amino acid) ligand;   reacting the first polymer with the poly(amino acid) ligand to prepare a ligand-bound polymer; and   mixing the ligand-bound polymer with a second, non-functionalized polymer, and the therapeutic agent;   such that the stealth nanoparticle is formed.   
     
     
         64 - 71 . (canceled) 
     
     
         72 . A stealth nanoparticle, comprising
 a copolymer of PLGA and PEG; and   a therapeutic agent;   wherein said nanoparticle contains targeting moieties attached thereto, wherein the targeting moiety comprises AKERC or CREKA.   
     
     
         73 . A stealth nanoparticle, comprising
 a polymeric matrix comprising a complex of a phospholipid bound-PEG and PLGA; and   a therapeutic agent;   wherein said nanoparticle contains targeting moieties attached thereto, wherein the targeting moiety is a poly(amino acid).   
     
     
         74 - 78 . (canceled) 
     
     
         79 . A controlled-release system, comprising a plurality of target-specific stealth nanoparticles;
 wherein said nanoparticles contain targeting moieties attached thereto, wherein the targeting moiety is a poly(amino acid).   
     
     
         80 . (canceled) 
     
     
         81 . The compounds: 
       
         
           
           
               
               
           
         
       
       wherein n is 20 to 1720; and 
       
         
           
           
               
               
           
         
       
       wherein R 7  is an alkyl groups, R 8  is an ester or amide linkage, X=0 to 1 mole fraction, Y=0 to 0.5 mole fraction, X+Y=20 to 1720, and Z=25 to 455.