Hydrophobic core carrier compositions for delivery of therapeutic agents, methods of making and using the same

Abstract

The present invention relates, in part, to a biocompatible hydrophobic-core carrier comprising a carrier, and a plurality of hydrophobic groups covalently linked to the polymeric carrier. The hydrophobic groups are capable of dissociably linking load molecules such as therapeutic agents. The hydrophobic-core carrier may also comprise protective side chains, orienting molecules, and targeting molecules.

1 . A composition comprising (i) a carrier; (ii) a plurality of first hydrophobic groups, wherein the first hydrophobic group is covalently linked to the carrier, is capable of binding a load molecule, and has a molecular weight of less than about 1,000 Daltons independent of the carrier weight; and (iii) a plurality of first protective side chains, wherein each first protective side chain is covalently linked to the carrier and has a molecular weight between about 400 and 20,000 Daltons independent of the carrier weight.  
     
     
         2 . The composition of  claim 1 , wherein the first protective side chain is polyethylene glycol, polypropylene glycol, a co-polymer of polyethylene glycol and polypropylene glycol, polysaccharide, or alkoxy derivatives thereof.  
     
     
         3 . The composition of  claim 2 , wherein the alkoxy derivative is methoxypolyethylene glycol, methoxypolypropylene glycol, a methoxylated co-polymer of polyethylene glycol and polypropyleneglycol, or ethoxylated polysaccharide.  
     
     
         4 . The composition of  claim 1 , wherein the first protective side chain is methoxypolyethylene glycol.  
     
     
         5 . The composition of  claim 1 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         6 . The composition of  claim 5 , wherein the load molecule is a therapeutic agent.  
     
     
         7 . The composition of  claim 6 , wherein the therapeutic agent is selected from the group consisting of glucagon-like-peptide, glucagon-like-peptide derivatives, exenatide, glucagon-like-peptide-1, glucagon-like-peptide-2, leptin fragment, Gastric inhibitory polypeptide (GIP), Epidermal Growth Factor (EGF) receptor ligand, EGF, Transforming Growth Factor alpha (TGF-alpha), Betacellulin, Gastrin/Cholecystokinin receptor ligand, Gastrin, Cholecystokinin, lysostaphin, interferon, interferon gamma, interferon beta, interferon alpha, interleukin-1, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-12, tumor necrosis factor, tumor necrosis factor alpha, tumor necrosis factor beta, auristatin, nisin, insulin, insulin-like growth factor, growth hormone, nerve growth factor, brain-derived neurotrophic factor, enzymes, endostatin, angiostatin, trombospondin, urokinase, streptokinase, blood clotting factor VII, blood clotting factor VIII, granulucyte-macrophage colony-stimulating factor (GM-CSF), granulucyte colony-stimulating factor (G-CSF), thrombopoetin, calcitonin, parathyroid hormone (PTH) and its fragments, erythropoietin, atrial natriuretic factor, monoclonal antibodies, monoclonal antibody fragments, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastin, prostaglandins, epoprostenol, prostacyclin, cyclosporine, vasopressin, terlipressin, desmopressin, cromolyn sodium (sodium or disodium chromoglycate), vasoactive intestinal peptide (VIP), vancomycin, antimicrobials, polymyxin b, anti-fungal agents, anti-viral agents, enfuvirtide, doxorubicin, etoposide, fentanyl, ketamine, and vitamins.  
     
     
         8 . The composition of  claim 6 , wherein the therapeutic agent is glucagon-like-peptide, Epidermal Growth Factor (EGF) receptor ligand, EGF, Transforming Growth Factor alpha (TGF-alpha), Betacellulin, Gastrin/Cholecystokinin receptor ligand, Gastrin, Cholecystokinin, prostaglandin, interferon, factor VIII, terlipressin, Gastric inhibitory polypeptide (GIP), vasoactive intestinal peptide (VIP) or nisin.  
     
     
         9 . The composition of  claim 6 , wherein the therapeutic agent is glucagon-like-peptide 1.  
     
     
         10 . The composition of  claim 6 , wherein the therapeutic agent is Epidermal Growth Factor (EGF) receptor ligand.  
     
     
         11 . The composition of  claim 6 , wherein the therapeutic agent is Epidermal Growth Factor (EGF).  
     
     
         12 . The composition of  claim 6 , wherein the therapeutic agent is Transforming Growth Factor alpha (TGF-alpha).  
     
     
         13 . The composition of  claim 6 , wherein the therapeutic agent is Betacellulin.  
     
     
         14 . The composition of  claim 6 , wherein the therapeutic agent is Gastrin/Cholecystokinin receptor ligand.  
     
     
         15 . The composition of  claim 6 , wherein the therapeutic agent is Gastrin.  
     
     
         16 . The composition of  claim 6 , wherein the therapeutic agent is Cholecystokinin.  
     
     
         17 . The composition of  claim 1 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         18 . The composition of  claim 17 , wherein the orienting molecule is selected from the group consisting of a peptide, sulfate, sulfonate, phosphate, phosphonate, bisphosphonate, carboxylate, metal binding moeity, amino group, lysine, and arginine.  
     
     
         19 . The composition of  claim 17 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         20 . The composition of  claim 1 , further comprising a targeting molecule covalently linked to the protective side chains.  
     
     
         21 . The composition of  claim 20 , wherein the targeting molecule is selected from the group consisting of an antibody, fragment of an antibody, chimeric antibody, lectins, receptor ligands, proteins, enzymes, peptides, saccharides, quasi substrates of enzymes, cell-surface-binding compounds, and extracellular-matrix-binding compounds.  
     
     
         22 . The composition of  claim 20 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         23 . The composition of  claim 20 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         24 . The composition of  claim 23 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         25 . The composition of  claim 1 , further comprising a second protective side chain and a plurality of second hydrophobic groups, wherein the second hydrophobic group has a first end that is covalently linked to the carrier and a second end that is covalently linked to the second protective side chain; 
 wherein the second hydrophobic group has a molecular weight of less than 1,000 Daltons independent of the carrier and protective side chain weights; and    wherein the second protective side chain covalently linked to the hydrophobic group has a molecular weight between 400 and 20,000 Daltons independent of the hydrophobic group weight.    
     
     
         26 . The composition of  claim 25 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         27 . The composition of  claim 25 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         28 . The composition of  claim 27 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         29 . The composition of  claim 25 , further comprising a targeting molecule covalently linked to the protective side chains.  
     
     
         30 . The composition of  claim 29 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         31 . The composition of  claim 29 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         32 . The composition of  claim 31 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         33 . A composition, comprising: 
 (i) a carrier; and    (ii) a plurality of first hydrophobic groups with a covalently linked protective side chain,    wherein the first hydrophobic group has a first end that is covalently linked to the carrier and a second end that is covalently linked to the protective side chain;    wherein the first hydrophobic group has a molecular weight between 150 to 1000 Daltons independent of the carrier and protective side chain weights; and    wherein the protective side chain has a molecular weight between about 400 and 20,000 Daltons independent of the carrier and hydrophobic group weights.    
     
     
         34 . The composition of  claim 33 , wherein the protective side chain is polyethylene glycol, polypropylene glycol, a co-polymer of polyethylene glycol and polypropylene glycol, or alkoxy derivatives thereof.  
     
     
         35 . The composition of  claim 34 , wherein the alkoxy derivative is methoxypolyethylene glycol, methoxypolypropylene glycol, or a methoxylated co-polymer of polyethylene glycol and polypropyleneglycol.  
     
     
         36 . The composition of  claim 33 , wherein the protective side chain is methoxypolyethylene glycol.  
     
     
         37 . The composition of  claim 33 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         38 . The composition of  claim 37 , wherein the load molecule is a therapeutic agent.  
     
     
         39 . The composition of  claim 38 , wherein the therapeutic agent is selected from the group consisting of glucagon-like-peptide, glucagon-like-peptide derivatives, exenatide, glucagon-like-peptide-1, glucagon-like-peptide-2, leptin fragment, Gastric inhibitory polypeptide (GIP), Epidermal Growth Factor (EGF) receptor ligand, EGF, Transforming Growth Factor alpha (TGF-alpha), Betacellulin, Gastrin/Cholecystokinin receptor ligand, Gastrin, Cholecystokinin, lysostaphin, interferon, interferon gamma, interferon beta, interferon alpha, interleukin-1, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-12, tumor necrosis factor, tumor necrosis factor alpha, tumor necrosis factor beta, auristatin, nisin, insulin, insulin-like growth factor, growth hormone, nerve growth factor, brain-derived neurotrophic factor, enzymes, endostatin, angiostatin, trombospondin, urokinase, streptokinase, blood clotting factor VII, blood clotting factor VIII, granulucyte-macrophage colony-stimulating factor (GM-CSF), granulucyte colony-stimulating factor (G-CSF), thrombopoetin, calcitonin, parathyroid hormone (PTH) and its fragments, erythropoietin, atrial natriuretic factor, monoclonal antibodies, monoclonal antibody fragments, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins, epoprostenol, prostacyclin, cyclosporine, vasopressin, terlipressin, desmopressin, cromolyn sodium (sodium or disodium chromoglycate), vasoactive intestinal peptide (VIP), vancomycin, antimicrobials, polymyxin b, anti-fungal agents, anti-viral agents, enfuvirtide, doxorubicin, etoposide, fentanyl, ketamine, and vitamins.  
     
     
         40 . The composition of  claim 38 , wherein the therapeutic agent is glucagon-like-peptide, Epidermal Growth Factor (EGF) receptor ligand, EGF, Transforming Growth Factor alpha (TGF-alpha), Betacellulin, Gastrin/Cholecystokinin receptor ligand, Gastrin, Cholecystokinin, prostaglandin, interferon, factor VIII, terlipressin, Gastric inhibitory polypeptide (GIP), vasoactive intestinal peptide (VIP) or nisin.  
     
     
         41 . The composition of  claim 38 , wherein the therapeutic agent is glucagon-like-peptide 1.  
     
     
         42 . The composition of  claim 38 , wherein the therapeutic agent is Epidermal Growth Factor (EGF) receptor ligand.  
     
     
         43 . The composition of  claim 38 , wherein the therapeutic agent is Epidermal Growth Factor (EGF).  
     
     
         44 . The composition of  claim 38 , wherein the therapeutic agent is Transforming Growth Factor alpha (TGF-alpha).  
     
     
         45 . The composition of  claim 38 , wherein the therapeutic agent is Betacellulin.  
     
     
         46 . The composition of  claim 38 , wherein the therapeutic agent is Gastrin/Cholecystokinin receptor ligand.  
     
     
         47 . The composition of  claim 38 , wherein the therapeutic agent is Gastrin.  
     
     
         48 . The composition of  claim 38 , wherein the therapeutic agent is Cholecystokinin.  
     
     
         49 . The composition of  claim 33 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         50 . The composition of  claim 49 , wherein the orienting molecule is selected from the group consisting of a peptide, sulfate, sulfonate, phosphate, phosphonate, bisphosphonate, carboxylate, metal chelating moiety, amino group, lysine, and arginine.  
     
     
         51 . The composition of  claim 49 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         52 . The composition of  claim 33 , further comprising a targeting molecule covalently linked to the protective side chains.  
     
     
         53 . The composition of  claim 52 , wherein the targeting molecule is selected from the group consisting of an antibody, fragment of an antibody, chimeric antibody, enzymes, peptides, quasi substrates of enzymes, lectins, receptor, and saccharide ligands of lectins.  
     
     
         54 . The composition of  claim 52 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         55 . The composition of  claim 52 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         56 . The composition of  claim 55 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         57 . The composition of  claim 33 , further comprising a plurality of second hydrophobic group, wherein the second hydrophobic group is covalently linked to the carrier and has a molecular weight less than 1,000 Daltons independent of the carrier weight.  
     
     
         58 . The composition of  claim 57 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         59 . The composition of  claim 57 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         60 . The composition of  claim 59 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         61 . The composition of  claim 57 , further comprising a targeting molecule covalently linked to the protective side chains.  
     
     
         62 . The composition of  claim 61 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         63 . The composition of  claim 61 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         64 . The composition of  claim 63 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         65 . A composition comprising: (i) a polymeric carrier selected from the group consisting of polylysine, polyaspartic acid, polyglutamic acid, polyserine, polythreonine, polycysteine, polyglycerol, polyethyleneimines, natural saccharides, aminated polysaccharides, aminated oligosaccharides, polyamidoamine, polyacrylic acids, polyalcohols, sulfonated polysaccharides, sulfonated oligosaccharides, carboxylated polysaccharides, carboxylated oligosaccharides, aminocarboxylated polysaccharides, aminocarboxylated oligosaccharides, carboxymethylated polysaccharides, and carboxymethylated oligosaccharides; and (ii) a plurality of hydrophobic groups capable of binding a load molecule and covalently linked to the carrier, wherein each hydrophobic group has a molecular weight of less than 1,000 Daltons independent of the carrier weight, and wherein each hydrophobic group is independently selected from the group consisting of a linear alkyl, branched alkyl, phenyl, naphthyl, cholesterol, vitamin D, and vitamin E.  
     
     
         66 . The composition of  claim 65 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         67 . The composition of  claim 66 , wherein the load molecule is a therapeutic agent.  
     
     
         68 . The composition of  claim 65 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         69 . The composition of  claim 68 , wherein the orienting molecule is selected from the group consisting of a peptide, sulfate, sulfonate, phosphate, phosphonate, bisphosphonate, carboxylate, amino group, metal binding molecule, lysine, and arginine.  
     
     
         70 . The composition of  claim 68 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         71 . The composition of  claim 70 , wherein the load molecule is a therapeutic agent.  
     
     
         72 . The composition of  claim 65 , further comprising a targeting molecule covalently linked to the carrier or the hydrophobic groups.  
     
     
         73 . The composition of  claim 72 , wherein the targeting molecule is selected from the group consisting of an antibody, fragment of an antibody, chimeric antibody, enzymes, peptides, receptor, quasi substrates of enzymes, lectins, and saccharide ligands of lectins.  
     
     
         74 . The composition of  claim 72 , further comprising a load molecule dissociably linked to the hydrophobic groups.  
     
     
         75 . The composition of  claim 74 , wherein the load molecule is a therapeutic agent.  
     
     
         76 . The composition of  claim 72 , further comprising an orienting molecule covalently linked to the carrier.  
     
     
         77 . The composition of  claim 76 , further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.  
     
     
         78 . The composition of  claim 77 , wherein the load molecule is a therapeutic agent.  
     
     
         79 . A method of treating diabetes in mammals, comprising administering a first composition selected from the group consisting of the compositions of claims  9 - 16  and  41 - 48 .  
     
     
         80 . The method of  claim 79 , further comprising administering a second composition selected from the group consisting of the compositions of claims  14 - 16  and  46 - 48 , wherein the first composition is selected from the group consisting of the composition of  claim 9  and the composition of  claim 41 .  
     
     
         81 . The method of  claim 80  further comprising administering a proton pump inhibitor as a third composition.  
     
     
         82 . The method of  claim 79  further comprising administering a proton-pump inhibitor as a second composition.  
     
     
         83 . The method of  claim 82 , wherein the proton-pump inhibitor is omeprazole.  
     
     
         84 . The method of  claim 82  further comprising administering a DPP4 inhibitor as a third composition.  
     
     
         85 . The method of  claim 79  further comprising administering a DPP4 inhibitor as a second composition.  
     
     
         86 . The method of  claim 79 , further comprising administering a second composition selected from the group consisting of the compositions of claims  14 - 16  and  46 - 48 , wherein the first composition is according to any one of claims  10 - 13  and  42 - 45 .  
     
     
         87 . The method of  claim 86  further comprising administering a proton-pump inhibitor as a third composition.  
     
     
         88 . The method of  claim 87 , wherein the proton-pump inhibitor is omeprazole.  
     
     
         89 . The method of  claim 79 , further comprising administering a proton-pump inhibitor as a second composition, wherein the first composition is according to any one of claims  10 - 13  and  42 - 45 .  
     
     
         90 . The method of  claim 89 , wherein the proton-pump inhibitor is omeprazole.