Multiple growth factor compositions, methods of fabrication, and methods of treatment

Abstract

Disclosed are compositions with sustained-release carriers associated with at least two different types of growth factors and methods of fabrication and treatments thereof. In some embodiments, simultaneous release of the growth factors may be preferred while in other embodiments, sequential release of the growth factors may be preferred. Application of at least two growth factors to an injury site, e.g., compromised cardiac tissue caused by, for example, myocardial infarction or ischemic heart failure, may better mimic and induce the complex growth factor signaling pathways necessary to improve cardiac function. When applied to a patient after a myocardial infarction or ischemic heart failure, multiple growth factors within a sustained-release carrier platform or platforms may cause a synergistic effect on injected cells intending to alleviate left ventricle remodeling. Methods of treatment include percutaneous, sub-xiphoid, and open chest methods using catheters and/or syringes.

What is claimed is: 
     
         1 . A composition, comprising:
 a first bioerodable carrier platform capable of sustained release of a first growth factor;   at least one second different bioerodable carrier platform capable of sustained release of a second growth factor, wherein the second different bioerodable carrier platform comprises at least two precursors of a two-component hydrogel, wherein the at least two precursors are operable to have a first liquid state in which they are capable of separate delivery and a second semi-solid gel state which forms when the at least two precursors mix; and   at least one cell type,   wherein a rate of release of the first growth factor from the first bioerodable carrier platform is faster than a rate of release of the second growth factor from the second bioerodable carrier platform, and   wherein the first growth factor and the second growth factor are different and each of the first growth factor and the second growth factor have a different function when delivered to the compromised cardiac tissue such that cell survival followed by cell homing is enhanced.   
     
     
         2 . The composition of  claim 1  wherein the two-component hydrogel is selected from the group consisting of hyaluronic acid, fibrin glue, alginate and silk elastin copolymers. 
     
     
         3 . The composition of  claim 1  wherein the at least one cell type selected from the group consisting of localized cardiac progenitor cells, cardiac stem cells, mesenchymal stem cells, bone marrow derived mononuclear cells, adipose-derived stem cells, embryonic stem cells, umbilical cord blood derived stem cells, smooth muscle cells, skeletal myoblasts, endothelial progenitor cells and a combination thereof. 
     
     
         4 . The composition of  claim 1  wherein one of the first or second carrier platforms is one of a liposome, a polymersome, a micelle, a particle, a core-shell particle, a hydrogel, a fiber, or a microbubble, wherein when the carrier platform is a polymersome, a particle, or a hydrogel, the carrier platform is fabricated from a material selected from the group consisting of fibrin glue, alginate gel, small intestinal submucosa/urinary bladder matrix, poly(ethylene glycol)-based materials, poly(N-isopropylacrylamide) copolymers, poly(D,L-lactide-co-glycolide), polyurethanes, polyurethane-ureas, poly(ester) copolymers, dextran, silk-elastin, hyaluronate, or a combination or a precursor thereof. 
     
     
         5 . The composition of  claim 1  wherein the first growth factor and the second growth factor comprise one of: (i) insulin-like growth factor 1 and hepatocyte growth factor; (ii) insulin-like growth factor 1 and stromal derived factor-1-alpha; (iii) vascular endothelial growth factor and platelet-derived growth factor; (iv) vascular endothelial growth factor and hepatocyte growth factor; (v) vascular endothelial growth factor and stem cell factor; (vi) vascular endothelial growth factor and stromal derived factor-1-alpha (vii) basic-fibroblast growth factor and hepatocyte growth factor; (viii) basic-fibroblast growth factor and stem cell factor; (ix) insulin-like growth factor 1 and basic-fibroblast growth factor; (x) granulocyte colony-stimulating factor and hepatocyte growth factor; (xi) granulocyte colony-stimulating factor and hepatocyte growth factor; (xii) granulocyte colony-stimulating factor and stem cell factor; (xiii) granulocyte colony-stimulating factor and insulin-like growth factor 1, or (xiv) granulocyte colony-stimulating factor and stromal derived factor 1-alpha, the composition optionally including sonic hedgehog protein. 
     
     
         6 . The composition of  claim 1  wherein the first growth factor and the second growth factor comprise one of: (i) insulin-like growth factor 1 and stromal derived factor-1-alpha; (ii) insulin-like growth factor 1 and hepatocyte growth factor; (iii) insulin-like growth factor-1 and stem cell factor, (iv) insulin-like growth factor 1 and granulocyte colony-stimulating factor; (v) hepatocyte growth factor and vascular endothelial growth factor; (vi) hepatocyte growth factor and beta-fibroblast growth factor; (vii) vascular endothelial growth factor and platelet-derived growth factor; (viii) vascular endothelial growth factor and angiopoietin-I; (ix) stem cell factor and insulin-like growth factor 1; (x) granulocyte colony-stimulating factor and insulin-like growth factor 1; (xi) stem cell factor and vasoendothelial growth factor; (xii) stem cell factor and beta-fibroblast growth factor; or (xiii) granulocyte colony-stimulating factor and beta-fibroblast growth factor, the composition optionally including sonic hedgehog protein. 
     
     
         7 . The composition of  claim 5  or  6 , further comprising, at least one of: (i) a matrix metallopeptidase 9 (MMP-9) inhibitor comprising one of tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-3, TIMP-4, nobiletin, indole-3-carbinol, batimastat, marimastat, solimastat, neovastat, Bay 12-9566, AG3340, COL-3, BMS-275291, or CGS27023A; (ii) major extrahepatic insulin-like growth factor-1; or, (iii) a cardiovascular treatment agent selected from the group consisting of an antiplatelet drug, a beta blocker, an angiotensin-converting enzyme inhibitor, a statin, an omega-3 fatty acid, or an aldosterone antagonist. 
     
     
         8 . The composition of  claim 1  wherein the first bioerodable carrier platform is capable of simultaneous release of the first treatment agent and at least one other treatment agent in a time interval of between 10 seconds and 10 weeks. 
     
     
         9 . The composition of  claim 1  wherein the first bioerodable carrier platform is capable of release of the first treatment agent in a time interval of between 10 seconds and 10 weeks and the second different bioerodable carrier platform is capable of release of the second treatment agent in a time interval sequential to that of the first treatment agent. 
     
     
         10 . The composition of  claim 1  wherein the first bioerodable carrier platform is capable of release of the first treatment agent in a time interval of between 10 seconds and 24 hours and the second different bioerodable carrier platform is capable of release of the second treatment agent in a time interval sequential to that of the first treatment agent. 
     
     
         11 . The composition of  claim 1  wherein the first bioerodable carrier platform includes arginine-aspartate-glycine (RGD). 
     
     
         12 . The composition of  claim 1  wherein the first bioerodable carrier platform is a liposome and the second different bioerodable carrier platform is a hydrogel. 
     
     
         13 . The composition of  claim 1  wherein the first growth factor comprises insulin-like growth factor 1. 
     
     
         14 . The composition of  claim 13  wherein the second growth factor comprises stromal derived factor-1-alpha. 
     
     
         15 . The composition of  claim 1  wherein the at least one cell type comprises cardiac progenitor cells. 
     
     
         16 . A composition, comprising:
 a first bioerodable carrier platform capable of sustained release of a first treatment agent and a second treatment agent simultaneously, wherein the second treatment agent is different from the first treatment agent;   at least one second different bioerodable carrier platform capable of sustained release of a third treatment agent wherein a rate of release of the first bioerodable carrier platform is different relative to a rate of release of the second bioerodable carrier platform such that the third treatment agent is delivered sequentially to the first treatment agent and the second treatment agent, and wherein the second different biodegradable carrier platform comprises at least two precursors of a two-component hydrogel, wherein the at least two precursors are operable to have a first liquid state in which they are capable of separate delivery and a second semi-solid gel state which forms when the at least two precursors mix,   wherein the first treatment agent and the second treatment agent are different from the third treatment agent and at least two of the first treatment agent, the second treatment agent and the third treatment agent have a different function when delivered to compromised cardiac tissue, the function selected from the group consisting of cell survival, cell recruitment, angiogenesis, arteriogenesis, and anti-fibrotic development.   
     
     
         17 . The composition of  claim 16  wherein the function of the third treatment agent is dependent on the function of one of the first treatment agent and the second treatment agent. 
     
     
         18 . The composition of  claim 16  wherein the first treatment agent and the second treatment agent, when released simultaneously, function to enhance cell survival at the compromised cardiac tissue and sequential release of the third treatment agent enhances the function of the first and second treatment agents. 
     
     
         19 . The composition of  claim 16  wherein the first treatment agent is insulin-like growth factor 1, the second treatment agent is hepatocyte growth factor and the third treatment agent is stromal derived factor-1-alpha such that cell survival at the compromised cardiac tissue is enhanced followed by enhanced cell homing.