Syndesomes for enhanced wound healing and therapeutic angiogenesis in a diabetic diseased state
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Peripheral vascular disease (PVD) affects more than 202 million people globally and about 20% of the population above 65 years of age in the United States alone. Type-2 diabetes afflicts around 347 million people worldwide and leads to the death of 4.6 million people. The rising prevalence of strong risk factors like smoking, hypertension, hypercholesterolemia, and obesity indicate that the affected population will continue to grow. Currently no long-term therapies exist in clinical practice for peripheral ischemia and non-healing chronic ulcers, both of which are common clinical consequences of PVD and type-2 diabetes. Current clinical treatments including exercise therapy, pharmaco- therapy, and surgical intervention can provide only relatively short-term relief from progressive vascular disease. Some attractive therapeutic strategies are to use growth factors, cytokines, viral delivery of growth factor genes, or the implantation of stem cells to revascularize ischemic tissue and heal chronic wounds. While these emerging therapies have been successfully applied in healthy animal models, they have achieved only limited success in humans with long-term disease. Thus, the overall goal of this thesis is to understand the reasons behind the failure of the clinical trials using growth factor therapy and to engineer therapeutics to circumvent the problems. We observed a dramatic reduction in the protein levels of growth factor co- receptors, including syndecan-4, in the diabetic mouse model. We speculated that since co-receptors are critical for growth factor signaling cascade, this reduction in expression might lead to inefficient growth factor signaling. Our hypothesis was confirmed in the diseased ob/ob mice where we observed significant resistance to angiogenesis via growth factor therapy. Co-delivery of syndecan-4 along with fibroblast growth factor-2 (FGF-2) in an optimized liposomal formulation (syndesome) drastically improved the body’s responsiveness to FGF-2. Treatment with syndesomes also enhanced revascularization in ischemic hind limbs and increased wound healing in full thickness cutaneous wounds in the diseased mouse model. The studies performed and described here are the first attempt, to our knowledge, for an effective understanding of the mechanisms involved in metabolic disorder in humans due to long-term disease and to explore steps for overcoming the associated clinical problems.