Novel Angiogenic Compounds for Targeted Drug Delivery
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Novel Angiogenic Compounds for Targeted Drug Delivery Kristen A. Wieghaus1, Scott M. Capitosti2, Milton L. Brown2, and Edward A. Botchwey1 Department of Biomedical Engineering, 2Department of Chemistry University of Virginia Box 800759, Health System 415 Lane Road, MR-5 Building Charlottesville, VA 22908
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ABSTRACT Induction of angiogenesis is necessary for the success of engineered implantable tissues in order to meet oxygen and nutrient requirements of cells during tissue repair. Insufficient vascularization in bone graft reconstruction may impede healing and initiate hypoxic cell death at the interior of the implant. As a result, endogenous growth factors have been studied to enhance angiogenesis during wound repair. However, these peptidebased molecules are highly sensitive to processing that occurs during scaffold biomaterial fabrication and treatment for tissue engineering purposes. We report here the development of new small molecule regulators of angiogenesis that may circumvent the impediments associated with protein-based growth factor delivery. In this study, we report the design and evaluation of SC-3-143 as a regulator of endothelial function. We show that the compound significantly increases the formation of microvascular networks in vitro, and selectively enhances endothelial survivability by reducing endothelial cell death under serum deprived culture conditions. INTRODUCTION Formation of functioning microvascular networks is a complex process, with numerous growth factors that are required to initiate sprouting and remodeling of vessels1,2,3 and to properly regulate cellular interactions. As a result, numerous therapeutic approcahes involving endogenous growth factor delivery have been proposed enhance angiogenesis during tissue repair. However, these biomolecules are highly sensitive to the thermal processing, sterilization, and exposure to solvents that occur during incorporation within scaffold biomaterials. These factors may limit the ability to obtain sufficient amounts of protein release necessary to obtain the desired biological responses when these growth factors are incorporated into and released from biomaterials. In this study, we report the development of new small molecule stimulators of angiogenesis that are suited for targeted drug delivery from polymeric biomaterials. Specifically, we report on novel organic compounds, based on a thalidomide analogue that can be modified to exhibit pro-angiogenic activity. Thalidomide has clinical relevance as a sedative, but has more recently been shown to be antiangiogenic4 and to function as an effective treatment for tumorigenic cancers.5 We have developed SC-3-149 (results not shown) and SC-3-143 (see Figure 1), thalidomide analogues that stimulate endothelial cell proliferation.
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Figure 1. Design strategy for SC-3-143, a novel analogue of thalidomide. We have previously shown that SC-3-149 enhances proliferation, su
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