Injectable biodegradable polymers for local drug delivery

这项提议是我的研究组正在进行的开发可生物降解的、可注射的聚合物用于局部蛋白质药物输送的项目的延伸。我的研究组的一个主要研究重点是开发一种有效的血管生成生长因子配方，以刺激局部氧气浓度较低的组织中的血管生长，以及提供用于治疗癌症的免疫调节剂。这些蛋白质疗法需要在受影响的组织中存在数周才能有效，因此聚合物控制释放载体是一种合适的方法。为了最大限度地减少患者的创伤，我们正专注于一种可注射、可生物降解的递送系统。我们选择了一种基于碳酸盐的聚合物作为新的可注射配方制备的构建块，因为它们会降解，但不会形成传统脂肪族聚酯存在问题的酸性降解产物。该方案的目标是合成低粘度的低分子聚碳酸三亚甲酯聚合物，在其中加入血管内皮生长因子等血管生成生长因子作为颗粒，评估这些生长因子在体外释放的因素，确定这些生长因子在释放时的生物活性，并评估新聚合物的体外降解率。为了实现这些目标，低分子量聚(三亚甲基碳酸酯)预聚体将利用容易在体内断裂的键结合在一起。聚合物将通过凝胶渗透色谱、核磁共振波谱、流变学和差示扫描量热法进行表征，包括制备和体外降解过程。这些聚合物的生长因子释放将通过我的实验室已经建立的基于细胞的增殖试验，在释放后使用ELISA法和生物活性来测量。这项工作的意义在于，新的、可能非常有用的聚合物生物材料将被开发出来，这些材料可能会有一系列药物输送应用。

This proposal is an extension of ongoing projects in my research group on the development of biodegradable, injectable polymers for localized protein drug delivery. A major research focus in my research group is the development of an effective formulation of angiogenic growth factors to stimulate blood vessel growth in tissues of low local oxygen concentration as well as the delivery of immunomodulators used to treat cancer. These protein therapeutics need to be present in the afflicted tissue for multiple weeks in order to be effective, and thus a polymeric controlled release vehicle is a suitable approach. To minimize patient trauma, we are focusing on an injectable, biodegradable delivery system. We have chosen a carbonate-based polymer as a building block for the preparation of new injectable formulations as they degrade but do not form the acidic degradation products that are problematic with the conventional aliphatic polyesters. The objectives of this proposal are to synthesize low molecular weight poly(trimethylene carbonate)-based polymers of low viscosity, incorporate angiogenic growth factors such as vascular endothelial growth factor as particles within them, assess the factors governing release of these growth factors in vitro, determine the bioactivity of these growth factors upon their release, and assess the in vitro degradation rates of the new polymers. To accomplish these objectives, the low molecular weight poly(trimethylene carbonate) prepolymers will be combined utilizing bonds that are readily cleavable in the body. The polymers will be characterized via gel permeation chromatography, nuclear magnetic resonance spectroscopy, rheology, and differential scanning calorimetry, both as prepared and during in vitro degradation. Growth factor release from the polymers will be measured using ELISA and bioactivity following release through cell-based proliferation assays already established in my laboratory. The significance of this work is that new, and potentially very useful, polymer biomaterials will be developed that could have a range of drug delivery applications.