Injectable biodegradable polymers for local drug delivery

该提案是我的研究小组正在进行的关于开发可生物降解的可注射聚合物用于局部蛋白质药物递送的项目的延伸。我的研究小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制剂，以刺激局部氧浓度低的组织中的血管生长，以及用于治疗癌症的免疫调节剂的递送。这些蛋白质治疗剂需要在患病组织中存在数周才有效，因此聚合物控释载体是合适的方法。 为了最大限度地减少患者创伤，我们专注于可注射，可生物降解的输送系统。我们选择了碳酸酯基聚合物作为制备新的可注射制剂的结构单元，因为它们降解但不形成传统脂肪族聚酯存在问题的酸性降解产物。该提案的目的是合成低粘度的低分子量聚（三亚甲基碳酸酯）基聚合物，将血管生成生长因子如血管内皮生长因子作为颗粒掺入其中，评估这些生长因子体外释放的控制因素，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速率。为了实现这些目的，低分子量聚（三亚甲基碳酸酯）预聚物将利用在体内易于裂解的键来组合。 聚合物将通过凝胶渗透色谱法、核磁共振光谱法、流变学和差示扫描量热法进行表征，包括制备时和体外降解过程。 将使用ELISA测量从聚合物中释放的生长因子，并通过我的实验室已经建立的基于细胞的增殖测定法测量释放后的生物活性。这项工作的意义在于，将开发出新的、可能非常有用的聚合物生物材料，这些材料可能具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.