Protein Stability in Polymer Delivery Systems

描述(逐字摘自申请者摘要)：蛋白质类药物 目前通过注射系统地给药。对于有以下需求的个人 慢性治疗，用针自我给药是不愉快的每一天 经验。然而，可注射生物降解聚合物的开发(例如， 可缓慢持续释放的聚(丙交酯-乙交酯，PLGA) 在两次注射之间持续数月的蛋白质可能会提供一种现实的替代方案 每天痛苦的注射。PLGA给药系统也用于局部治疗 以及运送疫苗的费用。发展PLGA递送的主要障碍 蛋白质系统的不可逆不稳定性是这些试剂在 它们在体内的释放。这些研究的总体目标是确定 蛋白质不稳定的潜在分子机制 PLGA，并利用这些信息开发广泛适用的稳定剂 接近了。在这项建议中，聚合物中的pH值将通过 抗酸辅料对模型蛋白稳定性的改善作用 PLGA。这种一般的稳定方法将在治疗后进行测试。 促进血管生成的蛋白质。缓释血管生成剂有 缺血性心脏病患者的重要应用(负责 在美国，每年约有50000例OOO死亡)。接下来的站点特定 新生血管可促进心肌灌注，减少心脏 并发症如心肌梗塞、心绞痛、心力衰竭、 和/或心源性猝死。缓释生长因子也可能有助于 提高组织工程支架植入后的组织存活率。 考虑到缓慢释放的PLGA递送系统的潜在影响 天然治疗性蛋白质，如那些促进血管生成的蛋白质，可能 对人类健康具有重要意义，在解决贫困的不稳定性 包裹在PLGA中的蛋白质变得明确无误。这项提议将检验 以下假设：蛋白质过程中PLGA内的水分和酸性pH 释放是导致系统不稳定的两个最常见的压力 PLGA递送系统中的蛋白质，包括微球。发展中的 调节聚合物中pH和蛋白质水溶液溶解度的方法 将成为广泛适用的稳定包裹蛋白质的技术。 这一假设将在以下具体目标中得到检验：(1) 聚合物微气候中物理化学过程的表征 影响包膜蛋白稳定性和释放性的因素； 模型蛋白在PLGA递送系统中的稳定性研究 稳定化方法学在治疗性药物输送中的应用 血管生成蛋白；以及(4)体内控释评价 具有生物活性的血管生成蛋白。

DESCRIPTION (Verbatim from the Applicant's Abstract): Protein drugs are currently administered systemically by injections. For individuals requiring chronic therapy, self-administration with a needle is an unpleasant everyday experience. However, development of injectable biodegradable polymers (e.g., poly(lactide-co-glycolides), PLGA) capable of slowly and continuously releasing proteins for months between injections may provide a realistic alternative to painful daily injections. PLGA delivery systems are also used for local therapy and for delivery of vaccines. The primary obstacle to develop PLGA delivery systems for proteins is the irreversible instability of these agents prior to their release in vivo. The overall goal of these studies is to determine the underlying molecular mechanisms responsible for the instability of proteins in PLGA and to use this information to develop widely applicable stabilization approaches. In this proposal, the pH in the polymer will be manipulated with antacid excipients to improve the stability of model proteins encapsulated in PLGA. This general stabilization approach will then be tested with therapeutic proteins that promote angiogenesis. Slow-release angiogenic agents have important applications for patients with ischemic heart disease (responsible for about 5OO,OOO deaths annually in the U. S.). The ensuing site-specific neovascularization would facilitate myocardial perfusion and reduce cardiac complications such as myocardial infarction, angina pectoris, heart failure, and/or sudden cardiac death. Slow-release growth factors may also be useful to improve survival of tissues after implantation of tissue engineering scaffolds. Considering the potential impact of PLGA delivery systems that slowly release native therapeutic proteins, such as those that promote angiogenesis, could have on human health, the importance in resolving the poor instability of proteins encapsulated in PLGAs becomes unmistakable. This proposal will test the following hypothesis: Moisture and acidic pH inside PLGAs during protein release are the two most common stresses responsible for instability of proteins in PLGA delivery systems, including microspheres. Development of methods to regulate pH in the polymer as well as aqueous protein solubility will become widely applicable techniques to stabilize encapsulated proteins. This hypothesis will be tested in the following specific aims: (1) Characterization of physical chemical processes in the polymer microclimate that influence stability and release of encapsulated proteins; (2) Investigation of stability of model proteins in PLGA delivery systems; (3) Application of the stabilization methodology to the delivery of therapeutic angiogenic proteins; and (4) In vivo assessment of the controlled release of biologically active angiogenic proteins.