Protein Stability in Polymer Delivery Systems

描述（来自申请人摘要的逐字）：蛋白质药物是 目前通过注射全身给药。对于需要 慢性治疗，用针自我管理是一个不愉快的日常 体验.然而，可注射的生物可降解聚合物（例如， 聚（丙交酯-共-乙交酯），PLGA）能够缓慢和连续地释放 蛋白质注射之间的几个月可能提供一个现实的替代， 每天注射一次。PLGA输送系统也用于局部治疗 以及疫苗的运送。开发PLGA递送的主要障碍 蛋白质系统是不可逆的不稳定性，这些代理人之前， 在体内释放。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 接近。在该提议中，聚合物中的pH将通过以下来操纵： 抗酸赋形剂，以改善包封在 PLGA。然后将用治疗性药物测试这种一般稳定方法。 促进血管生成的蛋白质。缓释血管生成剂具有 缺血性心脏病患者的重要应用（负责 美国每年约有500，000例死亡。S.）。随后的特定地点 新生血管形成可促进心肌灌注， 并发症如心肌梗死、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输送系统的潜在影响， 天然的治疗性蛋白质，例如那些促进血管生成的蛋白质， 对人类健康的重要性，在解决穷人的不稳定性， 包封在PLGA中的蛋白质变得明确无误。该提案将测试 以下假设：蛋白质降解过程中PLGA内部的水分和酸性pH值 释放是两种最常见的应力， 蛋白质的PLGA递送系统，包括微球。发展 调节聚合物中pH以及蛋白质水溶性的方法 将成为稳定包封蛋白质的广泛适用的技术。 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 影响包封蛋白的稳定性和释放;（2） 模型蛋白在PLGA缓释系统中的稳定性研究;（3） 稳定方法在治疗药物递送中的应用 血管生成蛋白;和（4）在体内评估的控制释放的 生物活性血管生成蛋白。

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.