Protein Stability in Polymer Delivery Systems

聚合物输送系统中的蛋白质稳定性

• 批准号: 6629146
• 负责人: STEVEN P. SCHWENDEMAN
• 金额: $ 19.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629146
• 关键词: acidity /alkalinity; angiogenesis; biodegradable product; chemical stability; drug delivery systems; drug screening /evaluation; laboratory rat; microcapsule; physical chemical interaction; polymers; protein degradation; slow release drug; stimulant /agonist; technology /technique development; water solubility

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.

描述（逐字摘自申请人摘要）：蛋白质药物是 目前通过注射进行全身给药。对于需要的个人 慢性治疗，用针自我给药是每天不愉快的事情 经验。然而，可注射生物降解聚合物的开发（例如， 聚（丙交酯-乙交酯），PLGA）能够缓慢且连续地释放 两次注射之间持续数月的蛋白质可能提供一种现实的替代方案 每天注射都很痛苦。 PLGA 递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 蛋白质系统的关键在于这些试剂在形成之前具有不可逆的不稳定性 它们在体内的释放。这些研究的总体目标是确定 导致蛋白质不稳定的潜在分子机制 PLGA 并利用这些信息来开发广泛适用的稳定性 接近。在该提案中，聚合物中的 pH 值将通过以下方式控制： 抗酸剂赋形剂可提高封装模型蛋白的稳定性 PLGA。然后将用治疗方法来测试这种一般的稳定方法 促进血管生成的蛋白质。缓释血管生成剂具有 对于缺血性心脏病患者的重要应用（负责 美国每年约有 500,000 人死亡）。接下来的具体地点 新生血管形成有利于心肌灌注并减少心脏 心肌梗塞、心绞痛、心力衰竭等并发症， 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组织的存活率。 考虑缓慢释放的 PLGA 输送系统的潜在影响 天然治疗蛋白，例如促进血管生成的蛋白，可以 对人类健康而言，解决贫困不稳定问题具有重要意义 封装在 PLGA 中的蛋白质变得明确无误。该提案将测试 以下假设：蛋白质加工过程中 PLGA 内的水分和酸性 pH 值 释放是造成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 调节聚合物 pH 值以及蛋白质水溶性的方法 将成为广泛应用的稳定封装蛋白质的技术。 该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 影响封装蛋白的稳定性和释放； (2) PLGA 递送系统中模型蛋白的稳定性研究； (3) 稳定方法在治疗药物递送中的应用 血管生成蛋白； (4) 体内控释评估 具有生物活性的血管生成蛋白。