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（逐字研究申请人的摘要）：蛋白质药物是 当前通过注射系统地进行管理。对于需要的个人 慢性疗法，用针的自我管理是每天不愉快的 经验。但是，开发可注射可生物降解的聚合物（例如， 聚（乳酸 - 糖糖苷），PLGA），能够缓慢而连续释放 两次注射之间几个月的蛋白质可能为现实的替代品提供 每天痛苦的注射。 PLGA输送系统也用于局部治疗 并用于输送疫苗。发展PLGA交付的主要障碍 蛋白质系统是这些药物之前的不可逆转的不稳定性 他们在体内释放。这些研究的总体目标是确定 负责蛋白质不稳定性的基本分子机制 PLGA并使用此信息来开发广泛适用的稳定 方法。在此提案中，聚合物中的pH值将被操纵 抗酸赋形剂以提高封装在的模型蛋白的稳定性 PLGA。然后，这种一般稳定方法将通过治疗进行测试 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 大约5OO，每年在美国死亡）。随后的特定地点 新血管形成将促进心肌灌注并减少心脏 并发症，例如心肌梗塞，心绞痛，心力衰竭， 和/或心脏猝死。缓慢释放的生长因子也可能对 提高组织工程支架植入后组织的存活。 考虑到慢慢释放的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质，可以 在人类健康方面，要解决不稳定的不稳定的重要性 封装在PLGA中的蛋白质变得明确。该建议将测试 以下假设：蛋白质期间PLGA内部的水分和酸性pH值 释放是导致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 调节聚合物中pH的方法以及水溶性溶解度 将成为稳定封装蛋白质的广泛适用技术。 该假设将在以下特定目的中进行检验：（1） 聚合物微气候中物理化学过程的表征 这会影响稳定性和封装蛋白质的释放； （2） 调查PLGA输送系统中模型蛋白的稳定性； （3） 稳定方法的应用到治疗的交付 血管生成蛋白； （4）对受控释放的体内评估 生物活性血管生成蛋白。