Protein Stability in Polymer Delivery Systems

聚合物输送系统中的蛋白质稳定性

• 批准号: 7844194
• 负责人: STEVEN P. SCHWENDEMAN
• 金额: $ 29.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844194
• 关键词: 3-Dimensional; Acid-Base Equilibrium; Acids; Angina Pectoris; Angiogenic Proteins; Angiopoietin-2; Animals; Antibody Formation; Antigens; Biotechnology; Blindness; Bone Regeneration; Cardiac; Cessation of life; Chemicals; Chemotherapy-Oncologic Procedure; Child; Chronic; Clinical; Clinical Trials; Collateral Circulation; Coronary; Data; Development; Disease; Dose; Drug Formulations; Encapsulated; Excipients; Explosion; Exubera; Fibroblast Growth Factor 2; Glycolates; Goals; Growth Factor; Heart failure; Hindlimb; Human; Immunization; Individual; Injectable; Injection of therapeutic agent; Insulin; Investigation; Journals; Laboratories; Literature; Local Therapy; Lung; Manuscripts; Maps; Methodology; Methods; Microclimate; Microspheres; Modeling; Molecular; Monitor; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Nature; Needles; Operative Surgical Procedures; Pain; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiological; Polymers; Prevention; Probability; Process; Production; Proteins; Publications; Reaction; Reporting; Research; Research Personnel; Route; Screening procedure; Self Administration; Site; Stress; Surface; System; Techniques; Technology; Temperature; Testing; Therapeutic; Time; Tissue Engineering; Vaccination; Vaccine Antigen; Vaccines; Vascular Endothelial Growth Factors; World Health Organization; Wound Healing; aged; angiogenesis; base; biodegradable polymer; controlled release; experience; improved; in vivo; method development; neovascularization; novel strategies; poly(lactide); programs; response; stem; success; sudden cardiac death; therapeutic protein; vaccine delivery

DESCRIPTION (provided by applicant): Protein drugs are currently administered systemically by injections. For individuals requiring chronic therapy, self administration with a needle is an unpleasant everyday experience. Development of injectable biodegradable polymers, e.g. poly(lactic-co-glycolic acid) (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 stablization approaches. In this proposal, the pH in the polymer will be manipulated to improve the stability of model proteins and peptides encapsulated in PLGA. This and other stabilization approaches will be applied to therapeutic proteins that promote angiogenesis. Slow-release angiogenic agents have important applications for patients with ischemic heart disease (responsible for >600,000 deaths annually in the US). 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. Considering the potential impact of PLGA delivery systems that slowly release native therapeutic proteins, such as those that promote angiogenesis, could have on human heath, the importance in resolving the poor instability of proteins encapsulated in PLGAs becomes unmistakeable. This proposal will test the following hypothesis: Moisture combined with uncontrolled and frequently acidic pH inside PLGAs are the two most common stresses responsible for instability of proteins in PLGA delivery systems, including microspheres. Development of methods to control polymer microclimate pH will become a widely applicable method 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 and peptides in PLGA delivery systems, 3) application of the stabilization methodology to the delivery of angiogenic proteins, and 4) in vivo assessment of the controlled release of biologically active angiogenic proteins

描述(申请人提供)：蛋白质药物目前是通过注射系统地给药。对于需要长期治疗的人来说，用针头自我给药是一种不愉快的日常体验。开发可注射的生物降解聚合物，如聚乳酸-乙醇酸(PLGA)，能够在两次注射之间缓慢而持续地释放蛋白质数月，可能为日常痛苦的注射提供一种现实的替代方案。PLGA递送系统也用于局部治疗和疫苗递送。发展PLGA蛋白质递送系统的主要障碍是这些药物在体内释放之前的不可逆转的不稳定性。这些研究的总体目标是确定导致PLGA中蛋白质不稳定的潜在分子机制，并利用这些信息开发广泛适用的稳定化方法。在这个方案中，聚合物中的pH将被操纵，以提高PLGA中包裹的模型蛋白质和多肽的稳定性。这种稳定方法和其他稳定方法将被应用于促进血管生成的治疗性蛋白质。缓释血管生成剂对缺血性心脏病患者有重要的应用(在美国每年导致60万人死亡)。随之而来的局部特异性新生血管将促进心肌灌注，减少心脏并发症，如心肌梗死、心绞痛、心力衰竭和/或心脏性猝死。考虑到PLGA递送系统缓慢释放天然治疗性蛋白质的潜在影响，例如那些促进血管生成的递送系统可能对人类健康产生的影响，解决PLGA中包裹的蛋白质的不良不稳定性的重要性变得不容置疑。这一提议将检验以下假设：PLGA内的水分和失控且经常是酸性的pH是导致PLGA递送系统(包括微球)中蛋白质不稳定的两个最常见的压力。控制聚合物微气候pH的方法的发展将成为稳定包裹蛋白质的一种广泛适用的方法。这一假说将在以下特定目标中得到检验：1)表征聚合物微气候中影响包裹蛋白质稳定性和释放的物理化学过程，2)研究PLGA递送系统中模型蛋白质和多肽的稳定性，3)将稳定化方法学应用于血管生成蛋白的递送，4)体内评估生物活性血管生成蛋白的受控释放。