Protein Stability in Polymer Delivery Systems

聚合物输送系统中的蛋白质稳定性

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：蛋白质药物目前通过注射进行全身给药。对于需要长期治疗的个体来说，用针进行自我给药是一种不愉快的日常经历。开发可注射的生物可降解聚合物，例如聚乳酸-乙醇酸 (PLGA) 能够在两次注射之间缓慢、连续地释放蛋白质数月，可能为痛苦的日常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。开发蛋白质 PLGA 递送系统的主要障碍是这些药物在体内释放之前具有不可逆的不稳定性。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方法。在该提案中，将控制聚合物中的 pH 值以提高封装在 PLGA 中的模型蛋白质和肽的稳定性。这种和其他稳定方法将应用于促进血管生成的治疗性蛋白质。缓释血管生成剂对于缺血性心脏病患者（在美国每年导致超过 600,000 例死亡）具有重要的应用。随后的位点特异性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/或心源性猝死。考虑到缓慢释放天然治疗性蛋白质（例如促进血管生成的蛋白质）的 PLGA 递送系统可能对人类健康产生的潜在影响，解决 PLGA 中封装的蛋白质的较差不稳定性的重要性变得显而易见。该提案将检验以下假设：水分与 PLGA 内部不受控制且经常呈酸性的 pH 相结合是导致 PLGA 递送系统（包括微球）中蛋白质不稳定的两种最常见的压力。开发控制聚合物微气候pH值的方法将成为稳定封装蛋白质的广泛适用的方法。该假设将在以下具体目标中进行测试：1）表征聚合物微气候中影响封装蛋白稳定性和释放的物理化学过程，2）研究模型蛋白和肽在 PLGA 递送系统中的稳定性，3）应用血管生成蛋白递送的稳定方法，以及4)生物活性血管生成蛋白的受控释放的体内评估