CONTROLLED RELEASE OF ATRIAL NATRIURETIC FACTOR

心房钠尿因子的受控释放

• 批准号: 6388410
• 负责人: MARIA A RUPNICK
• 金额: $ 12.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-04 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388410
• 关键词: atrial natriuretic peptide; chemical stability; chemical structure; copolymer I; drug delivery systems; drug design /synthesis /production; slow release drug

DESCRIPTION (Adapted from applicant's abstract) The long-term research objectives of this proposal are the formulation and synthesis of biodegradable polymeric matrices which can incorporate and stabilize macromolecules (MW>1000) and release them in a controlled fashion as bioactive agents for up to 1 month. Macromolecules, such as peptides and proteins, are becoming increasingly important for use in biopharmaceutical research and as potential therapeutic agents. However, their complex three-dimensional structures and large size generally results in easy inactivation, poor oral bioavailability and rapid metabolism, limiting their use to short-term parenteral settings. Controlled release polymer systems potentially offer many advantages which may overcome these obstacles. For example, protection during storage and delivery, maintenance of drug levels without peaks and troughs, reduced dosages, increased dosing intervals, localized delivery, and improved patient comfort and compliance. Delivery systems for low molecular weight molecules are being widely used both experimentally, to study chemotactic agents, cell extracts and others, and clinically, to treat prostate cancer using Lupron Depot or deliver contraceptives using Norplant. In spite of these advances, no clinically available controlled release system for large molecular weight compounds exists. This is because of both formulation (polymer) and stability (protein) issues. The candidate's hypothesis is that biodegradable controlled release polymers can be developed for the long-term delivery of bioactive macromolecules, such as peptides and proteins, at efficacious levels. She has chosen PLGA [poly(lactide-co-glycolide)], a biodegradable copolymer with FDA approval for biomedical application, as a release matrix. Atrial natriuretic peptide (ANP), a 3000 MW molecule with therapeutic potential in hypertension and congestive heart failure, will serve as a model compound. The hypothesis will be tested through the following specific aims. 1) To design a biodegradable controlled release system by optimizing the performance properties of PLGA for the delivery of ANP over one month, and study the role of polymer erosion in drug delivery using both theoretical and experimental approaches; 2) To examine protein stability as it relates to PLGA preparation, storage, and release and develop strategies to preserve ANP bioactivity: 3) To evaluate the pharmacokinetics of the PLGA delivery system and the efficacy of the controlled release form of ANP using cell culture and animal model bioassays. The candidate states her belief that the successful completion of these objectives will greatly facilitate, first the investigations, and ultimately, the clinical applications of large, bioactive protein macromolecules. (End of Abstract)

描述 (摘自申请者摘要)的长期研究目标 本方案是生物可降解聚合物的配方和合成 可结合和稳定大分子的基质(MW&GT；1000)和 以受控方式将它们作为生物活性物质释放，释放时间长达1个月。 大分子，如多肽和蛋白质，正变得越来越多 在生物制药研究和潜在治疗方面具有重要意义 探员们。然而，它们复杂的三维结构和庞大的尺寸 一般会导致容易失活、口服生物利用度差和快速 新陈代谢，将它们的使用限制在短期的非肠道环境中。 控制释放聚合物系统潜在地提供了许多优点， 可能会克服这些障碍。例如，存储期间的保护和 递送，维持无峰无谷的药物水平，减少 剂量、增加给药间隔、局部给药和改进 患者舒适度和遵从性。低分子量给药系统 分子在实验中被广泛用于研究趋化作用 药物、细胞提取物和其他，以及临床上用于治疗前列腺癌的药物 使用Lupron Depot或使用Norpot交付避孕药。尽管 这些进展，没有临床上可用的大剂量控释系统 存在分子量较大的化合物。这是因为这两种提法 (聚合物)和稳定性(蛋白质)问题。 候选人的假设是可生物降解的控释聚合物 可以为生物活性大分子的长期输送而开发， 例如多肽和蛋白质，在有效水平上。她选择了PLGA FDA批准的可生物降解共聚物[聚(丙交酯-乙交酯)] 用于生物医学应用，作为释放骨架。心钠素 心钠素(ANP)是一种3000 mW的分子，具有治疗高血压和 充血性心力衰竭，将作为模范化合物。假说 将通过以下具体目标进行测试。1)设计一个 生物可降解控释系统的性能优化 PLGA用于ANP一个月以上释放的性质，并研究了 聚合物侵蚀在药物输送中的作用 实验方法；2)检查蛋白质稳定性，因为它与 PLGA的准备、储存和释放，并制定保存策略 心钠素生物活性：3)评价PLGA制剂的药代动力学 心钠素细胞控释系统及其药效研究 培养和动物模型生物测定。这位候选人表示她相信 这些目标的成功实现将极大地便利：第一 这项研究，以及最终的临床应用， 生物活性蛋白质大分子。(摘要结束)