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 （摘自申请人摘要） 本研究提出了生物降解聚合物的配方和合成方法， 基质，其可以掺入并稳定大分子（MW>1000）， 作为生物活性剂以受控方式释放它们长达1个月。 大分子，如肽和蛋白质，正变得越来越多， 对于生物制药研究和作为潜在的治疗剂是重要的 剂. 然而，其复杂的三维结构和大尺寸 通常导致容易失活，口服生物利用度差， 代谢，限制了它们在短期胃肠外环境中的使用。 控释聚合物系统潜在地提供了许多优点， 可以克服这些障碍。 例如，存储期间的保护， 输送、维持药物水平而无波峰和波谷、降低 剂量，增加给药间隔，局部给药， 患者舒适度和依从性。 低分子量输送系统 分子被广泛用于实验，研究趋化性， 试剂、细胞提取物和其他，以及临床上用于治疗前列腺癌 使用Lupron Depot或使用Norplant提供避孕药具。 尽管 这些进展，没有临床上可用的控制释放系统， 存在分子量化合物。 这是因为这两个公式 （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 可以被开发用于生物活性大分子的长期递送， 如肽和蛋白质。 选择PLGA [聚（丙交酯-共-乙交酯）]，FDA批准的可生物降解共聚物 用于生物医学应用，作为释放基质。 心钠素 (ANP)，一种具有高血压治疗潜力的3000 MW分子， 充血性心力衰竭，将作为模型化合物。 的假设 将通过以下具体目标进行测试。 1)设计一个 通过优化性能的生物可降解控制释放系统 PLGA的性能，用于在一个月内递送ANP，并研究 聚合物侵蚀在药物递送中的作用， 实验方法; 2）检查蛋白质稳定性，因为它涉及 PLGA制备、储存和放行，并制定保存策略 ANP生物活性：3）评价PLGA递送的药代动力学 系统和使用细胞的ANP的控制释放形式的功效 培养和动物模型生物测定。 候选人表示她相信， 这些目标的顺利完成将大大促进， 研究，并最终，临床应用的大， 生物活性蛋白质大分子。 (End摘要）