Artificial Polymeric Lipoproteins as Drug Carriers

作为药物载体的人工聚合脂蛋白

• 批准号: 6678003
• 负责人: Glen S. Kwon
• 金额: $ 7.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678003
• 关键词: amphotericin B; antifungal agents; blood lipoprotein; candidiasis; chemical conjugate; chemical synthesis; clearance rate; disease /disorder model; drug screening /evaluation; drug vehicle; high performance liquid chromatography; kidney; laboratory mouse; laboratory rat; liposomes; liver; micelles; microorganism culture; nanotechnology; neutropenia; pharmacokinetics; polyethylene glycols; polymers; radiotracer; toxicology; ultraviolet spectrometry

DESCRIPTION (provided by applicant): The clinical role of many drugs currently used to fight opportunistic infections (OIs) and the impact of many potent drugs for OIs coming out of massive drug discovery programs have been hampered by poor watersolubility, high toxicity, and inadequate parenteral dosage forms despite encouraging results in preclinical and clinical testing. Current efforts to address these major bottlenecks in drug development fall in the realm of nanotechnology. In particular, polymeric micelles, nanoscopic supramolecular core-shell structures, have recently entered clinical trials for potent yet poorly water-soluble and toxic drugs, owing to safety, high drug loading, and improved pharmacokinetics. A unique aspect of polymeric micelles is the ability to adjust their chemical structures to fine-tune properties for drug delivery. Our results suggest that adjustments must be made with an individual drug or class of drugs in mind, and that easily made adjustments on poly(ethylene oxide)-block-poly(L-amino acid) (PEG-b-PLAA) micelles may enhance drug delivery. Our efforts focus on amphotericin B (AmB), the primary drug for opportunistic systemic fungal infections. These OIs are a major cause of morbidity among immunocompromised patients suffering from cancer or AIDS and organ transplant recipients. We believe that tailor-made PEG-b-PLAA micelles may increase the therapeutic index of AmB. Specifically, we hypothesize that beneficial changes in the pharmacokinetics of AmB, increased plasma halflife and reduced liver clearance, and changes in its self-aggregation state, owing to PEG-b-PLAA micelles may lower the drug's toxicity and increase its antifungal efficacy. In this context, we may adjust the structure of PEG-b-PLAA micelles to fine-tune the release kinetics of AmB and enhance its delivery. Specific Aims: (1) To study the pharmacokinetics (plasma profile, distribution in plasma, and tissue distribution) of AmB encapsulated by PEG-b-PLAA micelles in rodents. (2) To study the acute, renal and liver toxicity of AmB encapsulated in PEG-b-PLAA micelles in rodents. (3) To study the antifungal activity of AmB encapsulated in PEG-b-PLAA micelles in a neutropenic murine model of disseminated candidiasis. Comparisons will be made with a standard formulation of AmB and a liposomal AmB approved for refractory systemic fungal diseases. These proposed studies will provide insight into mechanisms behind the toxicity and antifungal activity of AmB and perhaps show that PEG-b-PLAA micelles increase the therapeutic index for the drug.

描述（由申请人提供）： 目前用于对抗机会性感染（OI）的许多药物的临床作用以及来自大规模药物发现计划的许多有效药物对OI的影响受到水溶性差、毒性高和胃肠外剂型不足的阻碍，尽管临床前和临床试验结果令人鼓舞。目前解决药物开发中这些主要瓶颈的努力属于纳米技术领域。特别是，聚合物胶束，纳米级超分子核-壳结构，最近进入临床试验的有效但水溶性差和毒性药物，由于安全性，高载药量，并改善药代动力学。聚合物胶束的一个独特方面是能够调节其化学结构以微调药物递送的性质。我们的结果表明，必须根据单个药物或一类药物进行调整，并且对聚环氧乙烷-嵌段-聚（L-氨基酸）（PEG-b-PLAA）胶束进行轻松调整可以增强药物递送。我们的努力集中在阿替霉素B（AmB），机会性全身真菌感染的主要药物。这些OIs是癌症或AIDS免疫功能低下患者和器官移植受者发病的主要原因。我们认为，定制的PEG-b-PLAA胶束可以增加AmB的治疗指数。具体而言，我们假设，由于PEG-b-PLAA胶束，AmB的药代动力学的有益变化，增加血浆半衰期和降低肝脏清除率，以及其自聚集状态的变化可能会降低药物的毒性并增加其抗真菌功效。在这种情况下，我们可以调整PEG-b-PLAA胶束的结构，微调AmB的释放动力学，并提高其交付。具体目标：（1）研究PEG-b-PLAA胶束包封AmB在啮齿动物体内的药代动力学（血浆、血浆和组织分布）。(2)目的：研究聚乙二醇-b-聚乳酸（PEG-b-PLAA）胶束包封AmB对啮齿动物的急性毒性、肾毒性和肝毒性。(3)目的：研究聚乙二醇-b-聚乳酸（PEG-b-PLAA）胶束包裹的AmB对小鼠播散性念珠菌病的抗真菌活性。将与AmB的标准制剂和批准用于难治性系统性真菌疾病的脂质体AmB进行比较。这些拟议的研究将提供深入了解AmB的毒性和抗真菌活性背后的机制，并可能表明PEG-b-PLAA胶束增加药物的治疗指数。