Artificial Polymeric Lipoproteins as Drug Carriers

作为药物载体的人工聚合脂蛋白

• 批准号: 6765906
• 负责人: Glen S. Kwon
• 金额: $ 14.34万
• 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/6765906
• 关键词: Artificial; Polymeric; Lipoproteins; Drug; Carriers

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)： 尽管在临床前和临床试验中取得了令人鼓舞的结果，但目前许多用于对抗机会性感染(OIS)的药物的临床作用以及从大规模药物发现计划中产生的许多有效药物对OIS的影响一直受到较差的水溶性、高毒性和不充分的非肠道剂型的阻碍。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。尤其是聚合物胶束，即纳米超分子核壳结构，由于其安全性、高载药量和改善药代动力学，最近已进入有效但难溶于水的毒性药物的临床试验。聚合物胶束的一个独特方面是能够调整其化学结构以微调药物输送的性能。我们的结果表明，调整必须针对单个药物或药物类别进行，并且容易地对聚氧乙烷-嵌段-聚(L-氨基酸)胶束(聚乙二醇b-丙交酯)进行调整可能会增强药物的传递。我们的工作重点是两性霉素B(Amb)，这是治疗机会性系统性真菌感染的主要药物。这些OIS是免疫功能低下的癌症或艾滋病患者以及器官移植接受者发病率的主要原因。我们认为，定制的聚乙二醇b-聚乙二醇胺胶束可以提高AMB的治疗指数。具体地说，我们假设由于聚乙二醇b-Plaa胶束，Amb的药代动力学发生了有益的变化，增加了血浆半衰期，降低了肝脏清除率，改变了其自聚集状态，可能会降低药物的毒性，提高其抗真菌效果。在这种情况下，我们可以调整聚乙二醇b-Plaa胶束的结构，以微调AMB的释放动力学，提高其释放性。具体目的：(1)研究聚乙二醇-b-丙交酯胶束包裹的阿米巴在啮齿动物体内的药代动力学(血药浓度、血浆分布和组织分布)。(2)研究聚乙二醇b-聚乙二醇胺胶束对小白鼠的急性毒性、肾毒性和肝脏毒性。(3)在中性粒细胞减少的播散性念珠菌病小鼠模型中，研究聚乙二醇b胶束包裹的Amb的抗真菌活性。将与标准配方的Amb和批准用于难治性系统性真菌病的脂质体Amb进行比较。这些拟议的研究将深入了解Amb的毒性和抗真菌活性背后的机制，并可能表明聚乙二醇b-Plaa胶束增加了该药物的治疗指数。