Prevention of HIV/AIDS by Stimuli-Sensitive Nanomedicine for Microbicide Delivery

描述（由申请人提供）：通过阴道性交感染HIV-1的妇女占流行地区新感染病例的60%左右。目前还没有已知的治疗方法。因此，迫切需要制定有效的控制方法和战略，以防止艾滋病毒/艾滋病继续蔓延，并打破新感染的循环。虽然有效的艾滋病毒疫苗将是最合适的预防战略，但尚未确定候选疫苗。因此，开发一种局部使用的杀微生物剂（与避孕套不同），可以让女性在伴侣不知情的情况下使用，这将为减缓HIV-1在全球的传播带来重大好处。理想情况下，一个成功的杀微生物剂输送系统必须(i)保护有HIV-1传播风险的粘膜表面，（ii）防止感染细胞在体内传播，（iii）提供杀微生物剂的可控释放，以确保持久的保护效果，（iv）对刺激敏感，以最大限度地提高药物疗效。目前的给药系统不能满足所有这些要求。我们最近设计了负载替诺福韦的、脂基的、生物粘合剂的、pH值和透明质酸酶敏感的纳米级药物（纳米药物，NMs），其平均尺寸小于500nm，代表了HIV预防的有前途的药物递送模板。我们的长期目标是确定新的、刺激敏感的NMs，用于控制HIV/AIDS预防中的药物输送。本提案的目的是开发一种新的纳米用于局部杀微生物剂的控制递送。我们假设含有刺激敏感NM的局部杀微生物剂与天然药物相比可以提高安全性和有效性。我们将用以下三个具体目标来检验这一假设。具体目标#1：配制和表征含有磷酸酶敏感NM的局部杀微生物剂，以利用酸性磷酸酶活性（人类精液中丰富的酶）的增加来触发性交过程中的药物释放。具体目标#2：配制和表征含有透明质酸酶敏感NM的局部杀微生物剂，以便利用人类精液中透明质酸酶活性的选择性增加作为替代触发剂。具体目标#3：制定和表征含有甘露糖敏感纳米的局部杀微生物剂，以触发甘露糖释放药物，甘露糖是HIV包膜的主要聚糖成分。在每个目标中，我们捕获T-20和替诺福韦（作为模型杀微生物剂），并基于理化，生物学和免疫学分析优化NMs。NM的规格和验收标准、化学、制造、控制、微生物学和临床前毒理学研究均按照现行的美国FDA指导进行。此外，与Sarah Kieweg博士（美国堪萨斯大学机械工程系）合作，利用计算机和数学模型阐明了纳米的生物学命运。安全性和有效性研究将由Carol Lackman-Smith和Roger Ptak（南方研究所，MD）进行。从这项针对艾滋病毒/艾滋病的创新和协作工作中获得的知识也将适用于其他疾病的管理。

DESCRIPTION (provided by applicant): Women who acquired HIV-1 through vaginal intercourse represent ~60% of new infections in endemic regions. There is no known cure for the condition. Thus, there is a critical and urgent need for effective control methods and strategies to prevent the continuous spread of HIV/AIDS and to break the cycle of new infections. Although an effective HIV vaccine would be the most suitable prevention strategy, a candidate has yet to be identified. Thus, the development of a topical microbicide, which can be used (unlike condoms) by women without the knowledge of their partner, would provide a major benefit for slowing the global spread of HIV-1. Ideally, a successful microbicide delivery system will have to (i) protect mucosal surfaces at risk of HIV-1 transmission, (ii) prevent the dissemination of infected cells in the body, (iii) provide a controlled release of the microbicide to ensure a long-lasting protective effect, and (iv) be stimuli-sensitive to maximize the drug efficacy. The current drug delivery systems do not meet all these requirements. We have recently engineered tenofovir loaded, lipid based, bioadhesive, pH and hyaluronidase-sensitive nanoscale medicines (nanomedicines, NMs) with average size less than 500nm that represent promising drug delivery templates for HIV prevention. Our long-term goal is to identify novel, stimuli-sensitive NMs for controlled drug delivery in HIV/AIDS prevention. The objective of this proposal is to develop a novel NM for controlled delivery of topical microbicides. We hypothesize that a topical microbicide containing stimuli-sensitive NM can improve both safety and efficacy compared to those of the native drug. We will test this hypothesis with the following three specific aims. Specific aim #1: To formulate and characterize a topical microbicide containing phosphatase- sensitive NM in order to take advantage of the increase in the acid phosphatase activity (abundant enzyme in human semen) to trigger drug release during intercourse. Specific aim #2: To formulate and characterize a topical microbicide containing hyaluronidase-sensitive NM in order to take advantage of the selective increase in the hyaluronidase activity of human semen as an alternative triggering agent. Specific aim #3: To formulate and characterize a topical microbicide containing mannose-sensitive NM in order to trigger drug release by mannose, a major glycan component of the HIV envelope. In each aim we entrap T-20 and Tenofovir (as model microbicides) and optimize the NMs based on physicochemical, biological, and immunological analyses. The specifications and acceptance criteria, chemistry, manufacturing, controls, microbiology, and preclinical toxicology studies of the NM are performed following the current US FDA guidance. Moreover, the biological fate of the NM is elucidated using computer and mathematical modeling in collaboration with Dr. Sarah Kieweg (Dept. Mechanical Engineering, University of Kansas, KS). The safety and efficacy studies are to be conducted with Carol Lackman-Smith and Roger Ptak (Southern Research Institute, MD). The knowledge gained from this innovative and collaborative work for HIV/AIDS will also be applicable to the management of other diseases. PUBLIC HEALTH RELEVANCE: Our long-term goal is to thoroughly identify and characterize a novel nanomedicine microbicide to improve the safety and efficacy of microbicides used in the prevention of the HIV/AIDS transmission process. Specifically, the objective of this application is to develop a model microbicide containing inside stimuli- sensitive nanomedicines that may be made available via either enzyme sensitive components (hyaluronidase, acid phosphatase, and mannose) for a triggered release by semen, or through a viral envelope taking advantage of the unusually high density of mannose on the HIV envelope. Moreover, we will use mathematical modeling to rationalize/optimize drug formulation, release, and transport through biological systems. It is anticipated that knowledge gained from this work may be applicable to other microbicides and to other sexually transmitted or human diseases.