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

通过刺激敏感纳米药物输送杀菌剂预防艾滋病毒/艾滋病

• 批准号: 8210713
• 负责人: Bi-Botti Celestin Youan
• 金额: $ 35.75万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-20 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210713
• 关键词: AIDS prevention; AIDS/HIV problem; Accounting; Acid Phosphatase; Acquired Immunodeficiency Syndrome; Address; Adherence; Amino Acids; Amyloid Fibrils; Anti-Retroviral Agents; Award; Biodistribution; Biological; Biological Assay; Biological Models; C-terminal; Cells; Cervical; Chemistry; Chitosan; Clinic; Collaborations; Commit; Computer Simulation; Cream; Development; Diabetes Mellitus; Disease; Dosage Forms; Dose; Drug Delivery Systems; Drug Formulations; Drug resistance; Engineering; Enhancers; Ensure; Enzymes; Forensic Sciences; Gel; Goals; Grant; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Half-Life; Human; Human Activities; Hyaluronic Acid; Hyaluronidase; Infection; Kansas; Knowledge; Lactobacillus; Lectin; Lipids; Local Microbicides; Malignant Neoplasms; Mannose; Mechanics; Medicine; Mentors; Methods; Microbiology; Modeling; Modification; Mucous Membrane; Nucleotides; Outcome; Pathologist; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Polymers; Polysaccharides; Prevention; Prevention strategy; Preventive; Procedures; Research; Research Institute; Research Personnel; Reverse Transcriptase Inhibitors; Risk; Safety; Seminal Plasma; Seminal fluid; Sodium; Stimulus; Surface; System; T-20; Tenofovir; Testing; Toxic effect; Toxicology; United States National Institutes of Health; Universities; Vagina; Viral; Virus; Water; Woman; Work; base; biological systems; comparative efficacy; compliance behavior; condoms; controlled release; cost; crosslink; density; drug efficacy; human disease; improved; in vivo; inhibitor/antagonist; innovation; lymph nodes; mathematical model; meetings; microbicide; nano; nanoformulation; nanomedicine; nanoscale; novel; pre-clinical; prevent; prostatic fraction Acid phosphatase isoenzyme; protective effect; response; skills; transmission process; tripolyphosphate

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.

描述（由申请人提供）：通过阴道性交获得HIV-1的妇女占流行地区新感染者的约60%。目前还没有治愈这种疾病的方法。因此，迫切需要有效的控制方法和战略，以防止艾滋病毒/艾滋病的持续蔓延，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，开发一种局部杀微生物剂，这种杀微生物剂可以在其伴侣不知情的情况下由妇女使用（与避孕套不同），这将为减缓HIV-1的全球传播提供重大益处。理想地，成功的杀微生物剂递送系统将必须（i）保护处于HIV-1传播风险下的粘膜表面，（ii）防止受感染细胞在体内传播，（iii）提供杀微生物剂的受控释放以确保持久的保护作用，以及（iv）是刺激敏感的以最大化药物功效。目前的药物递送系统不满足所有这些要求。我们最近设计了替诺福韦负载，脂质为基础的，生物粘附性，pH和透明质酸酶敏感的纳米级药物（纳米药物，NM），平均尺寸小于500 nm，代表有前途的药物递送模板艾滋病毒预防。 我们的长期目标是确定新的，刺激敏感的纳米材料，用于艾滋病毒/艾滋病预防的控制药物输送。本建议的目的是开发一种新的纳米控制交付的局部杀微生物剂。我们假设，与天然药物相比，含有刺激敏感NM的局部杀微生物剂可以提高安全性和有效性。我们将通过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性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）的增加来触发性交期间的药物释放。具体目标2：配制和表征含有透明质酸酶敏感性NM的局部杀微生物剂，以利用人精液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：配制和表征含有甘露糖敏感NM的局部杀微生物剂，以通过甘露糖（HIV包膜的主要聚糖组分）触发药物释放。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NM。按照现行美国FDA指南进行NM的质量标准和验收标准、化学、生产、控制、微生物学和临床前毒理学研究。此外，NM的生物学命运是使用计算机和数学建模与Sarah Kieweg博士合作阐明的。机械工程，堪萨斯大学，KS）。安全性和有效性研究将由Carol Lackman-Smith和Roger Ptak（Southern Research Institute，MD）进行。从这一艾滋病毒/艾滋病方面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。 公共卫生关系：我们的长期目标是彻底确定和表征一种新型纳米药物杀微生物剂，以提高用于预防艾滋病毒/艾滋病传播过程的杀微生物剂的安全性和有效性。具体地，本申请的目的是开发一种包含内部刺激敏感性纳米药物的模型杀微生物剂，所述纳米药物可以通过酶敏感性组分（透明质酸酶、酸性磷酸酶和甘露糖）或通过利用HIV包膜上异常高密度的甘露糖的病毒包膜来获得，所述酶敏感性组分用于由精液触发释放。此外，我们将使用数学建模来合理化/优化药物制剂，释放和通过生物系统的运输。预计从这项工作中获得的知识可能适用于其他杀微生物剂和其他性传播疾病或人类疾病。