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的妇女占地方性地区新感染的60％。没有已知的治疗条件。因此，迫切需要有效的控制方法和策略，以防止艾滋病毒/艾滋病的持续传播并打破新感染的周期。尽管有效的HIV疫苗将是最合适的预防策略，但候选人尚未确定。因此，在不知道伴侣的情况下可以使用（与避孕套不同的避孕套）的局部杀菌剂的开发将为减缓HIV-1的全球蔓延带来重大好处。理想情况下，成功的杀菌剂递送系统必须（i）保护面临HIV-1传播风险的粘膜表面，（ii）防止体内感染细胞的传播，（iii）提供了微生物的受控释放，以确保持久的保护作用，并具有刺激性的敏感性，以最大程度地提高药物效果。当前的药物输送系统不符合所有这些要求。我们最近设计了替诺福韦，脂质，生物粘附，pH和透明质酸酶敏感的纳米级药物（纳米医学，NMS，NMS），平均大小低于500nm，代表了预防HIV预防的有希望的药物输送模板。 我们的长期目标是确定对艾滋病毒/艾滋病预防中的受控药物递送的新型，刺激敏感的NM。该提案的目的是开发一种新的NM来控制局部菌皮的递送。我们假设与天然药物相比，含有刺激敏感性NM的局部菌糖可以提高安全性和功效。我们将以以下三个特定目标来检验这一假设。特定目的＃1：制定和表征含有磷酸酶敏感的NM的局部杀菌剂，以利用酸性磷酸酶活性的增加（人类精液中的丰富酶），以触发性交期间的药物释放。特定目的＃2：要制定和表征含有透明质酸酶敏感NM的局部菌心，以利用人类精液作为替代性触发剂的透明质酸酶活性的选择性增加。特定目的＃3：制定和表征含有甘露糖敏感性NM的局部杀菌剂，以触发HIV信封的主要聚糖成分Mannose释放药物。在每个目标中，我们都会捕获T-20和Tenofovir（作为模型菌皮），并基于物理化学，生物学和免疫学分析来优化NMS。在当前的美国FDA指导下，进行了NM的规格和接受标准，化学，制造，控制，微生物学和临床前毒理学研究。此外，使用计算机和数学建模与Sarah Kieweg博士（堪萨斯州堪萨斯大学）合作，使用计算机和数学建模来阐明NM的生物命运。安全和效力研究将与Carol Lackman-Smith和Roger Ptak（马里兰州南部研究所）一起进行。从艾滋病毒/艾滋病的这项创新和协作工作中获得的知识也适用于其他疾病的管理。 公共卫生相关性：我们的长期目标是彻底识别和表征新型的纳米医学微生物剂，以提高用于预防HIV/AIDS传播过程中使用的菌心的安全性和功效。具体而言，该应用的目的是开发一个含有刺激性敏感纳米医学的模型杀菌剂，可以通过酶敏感的成分（透明质酸酶，酸性磷酸酶和甘露糖）提供，以通过精液触发，或通过病毒包膜释放的释放，或通过病毒封装来释放。此外，我们将使用数学建模来通过生物系统合理化/优化药物制剂，释放和运输。可以预料，从这项工作中获得的知识可能适用于其他微生物和其他性传播或人类疾病。