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: 8508641
• 负责人: Bi-Botti Celestin Youan
• 金额: $ 32.13万
• 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/8508641
• 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; nanoencapsulated; 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.

描述(申请人提供)：通过阴道性交感染HIV-1的妇女约占流行区新感染病例的60%。目前还没有治愈这种疾病的已知方法。因此，迫切需要有效的控制方法和战略，以防止艾滋病毒/艾滋病的持续传播，打破新感染的循环。尽管有效的艾滋病毒疫苗将是最合适的预防策略，但候选疫苗尚未确定。因此，开发一种可供妇女在其伴侣不知情的情况下使用的局部杀微生物剂(与避孕套不同)，将为减缓艾滋病毒-1的全球传播提供重大好处。理想情况下，成功的杀微生物剂输送系统必须(I)保护有可能传播HIV-1病毒的粘膜表面，(Ii)防止感染细胞在体内扩散，(Iii)提供杀微生物剂的受控释放，以确保长期保护效果，以及(Iv)对刺激敏感，以最大限度地发挥药物效果。目前的药物输送系统不能满足所有这些要求。我们最近设计出了平均粒径小于500 nm的替诺福韦脂基生物粘附性、pH和透明质酸酶敏感的纳米药物(Nanomedines，NMS)，这些药物代表了用于HIV预防的有前景的药物传递模板。我们的长期目标是找到新的、对刺激敏感的NMS，用于艾滋病毒/艾滋病预防中的受控药物输送。这项提议的目的是开发一种用于局部杀菌剂控制传递的新型纳米材料。我们假设，与本地药物相比，含有刺激性NM的局部杀菌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：研制和鉴定一种含有磷酸酶敏感的NM的局部杀菌剂，以利用酸性磷酸酶(人类精液中丰富的酶)活性的增加来触发性交过程中的药物释放。具体目标#2：配制和表征一种含有透明质酸酶敏感NM的局部杀菌剂，以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：配制和表征一种含有甘露糖敏感NM的局部杀微生物剂，以便通过甘露糖触发药物释放，甘露糖是HIV包膜的主要多糖成分。在每个目标中，我们捕获T-20和替诺福韦(作为模型杀菌剂)，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按照当前美国FDA的指导进行。此外，利用计算机和数学模型与Sarah Kieweg博士合作，阐明了NM的生物学命运。堪萨斯大学机械工程)。安全性和有效性研究将与Carol Lackman-Smith和Roger Ptak(马里兰州南方研究所)一起进行。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。