Microbicide Loaded Nanocarriers for Topical Delivery in HIV/AIDS Prevention

负载杀菌剂的纳米载体用于局部递送以预防艾滋病毒/艾滋病

• 批准号: 7757000
• 负责人: Bi-Botti Celestin Youan
• 金额: $ 19.94万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7757000
• 关键词: AIDS prevention; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Africa; Anti-Retroviral Agents; Biological Assay; Caliber; Cells; Cervical; Charge; Chitosan; Cream; Dendritic Cells; Development; Disease; Dosage Forms; Dose; Drug Carriers; Drug Controls; Drug Formulations; Encapsulated; Ensure; Eudragit; Gel; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Heating; Heparin; Human; Immune; In Vitro; Infection; Knowledge; Lactobacillus; Lead; Ligands; Lipids; Local Microbicides; Malignant Neoplasms; Methods; Modeling; Morphology; Mucous Membrane; Nucleotides; Outcome; Particle Size; Penetration; Persons; Pharmaceutical Preparations; Physical Chemistry; Polyesters; Polymers; Prevention; Prevention strategy; Preventive; Research Personnel; Reverse Transcriptase Inhibitors; Risk; Safety; Scientist; Seminal Plasma; Seminal fluid; Services; Sexually Transmitted Diseases; Site; Solid; Stimulus; Structure; Surface; System; Tenofovir; Testing; Therapeutic; Toxic effect; Treatment Protocols; Vagina; Virus; Virus Diseases; Woman; Work; base; biomaterial compatibility; compliance behavior; condoms; controlled release; cost; dosage; drug efficacy; efficacy testing; falls; fluorescence imaging; human disease; improved; innovation; lymph nodes; meetings; methylmethacrylate-methacrylic acid copolymer; microbicide; monocyte; nanocarrier; nanoformulation; nanosized; novel; particle; polyarginine; prevent; public health relevance; safety testing; skills; trafficking; transmission process; uptake; vaccine candidate

DESCRIPTION (provided by applicant): Every day over 6800 new infections take place and 5700 persons die from Human immunodeficiency virus infections (HIV/AIDS) worldwide, mostly because of inadequate access to HIV prevention and treatment services. Women who acquired HIV-1 through vaginal intercourse represent <60% of new infections in Africa. Still today, 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 break the cycle of the new HIV infections. Although an HIV vaccine would be the most suitable prevention strategy, an effective or even partially effective vaccine 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 from the local mucosa to the regional lymph nodes and, (iii) provide a controlled release of the microbicide to ensure long lasting protecting effect, (iv) be stimuli-sensitive to maximize the drug efficacy and provide required preventive dose on demand. The currently use of gel-based systems do not meet all these requirements. Thus nanosized drug carriers or drug loaded nanocarriers (NC) appear as promising alternative. Our long term goal is to identify novel multifunctional nanocarriers for controlled delivery of the microbicide either for prevention or treatment of HIV/AIDS. The objective of this proposal is to use nanocarrier for the controlled delivery of a model topical microbicide (Tenofovir). We have recently prepared several bioactive agents loaded chitosan and polyester nanocarrier with particle diameter ranging from <100 nm to <1000 nm. The central hypothesis is that a topical microbicide loaded nanocarrier is safer and more effective than the native drug in HIV/AIDS prevention. We will test this hypothesis with the following three specific aims. Specific aim#1: To develop a microbicide loaded bioadhesive nanocarrier for topical delivery in order to enhance the drug local duration of action. Specific aim#2: To develop a microbicide loaded pH sensitive nanocarrier for topical delivery in order to take advantage of the pH increase during intercourse to trigger effective drug dose release for an enhanced action. Specific aim#3: To develop a microbicide loaded functionalized nanocarrier with cell penetrating ligands in order to prevent the dissemination of the virus from the local mucosa to the regional lymph nodes. In each aim in order to identify optimal NC, we will thoroughly characterize the developed NC physico-chemically, assess their safety by MTT and Lactobacillus toxicity assay, test their efficacy in vitro (with seminal plasma, human PBMC-based and cervical explants assays) and elucidate their intracellular trafficking mechanism. It is anticipated that this innovative approach will lead to the identification of NC as a safer and more effective alternative to current microbicide delivery systems in HIV/AIDS prevention. PUBLIC HEALTH RELEVANCE: Our long-term goal is to thoroughly identify and characterize a novel microbicide nanocarrier system to improve the safety and efficacy in the prevention of HIV/AIDS transmission process. Specifically, the objective of this application is to develop tenofovir (a model microbicide) loaded nanocarriers that may be made of either bioadhesive (for longer topical duration of action), pH-sensitive (for a triggered release by semen either pH) or functionalized solid lipid matrix (for deeper penetration across the potential path of HIV virus) for prevent the dissemination of the virus. It is anticipated that knowledge gained from this work may be applicable to other microbicides and to other sexually transmitted diseases or human diseases.

描述（由申请人提供）：全世界每天都会有超过 6800 例新感染病例，5700 人死于人类免疫缺陷病毒感染（HIV/AIDS），主要原因是缺乏艾滋病毒预防和治疗服务。通过阴道性交感染 HIV-1 的女性占非洲新感染者的 60% 以下。直到今天，这种疾病还没有已知的治疗方法。因此，迫切需要有效的控制方法和策略来防止艾滋病毒/艾滋病的持续传播，打破艾滋病毒新感染的循环。尽管艾滋病毒疫苗将是最合适的预防策略，但尚未确定有效甚至部分有效的候选疫苗。因此，与避孕套不同，女性可以在其伴侣不知情的情况下使用的局部杀微生物剂的开发将为减缓 HIV-1 的全球传播带来重大益处。理想情况下，成功的杀微生物剂输送系统必须（i）保护处于HIV-1传播风险的粘膜表面，（ii）防止受感染细胞从局部粘膜传播到区域淋巴结，（iii）提供杀微生物剂的受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功效并按需提供所需的预防剂量。目前使用的基于凝胶的系统不能满足所有这些要求。因此，纳米药物载体或载药纳米载体（NC）似乎是有前途的替代品。我们的长期目标是确定新型多功能纳米载体，用于控制递送杀菌剂，以预防或治疗艾滋病毒/艾滋病。该提案的目的是使用纳米载体来控制输送模型外用杀菌剂（替诺福韦）。我们最近制备了几种负载壳聚糖和聚酯纳米载体的生物活性剂，其粒径范围为<100 nm至<1000 nm。核心假设是，负载纳米载体的局部杀菌剂在预防艾滋病毒/艾滋病方面比天然药物更安全、更有效。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：开发一种用于局部递送的负载杀菌剂的生物粘附纳米载体，以提高药物的局部作用持续时间。具体目标#2：开发一种负载杀菌剂的 pH 敏感纳米载体，用于局部给药，以便利用性交过程中 pH 值的升高来触发有效的药物剂量释放，从而增强作用。具体目标#3：开发一种具有细胞穿透配体的负载杀菌剂的功能化纳米载体，以防止病毒从局部粘膜传播到区域淋巴结。在每个目标中，为了确定最佳的 NC，我们将彻底表征所开发的 NC 的物理化学特性，通过 MTT 和乳酸菌毒性测定评估其安全性，测试其体外功效（使用精浆、基于人 PBMC 的和宫颈外植体测定）并阐明其细胞内运输机制。预计这种创新方法将导致 NC 成为当前预防艾滋病毒/艾滋病的杀微生物剂输送系统的更安全、更有效的替代品。公共健康相关性：我们的长期目标是彻底鉴定和表征新型杀菌剂纳米载体系统，以提高预防艾滋病毒/艾滋病传播过程的安全性和有效性。具体来说，本申请的目的是开发负载替诺福韦（一种杀微生物剂模型）的纳米载体，该纳米载体可以由生物粘附剂（用于更长的局部作用持续时间）、pH敏感型（用于通过精液的pH值触发释放）或功能化固体脂质基质（用于更深入地渗透HIV病毒的潜在路径）制成，以防止病毒传播。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。