Nanoparticle microbicides for delivery of combination antiretroviral drugs

用于递送组合抗逆转录病毒药物的纳米颗粒杀微生物剂

• 批准号: 8676646
• 负责人: Kim A. Woodrow
• 金额: $ 44.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-14 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676646
• 关键词: AIDS prevention; Accounting; Adsorption; Animal Model; Anti-Retroviral Agents; Antiviral Agents; Architecture; Behavior; Biodistribution; Biological Availability; Biopsy; CCR5 gene; Cells; Charge; Chemicals; Chemistry; Clinical; Clinical Trials; Colposcopy; Cytology; Data; Detergents; Diffuse; Diffusion; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Drug usage; Encapsulated; Engineering; Epidemic; Epithelial; Epithelium; Exhibits; Female; Gel; Genital system; Geometry; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; Hydrophobicity; In Vitro; Individual; Infection; Laboratories; Libraries; Local Microbicides; Macaca; Macaca nemestrina; Measures; Methods; Modeling; Mucous Membrane; Mucous body substance; Mus; Nevirapine; Organ Culture Techniques; Outcome; Particulate; Penetration; Pharmaceutical Preparations; Physiological; Prevention; Property; Prophylactic treatment; Research; Resistance; Ritonavir; Route; Safety; Saquinavir; Sexual Transmission; Sexually Transmitted Diseases; Solubility; Surface; Suspension substance; Suspensions; Techniques; Tenofovir; Time; Tissues; Topical application; Toxic effect; Vaccines; Vagina; Viral; Virus; Woman; aqueous; base; chemical stability; clinically relevant; controlled release; cytotoxicity; design; drug testing; efficacy testing; efficacy trial; empowered; flexibility; genital secretion; in vivo; inhibitor/antagonist; microbicide; nanoparticle; nanoparticulate; next generation; novel; polyanion; preclinical safety; prevent; protective efficacy; rectal; residence; response; safety study; screening; simian human immunodeficiency virus; success; transmission process; vaginal transmission

PROJECT SUMMARY/ABSTRACT Sexual transmission through the genital tract or rectal mucosa is the most common route for acquiring new HIV infections and accounted for ~70% of the 2.7 million people worldwide who became newly infected in 2007. A cure or effective vaccine that would contain the global spread of this epidemic is not expected in the near term, and new HIV infections continue to outpace advances made in treatment with antiretroviral drugs. There is consequently an urgent need to develop agents that can be applied topically to mucosal surfaces to prevent the sexual transmission of HIV. However, several large-scale clinical trials testing the efficacy of agents that disrupt the integrity of the viral envelope (detergents) or prevent adsorption or fusion of the virus with its target cells (polyanions) have failed to protect against HIV infection. The success of highly active antiretroviral therapy (HAART) provides a paradigm for developing the next generation of microbicides, raising the possibility that a combination of potent and broadly active inhibitors that exhibit multiple and complementary mechanisms of action may be vastly superior to the delivery of single compounds. To fully realize the potential of these potent antiretroviral (ARV) drugs, the challenges of formulating and delivering compounds with markedly different chemical stability and aqueous solubility in a topical combination product must be overcome. This research plan is designed to evaluate nanoparticle-based vaginal drug delivery systems for HIV prevention. The experimental focus is to achieve protection against vaginal transmission of HIV-1 by topical delivery of a combination of antiretroviral drugs using mucus- and tissue-diffusing nanoparticle microbicides. This research would be the first to control the temporal and spatial co-delivery of a combination of antiretroviral agents that have different mechanisms of action against HIV-1 (Aim 1). If successful, our studies would be the first to determine the size range and penetration depth accessible for nanoparticulate drug delivery systems in the vaginal mucosa (Aim 2). Our proposed research will also provide valuable data on the transport, biodistribution, and pharmacokinetics of encapsulated and released antiretroviral agents that are administered topically to the vaginal mucosa using nanoparticle microbicides (Aim 3). Finally, we will conduct preclinical safety and anti-HIV efficacy studies to rapidly advance our nanoparticle-based microbicides to human safety and efficacy trials (Aim 4). The outcomes from our proposed research may highly impact the field of microbicide research for HIV and other sexually-transmitted infections.

项目概要/摘要 通过生殖道或直肠粘膜的性传播是感染新艾滋病毒的最常见途径 感染者，占 2007 年全球 270 万人新感染者的 70%。 预计短期内不会出现治愈或有效疫苗来遏制这种流行病的全球传播， 新的艾滋病毒感染数量继续超过抗逆转录病毒药物治疗的进展。有 因此，迫切需要开发可局部应用于粘膜表面的药物，以预防 艾滋病毒的性传播。然而，多项大规模临床试验测试了药物的功效， 破坏病毒包膜的完整性（去垢剂）或防止病毒与其目标吸附或融合 细胞（聚阴离子）未能防止艾滋病毒感染。高活性抗逆转录病毒药物的成功 疗法（HAART）为开发下一代杀菌剂提供了范例，提高了 具有多种和互补性的有效且广泛活性的抑制剂组合的可能性 作用机制可能远远优于单一化合物的递送。充分发挥潜力 在这些强效抗逆转录病毒 (ARV) 药物中，配制和递送化合物所面临的挑战 必须克服局部组合产品中明显不同的化学稳定性和水溶性。 该研究计划旨在评估基于纳米颗粒的艾滋病毒阴道药物输送系统 预防。实验重点是通过局部使用来实现防止 HIV-1 阴道传播的保护 使用粘液和组织扩散纳米颗粒杀微生物剂递送抗逆转录病毒药物组合。 这项研究将是第一个控制抗逆转录病毒药物组合的时间和空间共同递送的研究。 对 HIV-1 具有不同作用机制的药物（目标 1）。如果成功的话，我们的研究将是 首先确定纳米颗粒药物输送系统的尺寸范围和渗透深度 阴道粘膜（目标 2）。我们提出的研究还将提供有关交通的宝贵数据， 所施用的封装和释放的抗逆转录病毒药物的生物分布和药代动力学 使用纳米颗粒杀菌剂局部作用于阴道粘膜（目标 3）。最后，我们将进行临床前 安全性和抗艾滋病毒功效研究，以快速推进我们的纳米颗粒杀菌剂对人类安全的影响 和功效试验（目标 4）。我们提出的研究结果可能会对以下领域产生重大影响 针对艾滋病毒和其他性传播感染的杀菌剂研究。