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: 8110094
• 负责人: Kim A. Woodrow
• 金额: $ 17.3万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110094
• 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; 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; Screening procedure; 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; simian human immunodeficiency virus; success; transmission process; vaginal transmission

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Women are disproportionately impacted by the HIV epidemic and access to female-controlled prevention methods such as an effective topical microbicide is critical. To overcome challenges associated with formulating multiple anti-HIV compounds in a topical gel, we propose a single topical strategy that uses particulate-based microbicides to encapsulate individual agents that are delivered in combination. This approach will empower and provide women with an effective means of protecting themselves against sexual HIV-1 infection.

描述（由申请人提供）：通过生殖道或直肠粘膜的性传播是新感染艾滋病毒的最常见途径，占2007年全球270万新感染者的约70%。预计短期内不会出现一种能够遏制这一流行病在全球蔓延的治疗方法或有效疫苗，而且艾滋病毒新感染的速度继续超过抗逆转录病毒药物治疗方面取得的进展。因此，迫切需要开发可以局部应用于粘膜表面的药物，以防止艾滋病毒的性传播。然而，几项大规模的临床试验测试了破坏病毒包膜完整性（清洁剂）或阻止病毒与其靶细胞（多阴离子）吸附或融合的药物的功效，但未能防止HIV感染。高活性抗逆转录病毒疗法（HAART）的成功为开发下一代杀微生物剂提供了范例，提高了一种可能性，即具有多种互补作用机制的强效和广泛活性抑制剂的组合可能远远优于单一化合物的递送。为了充分发挥这些强效抗逆转录病毒（ARV）药物的潜力，必须克服在局部联合产品中配制和递送具有明显不同化学稳定性和水溶性的化合物的挑战。该研究计划旨在评估基于纳米颗粒的阴道给药系统用于艾滋病预防。实验的重点是通过局部递送使用黏液扩散和组织扩散的纳米颗粒杀微生物剂的抗逆转录病毒药物组合，实现对HIV-1阴道传播的保护。这项研究将首次控制对HIV-1具有不同作用机制的抗逆转录病毒药物组合的时间和空间共递送（目的1）。如果成功，我们的研究将是第一个确定纳米颗粒药物递送系统在阴道粘膜中的尺寸范围和渗透深度的研究（目的2）。我们提出的研究还将提供关于胶囊化和释放的抗逆转录病毒药物的运输、生物分布和药代动力学的宝贵数据，这些药物使用纳米颗粒杀微生物剂局部施用于阴道粘膜（目的3）。最后，我们将进行临床前安全性和抗hiv有效性研究，以迅速推进我们基于纳米颗粒的杀微生物剂的人体安全性和有效性试验（目标4）。我们提出的研究结果可能会对艾滋病毒和其他性传播感染的杀菌剂研究领域产生重大影响。