Nanoparticle microbicides for delivery of combination antiretroviral drugs

描述（由申请人提供）：通过生殖道或直肠粘膜的性传播是获得新的HIV感染的最常见途径，占2007年全球270万新感染者的约70%。预计短期内不会出现遏制这一流行病全球传播的治愈方法或有效疫苗，而且新的艾滋病毒感染继续超过抗逆转录病毒药物治疗的进展。因此，迫切需要开发可局部应用于粘膜表面以预防HIV的性传播的试剂。然而，几项大规模的临床试验测试了破坏病毒包膜完整性（去污剂）或防止病毒与其靶细胞吸附或融合（聚阴离子）的药物的功效，但未能保护免受艾滋病毒感染。高效抗逆转录病毒疗法（HAART）的成功为开发下一代杀微生物剂提供了一个范例，提高了一种可能性，即表现出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上级单一化合物的递送。为了充分实现这些有效的抗逆转录病毒（ARV）药物的潜力，必须克服在局部组合产品中配制和递送具有显著不同的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预防艾滋病毒。实验的重点是通过局部递送使用粘液和组织扩散纳米颗粒杀微生物剂的抗逆转录病毒药物的组合来实现对HIV-1的阴道传播的保护。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交付，这些药物对HIV-1具有不同的作用机制（目标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有价值的数据的运输，生物分布和药物动力学的封装和释放的抗逆转录病毒药物，局部施用到阴道粘膜使用纳米粒子杀微生物剂（目的3）。最后，我们将进行临床前安全性和抗HIV功效研究，以快速推进我们的纳米颗粒杀菌剂的人体安全性和功效试验（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微生物剂研究领域产生重大影响。 公共卫生相关性：妇女受艾滋病毒流行病的影响特别大，因此获得由女性控制的预防方法，如有效的局部杀微生物剂至关重要。为了克服与在局部凝胶中配制多种抗HIV化合物相关的挑战，我们提出了一种单一的局部策略，该策略使用基于颗粒的杀微生物剂来封装组合递送的单独药剂。这一办法将赋予妇女权力，并为她们提供有效的手段，保护自己不受性行为艾滋病毒-1感染。

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.