Nanoparticle microbicides for delivery of combination antiretroviral drugs

描述(申请人提供)：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，占2007年全球270万新感染者的约70%。短期内，预计不会有治愈或有效的疫苗来遏制这种流行病的全球传播，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的制剂，以防止艾滋病毒的性传播。然而，几项大规模临床试验测试了破坏病毒被膜完整性(洗涤剂)或阻止病毒与其靶细胞(聚阴离子)吸附或融合的药剂的有效性，但未能预防艾滋病毒感染。高效抗逆转录病毒疗法(HAART)的成功为开发下一代杀菌剂提供了一个范例，增加了一种具有多种和互补作用机制的有效和广谱活性抑制剂组合的可能性，可能远远优于单一化合物的释放。为了充分发挥这些有效的抗逆转录病毒(ARV)药物的潜力，必须克服在局部联合产品中配制和输送具有明显不同化学稳定性和水溶解性的化合物的挑战。这项研究计划旨在评估基于纳米颗粒的阴道给药系统用于预防艾滋病毒。实验的重点是通过局部使用粘液和组织扩散纳米微粒杀菌剂的抗逆转录病毒药物组合来实现对艾滋病毒-1经阴道传播的保护。这项研究将首次控制对艾滋病毒-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联合给药(目标1)。如果成功，我们的研究将是第一次确定纳米微粒药物在阴道粘膜中的大小、范围和渗透深度(目标2)。我们拟议的研究还将提供有关使用纳米杀菌剂局部给药到阴道粘膜的微囊化和释放型抗逆转录病毒药物的转运、生物分布和药代动力学的有价值的数据(目标3)。最后，我们将进行临床前安全性和抗艾滋病毒有效性研究，以迅速将我们的纳米颗粒杀微生物剂推向人类安全性和有效性试验(目标4)。我们提议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的影响不成比例，获得由妇女控制的预防方法，如有效的局部杀微生物剂至关重要。为了克服在一种外用凝胶中配制多种抗艾滋病毒化合物所面临的挑战，我们提出了一种单一的外用策略，即使用基于颗粒的杀菌剂来包裹单独的药物，这些药物是以组合的形式提供的。这一方法将赋予妇女权力，并为她们提供一种有效的手段来保护自己免受性艾滋病毒-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.