Nanoparticle microbicides for delivery of combination antiretroviral drugs

项目总结/摘要 通过生殖道或直肠粘膜的性传播是获得新艾滋病毒的最常见途径 感染，占2007年全球270万新感染者的70%。一 短期内预计不会有治愈或有效的疫苗来遏制这一流行病的全球传播， 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。有 因此迫切需要开发可局部应用于粘膜表面以防止 艾滋病毒的性传播。然而，一些大规模的临床试验测试的药物， 破坏病毒包膜的完整性（去污剂）或阻止病毒与其靶标的吸附或融合 细胞（聚阴离子）未能保护免受艾滋病毒感染。高效抗逆转录病毒药物的成功 HAART疗法为开发下一代杀微生物剂提供了一个范例， 可能性是，表现出多重和互补性的有效和广泛活性的抑制剂的组合 作用机制可能大大上级单一化合物的递送。为了充分发挥潜力 在这些有效的抗逆转录病毒（ARV）药物中，配制和递送具有以下特征的化合物的挑战是： 必须克服局部组合产品中显著不同的化学稳定性和水溶性。 这项研究计划旨在评估基于纳米颗粒的艾滋病毒阴道给药系统 预防实验的重点是通过局部给药来实现对HIV-1阴道传播的保护。 使用粘液和组织扩散的纳米颗粒杀微生物剂递送抗逆转录病毒药物的组合。 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（目的1）。如果成功，我们的研究将是 首先确定纳米颗粒药物递送系统可达到的尺寸范围和穿透深度， 阴道粘膜（目标2）。我们提议的研究还将提供有关运输的宝贵数据， 给药的包封和释放的抗逆转录病毒剂的生物分布和药代动力学 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 安全性和抗艾滋病毒功效研究，以迅速推进我们的纳米颗粒为基础的杀微生物剂，以人类安全 和疗效试验（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： 用于艾滋病毒和其他性传播感染的杀微生物剂研究。

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.