Microbicide delivery system to target lymphoid organs

描述(申请人提供)：艾滋病毒-1的性传播涉及复杂的过程，涉及将女性生殖道暴露在病毒或受感染细胞中，并将其转移到其他部位，包括在那里病毒复制和确定感染的当地淋巴结。已有研究表明，郎格汉斯细胞(LC)和树突状细胞(DC)从阴道表面或上层上皮层捕获病毒，并将其输送到引流和局部淋巴结，在那里感染CD4T细胞。目前正在加紧开发局部杀微生物剂，最终目标是减少艾滋病毒-1的性传播。目前的努力是在进入阴道前的阴道表面，或在阴道上皮的鳞状层或间质层灭活病毒。我们的物理传输模型预测，以局部凝胶形式传递的分子药物不能到达引流或局部淋巴结。将药物输送到阴道周围的淋巴部位的一种可能的方法是使用载药纳米颗粒。我们的初步结果提供了证据，表明纳米颗粒可以通过小鼠模型的阴道应用传递到局部淋巴结。为了进一步开发这一平台作为杀微生物剂或预防策略，我们为R21/R33的应用提出了以下计划。在R21阶段，我们将研究具有不同表面化学的量子点的传递，包括与靶向分子的结合，以确定它们向不同淋巴部位的运输方式。在R33阶段，我们将使用载药纳米颗粒，并验证该平台的适用性，以靶向女性生殖道的重要部位。将开发物理模型，以了解传输过程并指导纳米颗粒输送系统的开发。

DESCRIPTION (provided by applicant): Sexual transmission of HIV-1 involves complex processes involving exposure of the female genital tract to virus or infected cells and their transport to other sites, including local lymph nodes, where the virus replicates and establishes infection. It has been shown that Langerhans cells (LC) and dendritic cells (DC) capture the virus either from the vaginal surface or from top epithelium layers and transport it to draining and local lymph nodes, where it infects CD4+ T-cells. Intense development of topical microbicides is underway with the ultimate goal of decreasing the sexual transmission of HIV-1. Current efforts have been directed to inactivating the virus either at the surface of the vagina before entry, or in the squamous or stroma layers of the vaginal epithelium. Our physical transport modeling predicts that molecular drugs delivered as topical gels cannot reach draining or local lymph nodes. One possible way to deliver drugs to lymphoid sites surrounding the vagina is to use drug-loaded nanoparticles. Our preliminary results provide evidence indicating that nanoparticles can be delivered to local lymph nodes via vaginal application in a mouse model. To further develop this platform for use as a microbicide or prophylactic strategy, we propose the following plans for the R21/R33 application. In the R21 phase, we will study the delivery of quantum dots having different surface chemistry, including conjugation with targeting molecules, to determine the mode of their transport to different lymphoid sites. In the R33 phase, we will use drug-loaded nanoparticles and verify the applicability of this platform to target important sites in the female genital tract. Physical models will be developed to understand the transport processes and to guide the development of the nanoparticle delivery system.