Microbicide delivery system to target lymphoid organs

描述（由申请人提供）：HIV-1的性传播涉及复杂的过程，包括女性生殖道暴露于病毒或感染细胞，并将其运输到其他部位，包括局部淋巴结，病毒在其中复制并建立感染。已经显示朗格汉斯细胞（LC）和树突状细胞（DC）从阴道表面或从顶部上皮层捕获病毒，并将其运输到引流和局部淋巴结，在那里它感染CD 4 + T细胞。目前正在加紧开发局部杀微生物剂，其最终目标是减少HIV-1的性传播。目前的努力已经针对在进入之前在阴道表面或在阴道上皮的鳞状或基质层中灭活病毒。我们的物理运输模型预测，分子药物作为局部凝胶不能到达引流或局部淋巴结。将药物递送到阴道周围淋巴部位的一种可能方法是使用载药纳米颗粒。我们的初步结果提供的证据表明，纳米粒子可以通过阴道应用在小鼠模型中传递到局部淋巴结。为了进一步开发该平台作为杀微生物剂或预防策略，我们提出了以下R21/R33应用计划。在R21阶段，我们将研究具有不同表面化学的量子点的递送，包括与靶向分子的缀合，以确定它们转运到不同淋巴样位点的模式。在R33阶段，我们将使用载药纳米颗粒，并验证该平台靶向女性生殖道重要部位的适用性。物理模型将被开发，以了解运输过程，并指导纳米粒子输送系统的发展。

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.