Microbicide delivery system to target lymphoid organs

靶向淋巴器官的杀微生物剂输送系统

• 批准号: 7669867
• 负责人: MOHAMED E LABIB
• 金额: $ 20.8万
• 依托单位: ADVANCED BIODEVICES, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669867
• 关键词: Antigen-Presenting Cells; Antiviral Agents; CD4 Positive T Lymphocytes; Cells; Cervix Uteri; Chemistry; Complex; Dendritic Cells; Development; Drug Delivery Systems; Drug Formulations; Drug usage; Endocervix; Epithelial; Epithelium; Female; Gel; Genital system; Goals; Grant; HIV; HIV-1; Infection; Injury; Intercept; Knowledge; Langerhans cell; Lead; Lesion; Local Microbicides; Lymph; Lymphatic; Lymphoid; Lymphoid Tissue; Microscopy; Modeling; Molecular; Movement; Mucous Membrane; Oral; Organ; Phagocytosis; Pharmaceutical Preparations; Phase; Prevention strategy; Process; Quantum Dots; Route; Satellite Viruses; Sexual Transmission; Site; Submucosa; Surface; System; Techniques; Tenofovir; Tissues; Transport Process; Uterus; Vagina; Virion; Virus; base; design; lymph nodes; macrophage; microbicide; mouse model; nanoparticle; novel; particle; physical model; prevent; prophylactic; success; transmission process; uptake

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.

描述（由申请人提供）：HIV-1 的性传播涉及复杂的过程，涉及女性生殖道暴露于病毒或受感染的细胞，并将其运输到其他部位，包括局部淋巴结，病毒在那里复制并建立感染。研究表明，朗格汉斯细胞 (LC) 和树突状细胞 (DC) 从阴道表面或上皮层捕获病毒，并将其转运至引流淋巴结和局部淋巴结，在那里感染 CD4+ T 细胞。外用杀菌剂的大力开发正在进行中，最终目标是减少 HIV-1 的性传播。目前的努力主要是在进入阴道之前在阴道表面或在阴道上皮的鳞状或间质层中灭活病毒。我们的物理运输模型预测，以局部凝胶形式递送的分子药物无法到达引流淋巴结或局部淋巴结。将药物输送到阴道周围淋巴部位的一种可能方法是使用载药纳米粒子。我们的初步结果提供的证据表明，纳米颗粒可以通过小鼠模型中的阴道应用递送至局部淋巴结。为了进一步开发该平台作为杀微生物剂或预防策略，我们针对 R21/R33 应用提出以下计划。在R21阶段，我们将研究具有不同表面化学性质的量子点的递送，包括与靶向分子的缀合，以确定它们运输到不同淋巴部位的模式。在R33阶段，我们将使用载药纳米颗粒并验证该平台针对女性生殖道重要部位的适用性。将开发物理模型来了解运输过程并指导纳米颗粒输送系统的开发。