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，涉及将女性生殖道暴露于病毒或感染细胞及其转运到其他部位，包括局部淋巴结，病毒复制并建立感染。已经表明，Langerhans细胞（LC）和树突状细胞（DC）从阴道表面或顶部上皮层捕获病毒，并将其传输到排水和局部淋巴结中，并感染CD4+ T细胞。局部杀菌剂的强烈发展正在进行中，其最终目的是减少HIV-1的性传播。当前的努力已被指示进入进入前阴道表面或阴道上皮的鳞状或基质层的病毒。我们的物理运输模型预测，作为局部凝胶输送的分子药物无法达到排水或局部淋巴结。向阴道周围淋巴部位输送药物的一种可能方法是使用载有药物的纳米颗粒。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中的阴道应用传递到局部淋巴结。为了进一步开发该平台作为杀菌剂或预防策略，我们为R21/R33应用程序提出以下计划。在R21阶段，我们将研究具有不同表面化学的量子点的传递，包括与靶向分子结合，以确定其转运到不同淋巴样位点的方式。在R33阶段，我们将使用加载药物的纳米颗粒，并验证该平台针对女性生殖道中重要部位的适用性。将开发物理模型以了解运输过程并指导纳米颗粒输送系统的发展。