Long-acting antiretroviral nanoparticles for HIV prophylaxis

用于预防艾滋病毒的长效抗逆转录病毒纳米颗粒

• 批准号: 9005813
• 负责人: CHRISTOPHER J DESTACHE
• 金额: $ 55.65万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-04 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005813
• 关键词: AIDS prevention; Adherence; Adverse effects; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Award; Cell Culture System; Cell Culture Techniques; Characteristics; Coitus; Colon; Data; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug resistance; Drug usage; Epidemic; Extravasation; FDA approved; Female; Formulation; Freedom; Freeze Drying; Gel; Glucose; Goals; HIV; HIV Infections; HIV-1; Health; Human; In Vitro; Infection; Injection of therapeutic agent; Integrase Inhibitors; Intention; Intervention; Intravaginal Administration; Lead; Modality; Mus; Oral; Oral Administration; Outcome; Persons; Pharmaceutical Preparations; Polymers; Powder dose form; Prevention; Prevention strategy; Probability; Prophylactic treatment; Reporting; Research; Research Personnel; Route; Surveys; System; Tenofovir; Testing; Time; Tissues; Translating; Vagina; Woman; World Health Organization; base; cytotoxicity; design; forgetting; gastrointestinal; humanized mouse; improved; in vivo; men; mouse model; nanoparticle; non-nucleoside reverse transcriptase inhibitors; novel; pre-clinical; prevent; reconstitution; rectal; reproductive; reproductive tract; sex; sexual HIV transmission; subcutaneous; transmission process

 DESCRIPTION (provided by applicant): The goal of this R01 application is to continue to investigate the preclinical use of antiretroviral nanoparticles (AR NPs) as a weekly prevention strategy based on the previous R15 and R56 awards. Tenofovir disoproxil fumurate, TDF will be used along with other drugs (elvitegravir or rilpivirine) and fabricated into polymeric nanoparticles, (NPs). The polymeric NPs will be freeze-dried and reconstituted with 5% dextrose for subcutaneous (SubQ) administration as a long-acting drug delivery system. This application is designed to answer several questions regarding dissemination of combinations of anti-HIV drugs using in vitro and in vivo systems. Mice will be used to determine female reproductive tract (FRT) tissue drug and active metabolite levels using LC-MS/MS analysis. Ultimately, hu-BLT mice will be used to determine efficacy of the optimal doses of combination antiretroviral NPs. The specific aims are as follows. Specific Aim 1 will involve the fabrication o single or combinations of 2 antiretroviral drugs (TDF, elvitegravir, or rilpivirine) and test these polymeric NPs in vitro using cell culture systems. Specific Aim 2 will investigate 3 separate doses and tissue pharmacokinetics (PK) of these single or combination drugs from the polymeric NPs in reproductive tissues from NSG mice for both antiretroviral levels and TDF active metabolite using LC-MS/MS analysis. The first 2 years will be used to determine vaginal tissue concentrations that will be > 90 ng/mg for the drug(s) contained in the NPs at 7 days post SubQ administration as the go-no go determinant. Specific Aim 3 will be to apply the most optimal polymeric NP doses of combination NPs in the hu-BLT mouse model of HIV. It is our intention to determine in the hu-BLT mouse model whether these NPs are able to protect mice from HIV-1 infection over 7-days. The results of this application should offer a new long-acting formulation for SubQ administration that contains combinations of antiretroviral drugs fabricated into polymeric NPs. The weekly SubQ administration of polymeric NPs in hu-BLT mice will translate using allometry into monthly administration in humans.

 描述（由申请人提供）：本R 01申请的目标是继续研究抗逆转录病毒纳米颗粒（AR NP）作为基于先前R15和R56奖项的每周预防策略的临床前使用。富马酸替诺福韦二异丙酯，TDF将与其他药物（埃替拉韦或利匹韦林）一起沿着使用，并制成聚合物纳米颗粒（NP）。将聚合物NP冷冻干燥并用5%葡萄糖复溶，用于皮下（SubQ）给药，作为长效药物递送系统。本申请旨在回答有关使用体外和体内系统传播抗HIV药物组合的几个问题。将使用小鼠通过LC-MS/MS分析测定雌性生殖道（FRT）组织药物和活性代谢物水平。最终，hu-BLT小鼠将用于确定组合抗逆转录病毒NP的最佳剂量的功效。具体目标如下。具体目标1将涉及制造单一或2种抗逆转录病毒药物（TDF、埃替拉韦或利匹韦林）的组合，并测试这些药物。 使用细胞培养系统体外培养聚合物NP。具体目标2将使用LC-MS/MS分析研究NSG小鼠生殖组织中聚合物NP的这些单药或复方药物的3个单独剂量和组织药代动力学（PK），包括抗逆转录病毒水平和TDF活性代谢物。前2年将用于确定SubQ给药后7天NP中所含药物的阴道组织浓度> 90 ng/mg，作为决定因素。具体目标3将是在HIV的hu-BLT小鼠模型中应用组合NP的最佳聚合物NP剂量。我们的目的是在hu-BLT小鼠模型中确定这些NP是否能够在7天内保护小鼠免受HIV-1感染。本申请的结果应提供一种新的长效制剂SubQ管理，其中含有组合的抗逆转录病毒药物制成聚合物纳米粒子。在hu-BLT小鼠中聚合物NP的每周SubQ施用将使用异速生长转化为在人中的每月施用。