Long-acting antiretroviral nanoparticles for HIV prophylaxis

 描述(由申请人提供)：本次R01申请的目标是在之前的R15和R56奖项的基础上，继续调查抗逆转录病毒纳米粒(AR NPs)作为每周预防策略的临床前使用情况。替诺福韦富马酸二异丙酯，TDF将与其他药物(elvitegravir或利培韦林)一起使用，并制成聚合物纳米粒(NPs)。聚合物纳米粒将被冷冻干燥，并与5%的葡萄糖重组，用于皮下(SubQ)给药，作为长效药物输送系统。该应用程序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。小鼠将被用来通过LC-MS/MS分析来确定女性生殖道(FRT)组织药物和活性代谢物的水平。最终，HU-BLT小鼠将被用来确定最佳剂量组合抗逆转录病毒纳米粒的疗效。具体目标如下。具体目标1将涉及制造两种抗逆转录病毒药物(tdf、elvitegravir或利培韦林)的单一或组合，并对其进行测试。 使用细胞培养系统的体外聚合纳米粒子。具体目标2将利用LC-MS/MS分析方法，研究NSG小鼠生殖组织中聚合物纳米粒中这些单一或组合药物的3种不同剂量和组织药代动力学(PK)，以了解抗逆转录病毒水平和TDF活性代谢物。头两年将被用来确定阴道组织浓度将是&gt；90毫克/毫克的药物(S)在注射后7天作为去不去决定因素。具体目标3将是在HU-BLT小鼠HIV模型中应用组合NPs的最优聚合NP剂量。我们打算在HU-BLT小鼠模型中确定这些NPs是否能够在7天内保护小鼠免受HIV-1感染。这一应用的结果将为SubQ给药提供一种新的长效配方，其中包含制成聚合物纳米粒的抗逆转录病毒药物的组合。在HU-BLT小鼠中每周给药一次的聚合物NPs将在人类中使用异速生长转化为每月给药。

 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.