Improving the CNS Delivery of Anti-retroviral Compounds

描述（由申请人提供）：人类免疫缺陷病毒（HIV-1） 使宿主对各种严重的中枢神经系统 (CNS)艾滋病痴呆综合症和HIV-1脑病等疾病。使用 高效抗逆转录病毒治疗（HAART），包括蛋白酶抑制剂， 有效地减缓了病毒的传播，然而，耐药性 组织储库，例如大脑，仍然存在。脑内HIV-1的治疗 由于核苷类药物不能穿透细胞膜， 血脑屏障（BBB）以及更新的治疗，即，蛋白酶抑制剂， 也只有非常有限的药物进入大脑血脑屏障的一个组成部分， 限制HAART向CNS递送的是膜结合药物外排泵， 如P-糖蛋白（P-gp）和多药耐药相关蛋白 （MRPs）。最近的研究表明，核苷和蛋白酶 抑制剂是外排转运蛋白的底物。的长期目标 本研究旨在开发更好的治疗策略， 通过使用新药物将抗逆转录病毒药物靶向递送至CNS 递送系统，如聚合物载体（Pluronics）。我们的假设是 新的药物输送系统将增强大脑分布和中枢神经系统， HAART靶向治疗，从而提高疗效。测试的具体目的 这个假设是：1）检查Pluronics对 各种抗逆转录病毒药物与分离的P-gp膜，使用光亲和 标记和P-gp ATP酶测定; 2）研究Pluronics对细胞凋亡的影响。 抗逆转录病毒药物在体外血脑屏障中的转运特性及其疗效 在受感染的靶细胞中，即，单核细胞/巨噬细胞，和3）确定 这种新型药物递送技术对脑分布的影响 体内抗逆转录病毒药物的疗效特征最有前途的 在HIV-脑病的HIV感染的SCID小鼠模型中，的 目前的建议是在体外和体内研究HAART的CNS靶向作用， 血脑屏障的体内模型，以及靶向药物的疗效 交付.提高抗艾滋病毒药物脑渗透的新方法将在 在治疗HIV脑病和根除病毒方面有价值 可能的避难所

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV-1) renders the host susceptible to a variety of serious central nervous system (CNS) diseases such as AIDS dementia complex and HIV-1 encephalopathy. The use of highly active antiretroviral therapy (HAART), including protease inhibitors, has been effective in slowing the spread of the virus, however, drug resistant tissue reservoirs, such as the brain, remain. Treatment of HIV-1 in the brain has been hampered by the fact that nucleoside drugs do not penetrate the blood-brain barrier (BBB) well and newer treatments, i.e., protease inhibitors, also have very limited delivery to the brain. One component of the BBB that limits delivery of HAART into the CNS is the membrane-bound drug efflux pumps, such as p-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs). Recently, it has been shown that both nucleosides and protease inhibitors are substrates for efflux transporters. The long-term objective of this research is to develop better therapeutic strategies to enhance the targeted delivery of antiretroviral drugs to the CNS by using novel drug delivery systems, such as polymeric carriers (Pluronics). Our hypothesis is that novel drug delivery systems will enhance the brain distribution and CNS targeting of HAART and therefore improve efficacy. The specific aims to test this hypothesis are: 1) examine the effect of Pluronics on the interactions of various antiretrovirals with isolated P-gp membranes using photoaffinity labeling and P-gp ATPase assay, 2) study the effects of Pluronics on the transport properties of antiretroviral drugs in the in vitro BBB and efficacy in infected target cells, i.e., monocytes/macrophages, and 3) determine the effect of this novel drug delivery technology on the brain distribution of antiretrovirals in vivo characterizing the efficacy of the most promising formulations in an HIV-infected SCID mouse model of HIV- encephalopathy. The current proposal examines the CNS targeting of HAART in both in vitro and in vivo models of the blood-brain barrier, and the efficacy of that targeted drug delivery. New approaches to improve brain penetration of anti-HIV drugs will be valuable in the treatment of HIV-encephalopathy and in eradicating the virus from potential sanctuary sites.