Improving the CNS Delivery of Anti-retroviral Compounds

描述(申请人提供)：人类免疫缺陷病毒(HIV-1) 使宿主容易受到各种严重中枢神经系统的影响 (中枢神经系统)疾病，如艾滋病、痴呆症和HIV-1脑病。它的用途 高效抗逆转录病毒疗法(HAART)，包括蛋白酶抑制剂， 已经有效地减缓了病毒的传播，然而，抗药性 组织储存库，如大脑，仍然存在。HIV-1在大脑中的治疗 由于核苷药物不能穿透 血脑屏障(BBB)良好和较新的治疗方法，即蛋白酶抑制剂， 对大脑的传递也非常有限。BBB的一个组件，它 限制HAART进入中枢神经系统的是膜结合的药物外排泵， 如P-糖蛋白(P-gp)和多药耐药相关蛋白 (MRPS)。最近，有研究表明，核苷和蛋白水解酶 抑制剂是外排转运蛋白的底物。的长期目标是 这项研究是为了开发更好的治疗策略，以增强 利用新药向中枢神经系统靶向递送抗逆转录病毒药物 输送系统，如聚合物载体(Pluronics)。我们的假设是 新型药物递送系统将增强脑分布和中枢神经系统 靶向HAART，从而提高疗效。测试的具体目的是 这一假设是：1)考察Pluronics对 不同抗逆转录病毒药物与分离的P-gp膜的光亲和作用 标记法和P-gp-ATPase活性测定，2)研究Pluronics对大鼠脑缺血再灌注损伤的影响。 抗逆转录病毒药物在体外血脑屏障中的转运特性及疗效 在受感染的靶细胞，即单核/巨噬细胞中，以及3)确定 这一新型给药技术对大鼠脑内分布的影响 体内抗逆转录病毒最有希望的药效特征 HIV感染的SCID小鼠HIV脑病模型的配方。这个 目前的建议在体外和体内研究了HAART的CNS靶向 血脑屏障的活体模型和靶向药物的疗效 送货。提高抗艾滋病毒药物脑渗透率的新方法将是 在治疗艾滋病毒脑病和根除病毒方面有价值 从潜在的避难所地点。

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.