Polydrug Nanocarrier to Treat Opiate Addiction and HIV Disease

描述(申请人提供)：滥用药物，如鸦片类药物，已被证明具有免疫调节作用，从而成为艾滋病毒-1感染进展的辅助因素。阿片类药物和HIV病毒在大脑中的靶区，如基底节和皮质，富含5个阿片受体。先前的研究表明，阿片类药物与HIV蛋白(TAT和gp120)协同作用，增强HIV相关的神经毒性，最终导致神经艾滋病的进展。目前，还没有可用的治疗方法来缓解阿片类药物和艾滋病毒的协同作用，特别是由于治疗分子无法透过血脑屏障(BBB)。因此，开发一种包含5阿片类拮抗剂、神经保护剂和ART的药物传递系统，可以跨越血脑屏障，在治疗阿片成瘾和神经艾滋病方面可能具有显著的治疗优势。近年来，基于纳米颗粒的给药系统在药物靶向大脑定位方面显示出了很好的前景。在目前的方案中，我们将开发一种独特的磁引导纳米载体，与CTOP(血脑屏障不透性阿片拮抗剂)、BDNF(脑源性神经营养因子)和5‘-三磷酸-AZTP(AZTTP)结合，用于脑内靶向药物的治疗。这种纳米载体的表面将被标记RGD多肽，以促进其被单核/巨噬细胞摄取。纳米载体将通过外加磁力和/或通过单核/巨噬细胞介导的转运将药物输送到血脑屏障。因此，在具体目标1(A)中，我们将开发一种结合CTOP、BDNF和AZTTP的多功能纳米载体。在具体目标1(B)中，将对开发的配方进行体外测试，以确定其跨血脑屏障转运的能力。最后，在特定目标2中，我们将评估所开发的纳米载体在蜂巢SCID吗啡小鼠模型中的体内疗效。药效参数将包括抗逆转录病毒疗效、神经病理、神经保护和吗啡相关行为。我们的初步研究表明，AZTTP与纳米颗粒显著结合，并抑制病毒在PBMC中的复制，我们认为，所开发的纳米载体将为治疗阿片成瘾和神经艾滋病提供一种潜在的治疗方法。公共卫生相关性：这项申请与PAS-08-186的目的有重大相关性，阿片类药物等滥用药物已被证明具有免疫调节作用，从而成为艾滋病毒-1感染进展的辅助因素。目前，还没有可用的治疗方法来减轻阿片剂和艾滋病毒的协同神经毒性，特别是由于治疗分子在血脑屏障中的不可穿透性。本项目将评估一种新的磁导引纳米载体药物输送系统，用于跨血脑屏障同时靶向CTOP、BDNF和AZTTP，从而减少阿片成瘾和艾滋病毒感染者的神经艾滋病。

DESCRIPTION (provided by applicant): Drug of abuse such as opiates have been shown to exert immunomodulatory effects and thereby serve as a cofactor in the progression of HIV-1 infection. Opiate and HIV target areas in brain such as basal ganglia and cortex that are enriched in 5 opioid receptors. Previous studies have shown that opiates act synergistically with HIV proteins (Tat and gp120) to potentiate HIV- related neurotoxicity, which ultimately leads to progression of NeuroAIDS. Currently, there is no treatment available to alleviate the synergistic effects of opiates and HIV, especially due to impenetrability of therapeutic molecules across the blood brain barrier (BBB). Therefore development of a drug delivery system containing an 5 opioid antagonist, a neuroprotective agent and ART that can cross BBB may have significant therapeutic advantage for treatment of opiate addiction and NeuroAIDS. In recent years, nanoparticle based delivery systems have shown promising approach for drug targeting to the brain. In the present proposal, we will develop a unique magnetically guided nanocarrier bound to CTOP (BBB impenetrable < opioid antagonist), BDNF (Brain Derived Neurotrophic Factor) and 5'-triphosphate-AZT (AZTTP) for drug targeting to the brain. The surface of this nanocarrier will be tagged with RGD peptide to facilitate its uptake by monocytes/macrophages. The nanocarrier will deliver the drug across BBB by external magnetic force and/or via monocyte/macrophage mediated transport. Accordingly, in the Specific Aim 1(a) we will develop a magnetoliposome based multifunctional nanocarrier bound to CTOP, BDNF and AZTTP. In Specific Aim 1(b) the developed formulation will be tested in vitro for its ability to transmigrate across BBB. Finally, in Specific Aim 2 we will evaluate the in vivo efficacy of the developed nanocarrier in an HIVE SCID morphine mouse model. The efficacy parameters will be antiretroviral efficacy, neuropathology, neuroprotection and morphine related behaviors in mouse. Based on our preliminary study which shows that AZTTP binds significantly to nanoparticles and it inhibits viral replication in PBMCs, we propose that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction and NeuroAIDS. PUBLIC HEALTH RELEVANCE: This application has significant relevance to the purpose of the PAS-08-186, drug of abuse such as opiates have been shown to exert immunomodulatory effects and thereby serve as a cofactor in the progression of HIV-1 infection. Currently, there is no treatment available to alleviate the synergistic neurotoxicity of opiates and HIV, especially due to impenetrability of therapeutic molecules across the BBB. This project will evaluate a novel magnetically guided nanocarrier drug delivery system for simultaneous targeting of CTOP, BDNF and AZTTP across the BBB, thereby reduce opiate addiction and also NeuroAIDS in HIV infected subjects who are opiate users.