Polydrug Nanocarrier to Treat Opiate Addiction and HIV Disease

描述（由申请人提供）：滥用药物如阿片类药物已被证明具有免疫调节作用，因此在HIV-1感染的进展中作为辅助因素。大脑中富含5种阿片受体的基底节区和皮层等阿片和HIV靶区。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，还没有有效的治疗方法来减轻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穿透血脑屏障（BBB）。因此，开发一种含有5类阿片拮抗剂、神经保护剂和抗逆转录病毒药物的药物传递系统，可以穿过血脑屏障，可能对治疗阿片成瘾和神经艾滋病具有显著的治疗优势。近年来，以纳米颗粒为基础的给药系统在药物靶向到大脑方面表现出了良好的前景。在本提案中，我们将开发一种独特的磁引导纳米载体，结合CTOP （BBB不可穿透的<阿片拮抗剂），BDNF（脑源性神经营养因子）和5'-三磷酸盐- azt (AZTTP)，用于药物靶向到大脑。这种纳米载体的表面将被标记RGD肽，以促进其被单核细胞/巨噬细胞摄取。纳米载体将通过外部磁力和/或通过单核细胞/巨噬细胞介导的运输将药物输送过血脑屏障。因此，在具体目标1(a)中，我们将开发一种基于磁性脂质体的多功能纳米载体，与CTOP， BDNF和AZTTP结合。在特定目标1(b)中，开发的制剂将在体外测试其跨血脑屏障迁移的能力。最后，在Specific Aim 2中，我们将在HIVE SCID吗啡小鼠模型中评估所开发的纳米载体的体内功效。疗效指标为小鼠抗逆转录病毒疗效、神经病理学、神经保护和吗啡相关行为。基于我们的初步研究表明AZTTP与纳米颗粒显著结合并抑制PBMCs中的病毒复制，我们提出所开发的纳米载体将为治疗阿片成瘾和神经aids提供潜在的治疗方法。公共卫生相关性：这一应用与PAS-08-186的目的有重大相关性，滥用药物如阿片类药物已被证明具有免疫调节作用，因此在HIV-1感染的进展中作为辅助因素。目前，还没有有效的治疗方法来减轻阿片类药物和HIV的协同神经毒性，特别是由于治疗分子在血脑屏障上的不可穿透性。本项目将评估一种新型磁导纳米载体药物递送系统，该系统可以同时靶向CTOP、BDNF和AZTTP，从而减少阿片类药物使用者中感染HIV的阿片类药物成瘾和神经艾滋病。

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.