Polydrug Nanocarrier to Treat Opiate Addiction and HIV Disease

描述（由申请方提供）：已证明滥用药物（如阿片类药物）可发挥免疫调节作用，因此可作为HIV-1感染进展的辅助因子。阿片和HIV靶向大脑中富含5种阿片受体的区域，如基底神经节和皮质。以前的研究表明，阿片类药物与HIV蛋白（达特和gp 120）协同作用，增强HIV相关的神经毒性，最终导致NeuroAIDS的进展。目前，没有可用的治疗来减轻阿片类药物和HIV的协同作用，特别是由于治疗分子不能穿过血脑屏障（BBB）。因此，开发一种含有阿片类拮抗剂、神经保护剂和ART的药物递送系统，该系统可以穿过BBB，对于治疗阿片成瘾和NeuroAIDS可能具有显著的治疗优势。近年来，基于纳米颗粒的递送系统已经显示出用于药物靶向脑的有前途的方法。在本发明中，我们将开发一种独特的磁性引导纳米载体，其结合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-AZT（AZTTP）用于药物靶向脑。该纳米载体的表面将用RGD肽标记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/或经由单核细胞/巨噬细胞介导的转运递送药物穿过BBB。因此，在具体目标1（a）中，我们将开发结合CTOP、BDNF和AZTTP的基于磁性脂质体的多功能纳米载体。在特定目标1（B）中，将在体外检测开发的制剂穿过BB B的能力。最后，在具体目标2中，我们将评估所开发的纳米载体在HIVE SCID吗啡小鼠模型中的体内功效。疗效参数将是小鼠中的抗逆转录病毒疗效、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显着结合纳米颗粒，它抑制病毒在PBMC中的复制，我们建议开发的纳米载体将提供一个潜在的治疗方法来治疗阿片类药物成瘾和神经艾滋病。公共卫生相关性：该应用与PAS-08-186的目的具有显著相关性，已证明滥用药物（如阿片类药物）可发挥免疫调节作用，从而作为HIV-1感染进展的辅助因子。目前，没有可用的治疗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穿过BBB的不可穿透性。该项目将评估一种新型的磁性引导纳米载体药物递送系统，用于同时靶向CTOP，BDNF和AZTTP穿过BBB，从而减少阿片类药物成瘾以及阿片类药物使用者中HIV感染者的NeuroAIDS。

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.