Multifunctional Nanocarrier to Eradicate HIV from latently infected CNS cells and

描述(申请人提供)：美国目前正在经历甲基苯丙胺(冰毒)使用的严重流行，最近的研究表明，艾滋病毒-1感染和相关的神经认知障碍(HAND)在冰毒使用者中的高流行率。尽管高效抗逆转录病毒疗法(HAART)使艾滋病患者的发病率和死亡率显著下降，但病毒仍然潜伏在包括脑在内的不同避难所，因此不会暴露在HAART中。艾滋病毒药物无法通过血脑屏障(BBB)也有助于建立大脑避难所。因此，打破大脑中的HIV潜伏期，将激活的病毒暴露于大脑中的HIV药物中，对于根除神经艾滋病和相关的手是至关重要的。因此，系统地将潜伏期破裂剂、ARV药物和冰毒拮抗剂输送到大脑中可能是一种很有前途的方法，可以利用HIV感染者控制HIV和相关的手中冰毒。近年来，纳米技术在医学上的应用为新型药物传递系统的发展展示了令人振奋的前景。然而，现有技术在药物被RES细胞吞噬之前缺乏足够的跨内皮渗透，以及纳米载体到达大脑后药物从载体释放的不确定性。因此，从药物传递的角度来看，需要一种快速有效的方式从脑内的载体中传递和释放潜伏期破坏剂、艾滋病毒药物和冰毒受体拮抗剂，以根除艾滋病毒储存和预防冰毒感染的冰毒使用者引起的神经元损伤。我们最近在《自然通讯》上发表的手稿描述了磁电纳米颗粒(MENPs)作为场触发药物载体提供了一种独特的低能量和无耗散跨血脑屏障的按需药物释放能力。我们的初步研究表明，伏立诺能激活星形胶质细胞中潜伏感染的艾滋病毒。因此，在具体目标1中，我们将开发和评估多功能MENPs结合潜伏期断裂剂(Vorinostat)、抗逆转录病毒药物(如奈非那韦(PI)、5‘-三磷酸-AZTTP(NRTI)、利培韦林(NNRTI)和恩福韦肽(FI))和甲基拮抗剂(SB206553)在BBB-HIV感染模型系统中的跨血脑屏障转运、按需递送和疗效，以激活潜伏细胞，根除激活的HIV，并保护神经变性免受冰毒诱导的影响。具体目标2将使用HIV SCID meth小鼠模型评估体外测试的纳米制剂的体内疗效。在具体目标3中，我们将研究纳米疗法对HIV-SCID meth小鼠模型的神经行为调节作用。我们预计，这项史无前例的新3D技术将在诊断和药物输送方面具有重要意义。MENPs在特定药物靶向大脑方面的多学科新突破是对特定RFA的响应，将有助于重新激活潜伏的HIV，最终从CNS储备库中根除HIV，并用于治疗冰毒引起的神经元损伤。

DESCRIPTION (provided by applicant): US is currently experiencing a grave epidemic of methamphetamine (meth) use and recent studies show high prevalence of HIV-1 infection and associated neurocognitive disorders (HAND) in meth users. Although, highly active antiretroviral therapy (HAART) has resulted in remarkable decline in the morbidity and mortality in AIDS patients, virus still remains as latent in different sanctuaries including brain and therefore are ot exposed to HAART. The establishment of brain sanctuaries is also helped by the inability of HIV drugs to cross blood brain barrier (BBB). Thus, breaking of HIV latency in brain and exposing the activated virus to HIV drugs in the brain is quintessential for eradication of neuroAIDS and associated HAND. Therefore, systematic delivery of latency- breaking agent, ARV drugs and meth antagonist to the brain could be a promising way to control HIV and associated HAND in meth using HIV infected subjects. In recent years, use of nanotechnology in medicine has shown exciting prospect for development of novel drug delivery systems. However, the existing technology suffers from lack of adequate transendothelial penetration before the drugs are engulfed by the RES cells as well as the uncertainty of drug release from the carrier if and when the nanocarrier reaches the brain. So from a drug delivery point of view, a fast and effective way of delivering and releasing latency-breaking agent, HIV drugs, and meth receptor antagonist from the carrier in the brain is very much needed to eradicate HIV reservoir and to prevent meth induced neuronal impairments in HIV infected meth users. Our recently published manuscripts in "Nature Communication" describes magneto-electric nanoparticles (MENPs) as field triggered drug carriers offer an unique capability of low energy and dissipation free on-demand drug release across BBB. Our preliminary studies showed that vorinostat activates latently infected HIV in astrocytes. Accordingly in specific aim 1, we will develop and evaluate the transport, on-demand delivery, and efficacy of multifunctional MENPs bound latency-breaking agent (vorinostat), antiretrovirals (such as Nelfinavir (PI), 5'- triphosphate-AZTTP (NRTI), Rilpivirine (NNRTI), and Enfuvirtide (FI)), and meth antagonist (SB206553) across BBB to activate latent cells, eradicate activated HIV and to protect neurodegeneration from meth induced effects in BBB-HIV infection model system. The specific aim 2 will evaluate the in vivo efficacy of the in-vitro tested nanoformulation using HIV SCID meth mouse model. In the specific aim 3, we will study the neurobehavioral modulations induced by nano therapeutics in HIV SCID meth mouse model. We expect that the unprecedented new 3-D technology could be of high significance in diagnostics and drug delivery. This multidisciplinary new break-through in specific drug targeting to the brain using MENPs is in response to the specific RFA and will be useful for reactivation of latent HIV and final eradication of HIV from CNS reservoir and to treat meth induced neuronal impairments.