Nano-delivery of methanandamide across BBB to block cannabinoid induced effects in HIV-1 infection

 说明(申请人提供)：虽然大麻被认为是一种受管制物质，但大麻研究和大麻的医疗用途在治疗许多医疗问题方面显示出巨大的前景。研究表明，外源性大麻素、THC和合成大麻素，包括香料，会干扰存在于大脑中的内源性大麻素系统(ECS)的功能，这是神经发生所必需的。然而，在大麻素滥用期间，神经认知和行为功能明显受损，这些影响在有症状的艾滋病毒感染的受试者中加剧。HIV药物不能通过血脑屏障支持脑内HIV潜伏期的建立。近年来，纳米技术在医学上的应用为开发新型药物输送系统显示了广阔的前景。然而，现有技术缺乏足够的内皮穿透能力，以及纳米载体是否以及何时到达大脑的药物释放的不确定性。因此，从药物传递的角度来看，为了根除HIV储备库，防止外源性大麻素引起的神经元损伤，迫切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、HIV药物和mAEA。在目前的提案中，我们将使用体外血脑屏障和体内蜂窝SCID大麻小鼠模型，研究血脑屏障(BBB)不透性替诺福韦(Tenofovir)的作用，即稳定的内源性大麻类似物甲烷酰胺(MAEA)，通过多功能纳米载体结合的mAEA跨血脑屏障传递防止外源性大麻诱导的神经元缺陷。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。我们在CNS细胞中的初步研究表明，旋涡器可以潜伏地激活HIV感染的星形胶质细胞，mAEA上调突触可塑性基因，mAEA下调HIV诱导的炎症分子，并显著下调p24水平。因此，在具体目标1中，我们将开发和评估分别含有Vorinostat(VS)、Tenofovir(Tef)和mAEA的纳米制剂的转运、递送、按需释放和有效性，以激活潜伏的HIV感染，根除HIV，并使用体外BBB-HIV感染大麻素模型保护HIV/大麻诱导的神经元缺陷。在特定目标2中，我们将评价所开发的纳米载体在蜂窝SCID大麻样小鼠模型中的体内疗效，在特定目标3中，我们将研究纳米制剂对蜂窝SCID大麻样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。利用MENPs在特定药物靶向大脑方面的这一多学科新突破是对PA-13-302的回应，将有助于重新激活潜伏的艾滋病毒，最终从中枢神经系统储备库中根除艾滋病毒，并治疗大麻素引起的艾滋病毒受试者的神经元损伤。

 DESCRIPTION (provided by applicant): Although marijuana is considered a controlled substance, cannabis research and the medical use of cannabis have shown significant promise for the treatment of numerous medical problems. Studies have demonstrated that exocannabinoids, THC and synthetic cannabinoids, including "Spice", interfere with the functions of the endocannabinoid system (ECS) present in the brain and required for neurogenesis. However, during cannabinoid abuse, significant impairments in neurocognitive and behavioral functions are evident and these effects are exacerbated in subjects with symptomatic HIV infection. The establishment of HIV latency in brain is supported by the inability of HIV drugs to cross BBB. In recent years, use of nanotechnology in medicine has shown exiting prospect for development of novel drug delivery systems. However, the existing technology suffers from lack of adequate transendothelial penetration 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 mAEA from the carrier in the brain is very much needed to eradicate HIV reservoir and to prevent exocannabinoid-induced neuronal impairments in HIV infected cannabinoid users. In the current proposal, we will examine the role of the blood brain barrier (BBB) impenetrable tenofovir, the stable endocannabinoid analog methanandamide (mAEA) to prevent the exocannabinoid- induced neuronal deficits using multifunctional nanocarrier bound mAEA delivery across the BBB using the in vitro BBB and in vivo HIVE SCID cannabinoid mouse model. Our recently published manuscript 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 in CNS cells showed that vorinostat activates latently HIV-infected astrocytes, mAEA upregulates synaptic plasticity genes, mAEA down-regulates HIV-induced inflammatory molecules, and significantly down-regulates p24 levels. Accordingly in specific aim 1, we will develop and evaluate the transport, delivery, release on demand and efficacy of nanoformulations containing Vorinostat (VS), Tenofovir (Tef), and mAEA respectively to activate latent HIV infection, eradicate HIV and protect from HIV/cannabiniod induced neuronal deficits using an in-vitro BBB-HIV infection cannabinoid model. In specific aim 2, we will evaluate the in vivo efficacy of the developed nanocarrier in HIVE SCID cannabinoid mouse model, and in specific aim 3, the neurobehavioral modulations induced by nanoformulation in HIVE SCID cannabinoid mouse model will be studied. 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 PA-13-302 and will be useful for reactivation of latent HIV and final eradication of HIV from CNS reservoir and to treat cannabinoid-induced neuronal impairments in HIV subjects.