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

通过 BBB 纳米递送甲烷酰胺以阻断大麻素对 HIV-1 感染的影响

• 批准号: 8993465
• 负责人: MADHAVAN P. NAIR
• 金额: $ 52.01万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993465
• 关键词: 3-Dimensional; Absence of pain sensation; Agonist; Animal Model; Anti-HIV Agents; Anti-Retroviral Agents; Astrocytes; Behavioral; Binding; Biological Models; Blood - brain barrier anatomy; Body Temperature; Brain; CNR1 gene; Cannabinoids; Cannabis; Catabolism; Cells; Charge; Communication; Development; Diagnostic; Drug Carriers; Drug Delivery Systems; Drug Formulations; Drug Targeting; Electrostatics; Encapsulated; Endocannabinoids; Genes; HIV; HIV Infections; HIV-1; Half-Life; Health; Heating; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Latent Virus; Lead; Ligand Binding; Liposomes; Magnetism; Manuscripts; Marijuana; Medical; Medical Research; Medicine; Metabolic; Methods; Modeling; Motor Activity; Nanotechnology; Nature; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurons; Penetration; Pharmaceutical Preparations; Property; Publishing; Receptor Activation; Role; Spices; Surface; Synaptic plasticity; System; Technology; Tenofovir; Tetrahydrocannabinol; Therapeutic; Therapeutic Agents; Time; Uncertainty; Viral; Virus; Vorinostat; analog; anandamide; clinical application; controlled release; endogenous cannabinoid system; improved; in vivo; innovation; magnetic field; marijuana use; methanandamide; mouse model; multidisciplinary; nano; nanocarrier; nanodrug; nanoformulation; nanoparticle; neurobehavioral; neurogenesis; novel; prevent; response; synthetic cannabinoid; zidovudine triphosphate

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.

说明（由申请人提供）：虽然大麻被认为是一种管制物质，但大麻研究和大麻的医疗用途已显示出治疗许多医疗问题的重大希望。研究表明，外源性大麻素、四氢大麻酚和合成大麻素，包括“香料”，会干扰大脑中存在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HIV感染的受试者中加剧。HIV药物无法通过血脑屏障支持了HIV在脑内潜伏期的建立。近年来，纳米技术在医学上的应用显示出开发新型给药系统的良好前景。然而，现有技术存在缺乏足够的跨内皮渗透以及纳米载体到达大脑时药物从载体释放的不确定性等问题。因此，从药物传递的角度来看，一种快速有效的方式来传递和释放潜伏破坏剂，HIV药物，以及大脑中的载体mAEA，对于根除HIV库和防止感染HIV的大麻素使用者因外源性大麻素引起的神经元损伤是非常必要的。在目前的提案中，我们将通过体外血脑屏障和体内HIVE SCID大麻素小鼠模型，研究不可穿透的替诺福韦，稳定的内源性大麻素类似物甲胺（mAEA），通过多功能纳米载体结合的mAEA传递，在血脑屏障（BBB）中预防外源性大麻素诱导的神经元缺陷的作用。我们最近发表在《自然通讯》上的论文描述了磁电纳米粒子（MENPs）作为场触发药物载体，具有独特的低能量和耗散能力，可以在血脑屏障上按需释放药物。我们在中枢神经系统细胞中的初步研究表明，伏立诺他激活潜伏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，在特定目标1中，我们将开发和评估含有伏立诺他（VS），替诺福韦（Tef）和mAEA的纳米制剂的运输，递送，按需释放和功效，分别激活潜伏的HIV感染，根除HIV和保护HIV/大麻素诱导的神经元缺陷，使用体外BBB-HIV感染大麻素模型。在专项目标2中，我们将在HIVE SCID大麻素小鼠模型中评估所开发的纳米载体的体内功效；在专项目标3中，我们将研究纳米制剂对HIVE SCID大麻素小鼠模型的神经行为调节作用。我们期待这项前所未有的新3d技术在诊断和药物输送方面具有重要意义。这一多学科的新突破是针对PA-13-302使用MENPs靶向大脑的特异性药物，将有助于重新激活潜伏的HIV并最终从中枢神经系统库中根除HIV，并治疗大麻素诱导的HIV受试者神经元损伤。