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.

描述（由申请人提供）：尽管大麻被认为是受控物质，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巨大前景。研究表明，外源性大麻素、THC 和合成大麻素（包括“香料”）会​​干扰大脑中神经发生所需的内源性大麻素系统 (ECS) 的功能。然而，在大麻素滥用过程中，神经认知和行为功能明显受损，并且这些影响在有症状的艾滋病毒感染者中更为严重。 HIV药物无法穿过血脑屏障，支持了HIV在大脑中潜伏的建立。近年来，纳米技术在医学上的应用在开发新型药物递送系统方面显示出了令人兴奋的前景。然而，现有技术缺乏足够的跨内皮渗透能力，以及纳米载体到达大脑时载体释放药物的不确定性。因此，从药物输送的角度来看，非常需要一种快速有效的方法，从大脑中的载体中输送和释放潜伏期破坏剂、HIV药物和mAEA，以根除HIV储存库并防止外源性大麻素引起的神经元损伤感染艾滋病毒的大麻使用者。在当前的提案中，我们将研究血脑屏障（BBB）难以穿透的替诺福韦（一种稳定的内源性大麻素类似物甲烷酰胺（mAEA））的作用，使用多功能纳米载体结合mAEA通过体外血脑屏障递送来预防外源性大麻素诱导的神经元缺陷。 BBB 和体内 HIVE SCID 大麻素小鼠模型。我们最近在《自然通讯》上发表的手稿描述了磁电纳米粒子（MENP）作为场触发药物载体，提供了在血脑屏障上低能量和无耗散按需药物释放的独特能力。我们对 CNS 细胞的初步研究表明，vorinostat 激活潜伏感染 HIV 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，并显着下调 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，以激活潜伏的 HIV 感染、根除 HIV 并预防 HIV/使用体外 BBB-HIV 感染大麻素模型，大麻素诱导神经元缺陷。在具体目标 2 中，我们将评估所开发的纳米载体在 HIVE SCID 大麻素小鼠模型中的体内功效，在具体目标 3 中，将研究纳米制剂在 HIVE SCID 大麻素小鼠模型中诱导的神经行为调节。我们预计前所未有的新型 3D 技术可能在诊断和药物输送方面具有重要意义。这项利用 MENP 靶向大脑的特定药物的多学科新突破是对 PA-13-302 的回应，将有助于重新激活潜伏的 HIV 并最终根除中枢神经系统储存库中的 HIV，并治疗大麻素引起的神经元损伤。艾滋病毒受试者。