Multifunctional Nanocarrier to Eradicate HIV from latently infected CNS cells and

多功能纳米载体可从潜伏感染的中枢神经系统细胞中根除艾滋病毒

基本信息

批准号：
9247861
负责人：
MADHAVAN P. NAIR
金额：
$ 36.25万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247861
关键词：
3-Dimensional Absence of pain sensation Acquired Immunodeficiency Syndrome Affect Animal Model Anti-HIV Agents Anti-Retroviral Agents Astrocytes Binding Biological Availability Biological Models Blood - brain barrier anatomy Body Temperature Brain Cells Communication Couples Coupling Development Diagnostic Dopamine Drug Carriers Drug Delivery Systems Drug Targeting Electric Stimulation Electromagnetics Epidemic HIV HIV Infections HIV-1 High Prevalence Highly Active Antiretroviral Therapy Image Impairment In Vitro Infection Latent Virus Lead Liposomes Magnetic Resonance Imaging Magnetism Manuscripts Medicine Methamphetamine Methods Morbidity - disease rate Motor Activity Movement Nanotechnology Nature Nelfinavir Nerve Degeneration Neuraxis Neurons Paper Patients Penetration Pharmaceutical Preparations Physics Property Publishing Recreational Drugs Site Specificity Subgroup System T-20 Technology Therapeutic Uncertainty Viral reservoir Virus Virus Latency Vorinostat Zidovudine antiretroviral therapy base clinical application controlled release electric field experience in vitro testing in vivo magnetic field methamphetamine use methamphetamine user mortality mouse model multidisciplinary nano nanocarrier nanoformulation nanoparticle nanotherapeutic neuroAIDS neurobehavioral neurocognitive disorder non-nucleoside reverse transcriptase inhibitors novel novel strategies novel therapeutics particle prevent public health relevance reactivation from latency receptor response tripolyphosphate zidovudine triphosphate

项目摘要

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.

描述（由申请人提供）：美国目前正经历严重的甲基苯丙胺 (meth) 使用流行病，最近的研究表明，甲基苯丙胺 (meth) 使用者中 HIV-1 感染和相关神经认知障碍 (HAND) 的患病率很高。尽管高效抗逆转录病毒治疗（HAART）已使艾滋病患者的发病率和死亡率显着下降，但病毒仍然潜伏在包括大脑在内的不同避难所中，因此不会暴露于HAART。 HIV 药物无法穿过血脑屏障 (BBB)，也有助于建立大脑庇护所。因此，打破大脑中的艾滋病毒潜伏期并将大脑中激活的病毒暴露于艾滋病毒药物中是根除神经艾滋病和相关手部疾病的关键。因此，系统性地向大脑递送潜伏期破坏剂、抗逆转录病毒药物和冰毒拮抗剂可能是使用HIV感染者控制HIV和冰毒中相关HAND的有希望的方法。近年来，纳米技术在医学中的应用显示出开发新型药物输送系统的令人兴奋的前景。然而，现有技术存在药物被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时药物从载体释放的不确定性的问题。因此，从药物递送的角度来看，非常需要一种快速有效的方法，从大脑中的载体中递送和释放潜伏期破坏剂、HIV药物和甲基受体拮抗剂，以根除HIV储存库并防止甲基化诱导的神经元感染艾滋病毒的冰毒使用者受到损害。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。我们的初步研究表明，伏立诺他可以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 MENP 结合潜伏期破坏剂（伏立诺他）、抗逆转录病毒药物（如奈非那韦 (PI)、5'-三磷酸-AZTTP (NRTI) 的运输、按需递送和功效））、利匹韦林 (NNRTI) 和恩夫韦肽 (FI)) 和甲基拮抗剂 (SB206553) 穿过 BBB 激活潜伏细胞，根除激活的 HIV并保护 BBB-HIV 感染模型系统中神经变性免受冰毒诱导的影响。具体目标 2 将使用 HIV SCID 冰毒小鼠模型评估体外测试的纳米制剂的体内功效。在具体目标 3 中，我们将研究纳米疗法在 HIV SCID 冰毒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。这一利用 MENP 靶向大脑的特定药物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 并最终根除中枢神经系统储存库中的 HIV，并治疗冰毒引起的神经元损伤。