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:
  • 金额:
    $ 36.25万
  • 依托单位:
  • 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

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):美国目前正经历着甲基苯丙胺(冰毒)使用的严重流行,最近的研究显示,冰毒使用者中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著下降,但病毒仍潜伏在包括脑在内的不同的保护区内,因此不暴露于HAART。艾滋病毒药物无法穿过血脑屏障(BBB)也有助于建立脑保护区。因此,打破HIV在大脑中的潜伏期并将激活的病毒暴露于大脑中的HIV药物是根除神经AIDS和相关HAND的精髓。因此,将潜伏期阻断剂、ARV药物和甲氨蝶呤拮抗剂系统递送至脑可能是控制使用HIV感染受试者的甲氨蝶呤中的HIV和相关HAND的有希望的方法。近年来,纳米技术在医药领域的应用为新型药物传递系统的开发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,以及如果纳米载体到达大脑以及当纳米载体到达大脑时药物从载体释放的不确定性。因此,从药物递送的角度来看,非常需要一种从脑中的载体递送和释放潜伏期破坏剂、HIV药物和冰毒受体拮抗剂的快速有效的方法,以根除HIV储库并防止感染HIV的冰毒使用者中冰毒诱导的神经元损伤。我们最近在“Nature Communication”上发表的手稿描述了磁电纳米颗粒(MENP)作为场触发药物载体,提供了一种独特的低能量和无耗散的按需药物释放能力。我们的初步研究表明,伏立诺他激活星形胶质细胞中潜伏感染的HIV。因此,在具体目标1中,我们将开发和评估多功能电磁纳米颗粒结合的潜伏期打破剂的运输、按需递送和功效。(伏立诺他),抗逆转录病毒药物(如奈非那韦(PI)、5 ′-三磷酸-AZTTP(NRTI)、阿匹韦林(NNRTI)和恩夫韦肽(FI))和甲氨蝶呤拮抗剂(SB 206553)在BBB-HIV感染模型系统中活化潜伏细胞,根除活化的HIV并保护神经变性免受甲氧苯丙胺诱导的作用。具体目标2将使用HIV SCID小鼠模型评价体外测试的纳米制剂的体内功效。在具体目标3中,我们将研究纳米治疗剂在HIV SCID小鼠模型中诱导的神经行为调节。我们预计,前所未有的新3D技术可能在诊断和药物输送方面具有重要意义。这种多学科的新突破,在特定的药物靶向大脑使用电磁纳米粒子是响应于特定的射频消融,并将有助于重新激活潜伏的艾滋病毒和最终根除艾滋病毒从中枢神经系统水库和治疗甲基诱导的神经元损伤。

项目成果

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MADHAVAN P. NAIR其他文献

MADHAVAN P. NAIR的其他文献

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{{ truncateString('MADHAVAN P. NAIR', 18)}}的其他基金

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:
    9926429
  • 财政年份:
    2015
  • 资助金额:
    $ 36.25万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 36.25万
  • 项目类别:
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
  • 批准号:
    8736460
  • 财政年份:
    2014
  • 资助金额:
    $ 36.25万
  • 项目类别:
Cocaine in the Neuropathogenesis of HIV infection: Role of HDAC2
可卡因在 HIV 感染的神经发病机制中:HDAC2 的作用
  • 批准号:
    8410634
  • 财政年份:
    2013
  • 资助金额:
    $ 36.25万
  • 项目类别:
Novel Magneto-Electric Nanodelivery of Drugs to Eradicate HIV from CNS
新型磁电纳米递送药物可根除中枢神经系统中的艾滋病毒
  • 批准号:
    8655176
  • 财政年份:
    2013
  • 资助金额:
    $ 36.25万
  • 项目类别:
Cocaine in the Neuropathogenesis of HIV infection: Role of HDAC2
可卡因在 HIV 感染的神经发病机制中:HDAC2 的作用
  • 批准号:
    8623124
  • 财政年份:
    2013
  • 资助金额:
    $ 36.25万
  • 项目类别:
Novel Magneto-Electric Nanodelivery of Drugs to Eradicate HIV from CNS
新型磁电纳米递送药物可根除中枢神经系统中的艾滋病毒
  • 批准号:
    8544686
  • 财政年份:
    2013
  • 资助金额:
    $ 36.25万
  • 项目类别:
Mechanisms of Neuro-AIDS by HIV 1B and C Clades
HIV 1B 和 C 进化枝导致神经艾滋病的机制
  • 批准号:
    8432831
  • 财政年份:
    2010
  • 资助金额:
    $ 36.25万
  • 项目类别:
Mechanisms of Neuro-AIDS by HIV 1B and C Clades
HIV 1B 和 C 进化枝导致神经艾滋病的机制
  • 批准号:
    8245854
  • 财政年份:
    2010
  • 资助金额:
    $ 36.25万
  • 项目类别:
Mechanisms of Neuro-AIDS by HIV 1B and C Clades
HIV 1B 和 C 进化枝导致神经艾滋病的机制
  • 批准号:
    8015185
  • 财政年份:
    2010
  • 资助金额:
    $ 36.25万
  • 项目类别:
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