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.
This application entitled 'Nano-delivery of methanandamide across BBB to block cannabinoid-induced effects in HIV-1 infection.' has significant relevance to PA-13-302. Existing nanodelivery of ART to eradicate latent HIV reservoir in the brain and to protect the neurons from exocannabinioid induced neuronal deficits have limitations, including the delivery and release of the agents in the brain; therefore, this newly invented nano- carrier with surface functionalized MEMP containing tenofovir (tef), vorinostat (VS), and methanandamide (mAEA) will be delivered across blood brain barrier (BBB) by external magnetic force in a non-invasive way by which the HIV activating VS and stable endocannabinoid agonist, mAEA, will be released from liposomal encapsulation overtime while the anti-HIV drug, tef, will be released from MENP on demand by electric forces at body temperature without exploiting heat. The results emanating from these innovative studies may lead to the development of a novel and promising drug targeting system to eradicate latent HIV reservoir in CNS and to treat and prevent neurological deficits observed in cannabinoid using HIV infected subjects.
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