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.
This application has significant relevance to RFA-MH-14-170 'Eradication of HIV-1 from CNS Reservoir: Implications for therapeutics'. Existing nanodelivery of ART to eradicate latent HIV reservoir in the brain and to protect the neurons have limitations, including the delivery and release of the agents in the brain. This newly invented novel nanotechnology that couples both magnetic and electric forces at body temperature without exploiting heat will (a) deliver the HIV reactivating agent (vorinostat) by magnetic forces and then (b) release the vorinostat 'on demand by electric forces' and (c) expose the activated virus to HIV drugs on demand and (d) protect the neurons from meth induced neuronal deficits by meth antagonists. This may lead to develop a novel and promising drug targeting system to eradicate latent HIV reservoir in CNS and to treat in HIV infected meth users.
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