Highly Active Antiretroviral Therapy (HAART) has resulted in remarkable decline in the morbidity and mortality in AIDS Patients. Nevertheless, inadequate or zero reachability of anti-retro viral (ARV) drugs across the blood brain barrier (BBB) results in viral reservoir in the brain hideout. In recent years, use of nanotechnology in medicine has shown exciting prospect for development of novel drug delivery systems. However, the existing technologies suffer from the lack of adequate transendothelial penetration before the drugs are engulfed by the reticuloendothelial system (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 the drugs on demand from the carrier in the brain is very much needed to eradicate HIV reservoir. Magnetic or electric fields have been shown separately to exert beneficial effects on the biological systems including brain diseases. Hence we hypothesize that coupling of these two properties using magneto- electric nanoparticles (MENPs) will serve as an effective carrier to deliver and, most importantly, to release the drugs on demand in the brain. Our preliminary studies showed that AZTTP binds to MENPs and the bound drug could be released on demand to almost 100% by AC triggering (magneto-electric field with a 65 Oe magnitude at a frequency of less than 100 Hz). Accordingly in the Specific Aim# 1, we will develop magnetoelectro (ME)-liposome based novel multi-ferrous nanoparticles (20-40 nm) with ME properties bound to HIV drugs, (which are undetectable/less detectable in brain) such as Nelfinavir (PI), 5'-triphosphate-AZT (AZTTP) (NRTI), Rilpivirine (NNRTI) and Enfuvirtide (FI), and evaluate the binding, pharmacokinetics, dynamics, stability and toxicity.
In Specific Aim #2, the developed formulation will be tested in vitro for its ability to transmigrate across BBB, and release of the drugs with external ME forces and study the antiviral activity of released drugs. According to this invented ME nanotechnology (patent pending), DC and AC external magnetic fields (by miniaturized coil chips) are used for the purposes of speedy delivery of the drug bound nanocarrier and on demand drug release, respectively. Consequently, such low-energy-consumption requirements enable an extreme portability of the device implementation. The new technology enables an unprecedented 3-D diagnostics and drug delivery and further allows to clear the ME nanoparticles from the brain to the periphery by the reverse external magnetic force once the specific drugs have been released on demand in the brain through AC triggering. We expect the ultimate device to be user-friendly, adequately lightweight, relatively small size, and sourced by a portable battery. 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 complete eradication of the HIV-1 virus reservoir in the brain.
This application has significant relevance to RFA -MH-13-031. Existing nanodelivery of drugs to HIV reservoir, such as brain, have limitations, including the delivery and release of the drugs in the brain. This newly invented technology coupling both magnetic and electric forces will deliver the drugs by magnetic forces and release the drugs on demand by electric forces, in the brain to eradicate the HIV reservoir.
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