The major limitation of the currently used anti-HIV drugs such as protease inhibitors is their poor passage through the blood-brain barrier (BBB) to the center nervous system (CNS), which acts as a hidden cellular reservoir for HIV-1. The poor permeability of these agents is considered to be due to the efflux action of the membrane associated MDR1 multidrug transporter, p-glycoprotein (Pgp). In this study, we propose to investigate the TAT-peptide conjugated nanoparticles as a drug delivery mechanism to enhance the CNS delivery of anti-HIV drugs. Nanoparticles in our study are extremely small biodegradable colloidal particles (20 to 40 nm in diameter) with a therapeutic agent encapsulated (entrapped) in the polymer matrix. The hypothesis of the proposed research is that the TAT-peptide conjugated to nanoparticles would increase their permeability across the BBB and hence the transport of the encapsulated drug to the CNS. Nanoparticles once localized in the CNS would release the encapsulated therapeutic agent slowly due to their biodegradation. Thus, it is anticipated that the nanoparticle-mediated drug delivery would enhance the CNS bioavailability of the drug as well as its retention, which would enhance the therapeutic efficacy of the drug.
The specific aims are to test the hypotheses that -i) the TAT-conjugated nanoparticles result in a greater CNS delivery of a model anti-HIV drug and ii) the nanoparticle-mediated delivery results in sustained CNS drug retention than the drug in solution. The successful outcome of the proposed approach could provide a novel modality to deliver several classes of therapeutic agents including anticancer agents, proteins, peptides, and genes to the CNS. ? ? ?
