The major limitation of the currently used anti-HIV drugs such as protease inhibitors is their poor passage through the blood-brain barrier to the center nervous system, which acts as a hidden cellular reservoir for HIV-I. The poor permeability of these agents is considered to be due to the efflux action of the membrane associated MDR1 multidrug transporter, p-glycoprotein (P-gp). Furthermore, the high drug protein binding of protease inhibitors limits the free drug available in the serum for uptake by the brain. In this study, we propose to investigate TAT-peptide conjugated nanoparticles as a 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 a 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 the -i) TATconjugated nanoparticles bypass the efflux action of the membrane bound P-gp and ii) TATconjugated nanoparticles result in greater CNS delivery and sustained drug retention than that with 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.
|Borgmann, Kathleen; Rao, Kavitha S; Labhasetwar, Vinod et al. (2011) Efficacy of Tat-conjugated ritonavir-loaded nanoparticles in reducing HIV-1 replication in monocyte-derived macrophages and cytocompatibility with macrophages and human neurons. AIDS Res Hum Retroviruses 27:853-62|
|Rao, Kavitha S; Ghorpade, Anuja; Labhasetwar, Vinod (2009) Targeting anti-HIV drugs to the CNS. Expert Opin Drug Deliv 6:771-84|
|Peetla, Chiranjeevi; Stine, Andrew; Labhasetwar, Vinod (2009) Biophysical interactions with model lipid membranes: applications in drug discovery and drug delivery. Mol Pharm 6:1264-76|
|Peetla, Chiranjeevi; Rao, Kavitha S; Labhasetwar, Vinod (2009) Relevance of biophysical interactions of nanoparticles with a model membrane in predicting cellular uptake: study with TAT peptide-conjugated nanoparticles. Mol Pharm 6:1311-20|
|Reddy, Maram K; Wu, Li; Kou, Wei et al. (2008) Superoxide dismutase-loaded PLGA nanoparticles protect cultured human neurons under oxidative stress. Appl Biochem Biotechnol 151:565-77|
|Rao, Kavitha S; Reddy, Maram K; Horning, Jayme L et al. (2008) TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs. Biomaterials 29:4429-38|
|Vasir, Jaspreet K; Labhasetwar, Vinod (2007) Biodegradable nanoparticles for cytosolic delivery of therapeutics. Adv Drug Deliv Rev 59:718-28|