3. NANOMATERIALS AND POLYMERS

3A. PEPTIDE NANOSTRUCTURES AS CELL-PENETRATING MOLECULAR TRANSPORTERS

The objective of this project is to create nanoscale self-assembled molecular transporters from peptides for the efficient targeted delivery of therapeutics including anti-cancer and anti-HIV agents. Our hypothesis is that peptides containing appropriate residues can form nanostructures with potential application for encapsulation, cellular targeting, and drug delivery.

We are also collaborating with Dr. Geoffrey Bothun in Department of Chemical Engineering at the University of Rhode Island to design cell-penetrating peptides and to evaluate their interactions with phospholipid bilayer membranes.

3B. POLYMER-BASED DRUG DELIVERY

Our hypothesis is that the dextran-drug conjugates will preferentially accumulate in the liver, where it gradually regenerates the active drug, resulting in sustained local effect in liver. The aim of the present study is to synthesize and characterize conjugate of antiviral, anticancer, or immunosuppressive agents with dextran, intended for selective delivery of the drug to the liver. This aspect of my research is carried out with collaboration with Dr. Reza Mehvar at Texas Tech School of Pharmacy.

Furthermore, in collaboration with Dr. Gustavo Doncel in Eastern Virginia Medical School (CONRAD), various anti-HIV nucleosides known as reverse transcriptase inhibitors are conjugated with anti-HIV polyanionic polymeric derivatives, such as cellulose sulfate and cellulose sulfate acetate, to develop anti-HIV-1 microbicide agents.

Some of the results of these investigations were published in several peer-reviewed manuscripts:

1. Gupta, A., Mandal, D., Ahmadibeni, Y., Parang, K., Bothun, G. Hydrophobicity drives the non-specific cellular uptake of short cationic peptide ligands. Eur. Biophysics J. (2011) 40, 727-736.

2. Ye, G., Gupta, A., DeLuca, R., Parang, K., Bothun, G. D. Bilayer disruption and liposome restructuring by a homologous series of small Arg. Rich synthetic peptides. Colloids and Surfaces B.: Biointerfaces (2010) 76, 76-81.

3. Agarwal, H. K., Kumar, A., Doncel, G. F., Parang K. Synthesis, antiviral and contraceptive activities of nucleoside-sodium cellulose sulfate acetate and succinate conjugates. Bioorg. Med. Chem. Lett. (2010) 20, 6993-6997.

4. Penugonda, S., Agarwal, H. K., Parang, K., Mehvar, R. Plasma pharmacokinetics and tissue disposition of novel dextran-methylprednisolone conjugates with peptide linkers in rats. J. Pharm. Sci. (2010) 99, 1627-1637.

5. Penugonda, S., Kumar, A., Agarwal, H. K., Parang, K., Mehvar, R. Synthesis and in vitro characterization of novel dextran-methylprednisolone conjugates with peptide linkers: Effects of linker length on hydrolytic and enzymatic release of methylprednisolone and its peptidyl intermediates. J. Pharm. Sci. (2008) 97, 2649-2664.

6. Chimalakonda, C., Agarwal, H., Kumar, A., Parang, K., Mehvar, R. Synthesis, analysis, in vitro characterization, and in vivo disposition of a lamivudine-dextran conjugate for selective antiviral delivery to the liver. Bioconjugate Chem. (2007) 18, 2097-2108.

7. Ye, G., Nam, N. H., Saleh, A., Kumar, A., Sun, G., Shenoy, D. B., Amiji, M. M., Parang, K. Cellular delivery of phosphopeptides with tripodal peptide analogues. J. Med. Chem. (2007) 50, 3604-3617.