Grant: Discovery Grants Program - Individual

Nanoparticle therapeutics, based on natural and synthetic polymers with water-soluble polymers, offer new routes to improve cancer drug delivery. This aids the drug solubility, increases the therapeutic process through long circulation and enhances the uptake into tumors by achieving the permeability and retention effect. Among natural cationic polymers used in drug delivery systems, chitosan has attracted a major interest in the nanobiomedical technology sector since it is a biocompatible, biodegradable and versatile polymer. Chitosan and its derivatives have the desired properties for safe use as pharmaceutical drug delivery tools. The principal interest in using chitosan and its derivatives as a pharmaceutical carrier is to enhance the bioavailability of therapeutic drugs (peptides, proteins, antigens and plasmid DNAs) in vivo. However, chitosan is only soluble in acidic solution and not at neutral pH, which causes a major problem for drug-carrier formulation. Modifications of polymer structure are needed, in order to increase chitosan solubility and affinity. Chitosan-protein conjugation will increase polymer solubility in physiological pH and will enhance markedly chitosan efficiency in a drug delivery system.*In this proposal chitosan nanoparticles of different sizes (15, 50, 100 and 200 KDa) will be conjugated with different transporter proteins, such as human and bovine serum albumins and beta-lactoglobulin. Since selected proteins are different in hydrophobicity, chitosan-protein nanoparticles will be more selective towards hydrophilic and hydrophobic drugs. Encapsulation of several anticancer drugs such as doxorubicin, daunorubicin, idarubicin, tamoxifen, 4-hydrotamoxifen and endoxifen with chitosan-protein nanocapsules will be carried out using multiple spectroscopic methods and thermodynamic analysis in combination with TEM, SEM, AFM microscopic imaging, resonance light scattering (RLS)/zeta potential and molecular modeling. The effects of polymer size and molecular weight on drug-nanoparticle encapsulation will be evaluated. Control and release of the drug will be monitored and the efficiency of each conjugate in drug delivery will be determined.*This study is important, as non-covalent association of carrier and drug is one of the most significant molecular aspects that dictate the encapsulation efficacy and drug release efficiency. The generated information will facilitate a more rational chitosan design, resolving problems in drug delivery system; meanwhile it will advance novel and emerging technologies toward clinical investigation. The proposal is multidisciplinary and provides our students with important knowledge related to drug delivery, enabling them to be highly competitive in the job market.*