Title: In vivo pharmacokinetic and biodistribution of pH sensitive PEGYlated Chitosan microsphere loaded with 5-fluorouracil

Abstract:

Purpose: PEGylated chitosan microspheres were prepared by emulsion-cross-linking followed by the solvent evaporation technique. The formulations were tested in vivo for pharmacokinetic and biodistribution followed by pharmacodynamic efficacy in colorectal carcinoma model in rats. Methods: In vivo activity was evaluated for dimethyl hydrazine-induced colorectal cancer in albino male Wistar rats. Pharmacokinetic parameters were measured and biodistribution in different tissues and organs were studied by HPLC techniques. Biochemical and histological parameters were evaluated to understand their effectiveness for colon cancer therapy with colon targeted localized delivery. Results: The 5-FU immediate release (IR) formulations showed an immediate cytotoxic effect, whereas controlled release microspheres inhibited proliferation of tumor cells to induce apoptosis over an extended time. Minimum inhibitory concentration (IC50) values for both standard plain 5-FU and 5-FU-loaded microspheres were respectively 5.00 ± 0.004 µg/mL and 165 ± 1.9 µg/mL which showed the improved safety profile of the microsphere formulation. Tissue distribution showed high concentration of 5-FU in colon that was higher than IC50 value required to stop the growth or death of colon cancer cells from the colonic dysplasia in Duke’s stage A. Significant reduction in tumor volume and multiplicity was observed with increased levels of liver enzymes in animals when treated with standard 5-FU formulation compared with 5-FU loaded microspheres. Elevated levels of serum albumin, creatinine, leukocytopenia, and thrombocytopenia were observed in animals for the standard 5-FU formulation. This was reduced in controlled release microsphere formulation which clearly indicates better safety profile with prolonged duration of action of these microspheres formulation. Conclusion: The PEGylated chitosan microspheres showed a better efficacy with controlled release profile, thereby increasing the safety profile of the drug along with high localized drug concentrations in colorectal carcinoma showing enhanced antitumor activity.

Biography:

Dr. Kuntal Ganguly holds a M.Pharm degree from the Rajiv Gandhi University Of Health Sciences, Bangalore and has completed his PhD (Tech.) from Jawaharlal Nehru Technological University, Hyderabad , India in Collaboration with University of Texas at Austin, USA. He has over 18 years of extensive experience in the global pharmaceuticals industry. He is responsible for leading the Company’s business, research and technical operations and steering its investments in developing and strengthening its capabilities and capacity. He held leadership positions at CSIR, ICMR and Venus Remedies Limited for over a decade, including Head of Formulations R&D, Venus Remedies Limited, India and Germany.