Overcoming Multidrug Resistance in 2D and 3D Culture Models by Controlled Drug Chitosan‐Graft Poly(Caprolactone)‐Based Nanoparticles

Abstract

AbstractThe principal limitations of chemotherapy are dose‐limiting systemic toxicity and the development of multidrug‐resistant phenotypes. The aim of this study was to investigate the efficiency of a new sustained drug delivery system based on chitosan and ε‐caprolactone to overcome multidrug resistance in monolayer and drug resistance associated with the three‐dimensional (3D) tumor microenvironment in our established 3D models. The 5‐fluorouracil (5‐FU)‐loaded nanoparticles (NPs) were characterized by transmission electron microscope and dynamic light scattering, and its released property was determined at different pH values. 5‐FU/NPs exhibited well‐sustained release properties and markedly enhanced the cytotoxicity of 5‐FU against HCT116/L‐OHP or HCT8/VCR MDR cells in two‐dimensional (2D) and its parental cells in 3D collagen gel culture with twofold to threefold decrease in the IC50 values, as demonstrated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, Hoechst/propidium iodide staining and flow cytometry analysis. Furthermore, the possible mechanism was explored by high‐performance liquid chromatography and rhodamine 123 accumulation experiment. Overall, the results demonstrated that 5‐FU/NPs increase intracellular concentration of 5‐FU and enhance its anticancer efficiency by inducing apoptosis. It was suggested that this novel NPs are a promising carrier to decrease toxic of 5‐FU and has the potential to reverse the forms of both intrinsic and acquired drug resistance in 2D and 3D cultures. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1064–1074, 2014