title: Overcoming multidrug resistance in 2D and 3D culture models by controlled drug chitosan-graft poly(caprolactone)-based nanoparticles.
abstract: The 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.
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors: Wei-Bin
authors: WB
authors: Shi
authors: Van-Minh
authors: VM
authors: Le
authors: Chun-Hua
authors: CH
authors: Gu
authors: Yuan-Hong
authors: YH
authors: Zheng
authors: Mei-Dong
authors: MD
authors: Lang
authors: Yan-Hua
authors: YH
authors: Lu
authors: Jian-Wen
authors: JW
authors: Liu
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry* / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D011091:Polyesters / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D011091:Polyesters; C016240:polycaprolactone; D048271:Chitosan; D005472:Fluorouracil
keywords: 3D cultures; 5-fluorouracil; chitosan; drug delivery; in vitro models; multidrug resistance; nanoparticles