title: Paclitaxel-loaded N-octyl-O-sulfate chitosan micelles for superior cancer therapeutic efficacy and overcoming drug resistance.
abstract: The nanoparticle-based drug delivery system holds great attraction to overcome or circumvent multidrug resistance (MDR) in cancer to date. In this work, a synthesized amphiphilic graft copolymer, N-octyl-O-sulfate chitosan (NOSC), and its paclitaxel (PTX)-encapsulated micelles (PTX-M) have been systematically investigated on the MDR reversal effect in vitro and in vivo as well as the mechanism of P-glycoprotein (P-gp) inhibition. NOSC in a wide concentration range even above the critical micelle concentration showed an effective effect on inhibiting P-gp-mediated PTX efflux, which was remarkably different from the surfactants and the Pluronic copolymers. Multiple mechanisms were involved in this effect of NOSC, such as stimulating P-gp ATPase, competitively impeding the binding of PTX with P-gp and reducing the fluidity of the cell membrane. PTX-M presented the highest cellular uptake and the lowest efflux rate of PTX, thereby yielding the optimal cytotoxicity on both the human hepatocellular liver carcinoma (HepG2) cells and the multidrug resistance HepG2 (HepG2-P) cells, which resulted from a combination of the inhibiting P-gp effect of NOSC and the bypassing P-gp action of the intact PTX-M. Additionally, PTX-M had superior blood persistence, tumor accumulation, and therapeutic efficacy after intravenous injection into the tumor-bearing mice. Furthermore, it was demonstrated that most of PTX-M as an intact form was delivered at the tumor site, which ensures the synergetic effect of NOSC micelles on drug delivery and P-gp inhibition. The aforementioned results suggested that NOSC micelles presented promising potential as an anticancer drug carrier for enhanced MDR cancer therapy.
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Jin
authors.forename: Ran
authors.initials: R
authors.lastname: Mo
authors.forename: Ya
authors.initials: Y
authors.lastname: Ding
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008823:Micelles; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; C528556:N-octyl-O-sulfate chitosan; D048271:Chitosan; D017239:Paclitaxel