title: Tumor pH(e)-triggered charge-reversal and redox-responsive nanoparticles for docetaxel delivery in hepatocellular carcinoma treatment.
abstract: The insufficient cellular uptake of nanocarriers and their slow drug release have become major obstacles for achieving satisfactory anticancer outcomes in nano-medicine therapy. Because of the slightly acidic extracellular environment (pHe≈ 6.5) and a higher glutathione (GSH) concentration (approximately 10 mM) in tumor tissue/cells, we firstly designed a novel d-α-tocopheryl polyethylene glycol 1000-poly(β-amino ester) block copolymer containing disulfide linkages (TPSS). TPSS nanoparticles (NPs) with pH- and redox-sensitive behaviors were developed for on-demand delivery of docetaxel (DTX) in hepatocellular carcinoma. DTX/TPSS NPs exhibited sensitive surface charge reversal from -47.6 ± 2.5 mV to +22.5 ± 3.2 mV when the pH decreased from 7.4 to 6.5, to simulate the pHe. Meanwhile, anabatic drug release of DTX/TPSS NPs was observed in PBS buffer (pH 6.5, 10 mM GSH). Due to the synergism between the pHe-triggered charge reversal and the redox-triggered drug release, enhanced drug uptake and anticancer efficacy were observed in HepG2 and SMMC 7721 cells treated with DTX/TPSS NPs. The positively charged NPs exhibited a stronger inhibitory effect on cell proliferation, promoted cell cycle arrest in the G2/M phase, and increased the rate of apoptosis. More importantly, based on the higher tumor accumulation of TPSS vehicles in vivo, a significant suppression of tumor growth, but without side-effects, was observed when DTX/TPSS NPs were injected intravenously into HepG2 xenograft tumor-bearing mice. Collectively, these results demonstrate that the newly developed dual-functional TPSS copolymer may be utilized as a drug delivery system for anticancer therapy.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China. ytwang@umac.mo mwchen@umac.mo.
authors.forename: Fengqian
authors.initials: F
authors.lastname: Chen
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.forename: Meiwan
authors.initials: M
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D000077143:Docetaxel; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008113:Liver Neoplasms / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D010084:Oxidation-Reduction; D043823:Taxoids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel