title: Enhanced Cellular Internalization and On-Demand Intracellular Release of Doxorubicin by Stepwise pH-/Reduction-Responsive Nanoparticles.
abstract: The efficient delivery of antitumor agents to tumor sites faces numerous obstacles, such as poor cellular uptake and slow intracellular drug release. In this regard, smart nanoparticles (NPs) that respond to the unique microenvironment of tumor tissues have been widely used for drug delivery. In this study, novel charge-reversal and reduction-responsive histidine-grafted chitosan-lipoic acid NPs (HCSL-NPs) were selected for efficient therapy of breast cancer by enhancing cell internalization and intracellular pH- and reduction-triggered doxorubicin (DOX) release. The surface charge of HCSL-NPs presented as negative at physiological pH and reversed to positive at the extracellular and intracellular pH of the tumor. In vitro release investigation revealed that DOX/HCSL-NPs demonstrated a sustained drug release under the physiological condition, whereas rapid DOX release was triggered by both endolysosome pH and high-concentration reducing glutathione (GSH). These NPs exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against 4T1 cells in vitro. Excellent tumor penetrating efficacy was also found in 4T1 tumor spheroids and solid tumor slices. In vivo experiments demonstrated that HCSL-NPs exhibited excellent tumor-targeting ability in tumor tissues as well as excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing BALB/c mice. These results indicated that the novel charge-reversal and reduction-responsive HCSL-NPs have great potential for targeted and efficient delivery of chemotherapeutic drugs in cancer treatments.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Ben-Gang
authors.initials: BG
authors.lastname: You
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Shu-di
authors.initials: SD
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Ji-Zhao
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Chen-Xi
authors.initials: CX
authors.lastname: Qu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Ye-Juan
authors.initials: YJ
authors.lastname: Zhou
authors.affiliation: Changshu Hospital of Traditional Chinese Medicine , Changshu 215500, PR China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Suzhou People's Hospital, Nanjing Medical University , Suzhou, 215000, PR China.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, PR China.
authors.forename: Xue-Nong
authors.initials: XN
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004317:Doxorubicin; D004337:Drug Carriers; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles
chemical_list: D004337:Drug Carriers; D004317:Doxorubicin
keywords: charge reversion; chitosan; drug delivery; dually pH-/reduction-responsive; efficient delivery; smart NPs; tumor targeting