title: Self-Assembled Redox Dual-Responsive Prodrug-Nanosystem Formed by Single Thioether-Bridged Paclitaxel-Fatty Acid Conjugate for Cancer Chemotherapy.
abstract: Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S-OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug-nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.affiliation: Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Bingjun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.affiliation: Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Sara
authors.initials: S
authors.lastname: Musetti
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, P. R. China.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers; D065546:Drug Liberation; D005227:Fatty Acids / Q000737:chemistry*; D006801:Humans; D058726:Nanoconjugates; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage*; D017207:Rats, Sprague-Dawley; D013440:Sulfides
chemical_list: D004337:Drug Carriers; D005227:Fatty Acids; D058726:Nanoconjugates; D011355:Prodrugs; D013440:Sulfides; D017239:Paclitaxel
keywords: Paclitaxel; prodrug nanoparticles; redox dual-responsive; single thioether; small-molecule prodrug