title: A shell-crosslinked polymeric micelle system for pH/redox dual stimuli-triggered DOX on-demand release and enhanced antitumor activity.
abstract: Based on targeted amphiphilic block copolymer N-acetyl glucosamine-poly (styrene-alt-maleic anhydride)58-b-polystyrene130(NAG-P(St-alt-MA)58-b-PSt130), a pH/redox dual-triggered shell-crosslinked polymeric micelle system was constructed. The shell-crosslinked micelles (CLM) were prepared by post-crosslinking method to regulate drug release kinetics using cystamine as linkers between carboxy groups of the shell. Compared with non-crosslinked micelles (NCLM), CLM showed spherical shapes with little increased mean diameter of 102.40±0.54nm, low polydispersity index (PDI) of 0.19±0.36, enlarged zeta potential value from -41.46±0.99 to -9.31±0.50mV, indicating the successful modification of disulfide bonds in shell. In vitro drug release study clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release under pH 5.0 and 10mM GSH conditions (46.84% in 96h) without burst release. Both CLM and NCLM showed quite different release profiles between physiological (pH 7.4) and tumoral microenvironment (pH 5.0), effectively avoiding the premature drug leakage and realizing on-demand drug release. The MTT assay implied that CLM presented a time- and concentration-dependent manner to inhibit proliferation of A549 and MCF-7 cells and much lower IC50values in comparison with that of NCLM after 72h incubation. Both FCM and CLSM results showed that CLM displayed much higher cellular uptake efficiency and anti-tumor activities than NCLM and free DOX. CLM and NCLM could be internalized by energy-dependent endocytosis mechanism due to similar surface properties. Overall, this dual-stimuli triggered micelle system provided a promising tumor-responsive platform for cancer therapy.
authors.affiliation: School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
authors.forename: Lele
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
authors.forename: Meijia
authors.initials: M
authors.lastname: Song
authors.affiliation: School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
authors.forename: Baocheng
authors.initials: B
authors.lastname: Tian
authors.affiliation: School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
authors.forename: Keke
authors.initials: K
authors.lastname: Li
authors.affiliation: School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China. Electronic address: hanjingtian002@163.com.
authors.forename: Jingtian
authors.initials: J
authors.lastname: Han
authors.affiliation: School of Pharmacy, Yantai University, 32 Qingquan Road, Yantai 264005, PR China. Electronic address: z.wu@auckland.ac.nz.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000072283:A549 Cells; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008823:Micelles; D011108:Polymers / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin
keywords: Controlled release; Drug delivery; Polymeric micelles; Shell-crosslinked; Stimuli-triggered