title: Co-delivery of doxorubicin and siRNA with reduction and pH dually sensitive nanocarrier for synergistic cancer therapy.
abstract: Drug resistance is the greatest challenge in clinical cancer chemotherapy. Co-delivery of chemotherapeutic drugs and siRNA to tumor cells is a vital means to silence drug resistant genes during the course of cancer chemotherapy for an improved chemotherapeutic effect. This study aims at effective co-delivery of siRNA and anticancer drugs to tumor cells. A ternary block copolymer PEG-PAsp(AED)-PDPA consisting of pH-sensitive poly(2-(diisopropyl amino)ethyl methacrylate) (PDPA), reduction-sensitive poly(N-(2,2'-dithiobis(ethylamine)) aspartamide) PAsp(AED), and poly(ethylene glycol) (PEG) is synthesized and assembled into a core-shell structural micelle which encapsulated doxorubicin (DOX) in its pH-sensitive core and the siRNA-targeting anti-apoptosis BCL-2 gene (BCL-2 siRNA) in a reduction-sensitive interlayer. At the optimized size and zeta potential, the nanocarriers loaded with DOX and BCL-2 siRNA may effectively accumulate in the tumor site via blood circulation. Moreover, the dual stimuli-responsive design of micellar carriers allows microenviroment-specific rapid release of both DOX and BCL-2 siRNA inside acidic lysosomes with enriched reducing agent, glutathione (GSH, up to 10 mM). Consequently, the expression of anti-apoptotic BCL-2 protein induced by DOX treatment is significantly down-regulated, which results in synergistically enhanced apoptosis of human ovarian cancer SKOV-3 cells and thus dramatically inhibited tumor growth.
authors.affiliation: PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Weicai
authors.initials: W
authors.lastname: Chen
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Du
authors.initials: D
authors.lastname: Cheng
authors.forename: Jifeng
authors.initials: J
authors.lastname: Chen
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Xintao
authors.initials: X
authors.lastname: Shuai
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D004357:Drug Synergism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D036103:Nanotechnology; D009369:Neoplasms / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D000903:Antibiotics, Antineoplastic; D034741:RNA, Small Interfering; D004317:Doxorubicin
keywords: chemotherapy; co-delivery; gene silencing; pH sensitivity; reduction; tumor apoptosis