title: Redox and pH-responsive degradable micelles for dually activated intracellular anticancer drug release.
abstract: Redox and pH dual-responsive biodegradable micelles were developed based on poly(ethylene glycol)-SS-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PEG-SS-PTMBPEC) copolymer and investigated for intracellular doxorubicin (DOX) release. PEG-SS-PTMBPEC copolymer with an Mn of 5.0-4.1kg/mol formed micellar particles with an average diameter of 140nm and a low polydispersity of 0.12. DOX was loaded into PEG-SS-PTMBPEC micelles with a decent drug loading content of 11.3wt.%. The in vitro release studies showed that under physiological conditions only ca. 24.5% DOX was released from DOX-loaded micelles in 21h. The release of DOX was significantly accelerated at pH5.0 or in the presence of 10mM glutathione (GSH) at pH7.4, in which 62.8% and 74.3% of DOX was released, respectively, in 21h. The drug release was further boosted under 10mM GSH and pH 5.0 conditions, with 94.2% of DOX released in 10h. Notably, DOX release was also facilitated by 2 or 4h incubation at pH 5.0 and then at pH 7.4 with 10mM GSH, which mimics the intracellular pathways of endocytosed micellar drugs. Confocal microscopy observation indicated that DOX was delivered and released into the nuclei of HeLa cells following 8h incubation with DOX-loaded PEG-SS-PTMBPEC micelles, while DOX was mainly located in the cytoplasm for reduction-insensitive PEG-PTMBPEC controls. MTT assays revealed that DOX-loaded PEG-SS-PTMBPEC micelles had higher anti-tumor activity than reduction-insensitive controls, with low IC50 of 0.75 and 0.60μg/mL for HeLa and RAW 264.7 cells, respectively, following 48h incubation. PEG-SS-PTMBPEC micelles displayed low cytotoxicity up to a concentration of 1.0mg/mL. These redox and pH dual-bioresponsive degradable micelles have appeared as a promising platform for targeted intracellular anticancer drug release.
authors.affiliation: Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.forename: Ru
authors.initials: R
authors.lastname: Cheng
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.forename: Jan
authors.initials: J
authors.lastname: Feijen
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000737:chemistry; D002254:Carbonates / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy*; D010084:Oxidation-Reduction; D011092:Polyethylene Glycols / Q000737:chemistry; D011409:Propylene Glycols / Q000737:chemistry; D013388:Succinimides / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D001597:Benzylidene Compounds; D002254:Carbonates; D003692:Delayed-Action Preparations; D008823:Micelles; D011409:Propylene Glycols; D013388:Succinimides; D011092:Polyethylene Glycols; D004317:Doxorubicin; C050761:polyethylene glycol bis(succinimidyl succinate); C008783:pentaerythritol