title: Facile construction of dual-bioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release.
abstract: It is still a major challenge for targeted cancer chemotherapy to design stable biodegradable micellar drug delivery systems which show a rapid and complete intracellular drug release. Here, reversibly core-crosslinked pH-responsive biodegradable micelles were developed based on poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-pyridyl disulfide carbonate) [PEG-P(TMBPEC-co-PDSC)] copolymers and investigated for intracellular doxorubicin (DOX) release. PEG-P(TMBPEC-co-PDSC) copolymers formed micelles with a small size of 58.6nm were readily crosslinked by the addition of dithiothreitol (DTT). Notably, in vitro release studies showed that under physiological conditions only ca. 19.9% of DOX was released from the reversibly crosslinked micelles in 24h at a low micelle concentration of 40μg/mL. The release of DOX was accelerated at pH5.0 or in the presence of 10mM glutathione (GSH) at pH7.4, in which 64.2% and 44.1% of DOX was released, respectively, in 24h. The drug release was further boosted at pH5.0 and 10mM GSH, with 98.8% of DOX released in 12h. Moreover, DOX release was also facilitated by a 4h incubation at pH5.0 followed by incubation at pH7.4 with 10mM GSH. Confocal microscopy indicated that DOX was delivered and released into the nuclei of RAW 264.7 cells following a 12h incubation with DOX-loaded reversibly crosslinked micelles. MTT assays revealed that DOX-loaded reversibly crosslinked micelles had much higher antitumor activity than irreversibly crosslinked controls, with low IC50 values of 1.65 and 1.14μg/mL for HeLa and RAW 264.7 cells, respectively, following a 48h incubation. The blank crosslinked micelles had a low cytotoxicity of up to a concentration of 0.8mg/mL. These reversibly crosslinked pH-sensitive biodegradable micelles with superior extracellular stability but activated intracellular drug release provide a novel platform for tumor-targeting drug delivery.
authors.affiliation: Biomedical Polymers Laboratory, 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; Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Biomedical Polymers Laboratory, 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: Fenghua
authors.initials: F
authors.lastname: Meng
authors.affiliation: Biomedical Polymers Laboratory, 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: Ru
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Biomedical Polymers Laboratory, 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: Chao
authors.initials: C
authors.lastname: Deng
authors.affiliation: Biomedical Polymers Laboratory, 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; Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands. Electronic address: j.feijen@utwente.nl.
authors.forename: Jan
authors.initials: J
authors.lastname: Feijen
authors.affiliation: Biomedical Polymers Laboratory, 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. Electronic address: zyzhong@suda.edu.cn.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005978:Glutathione / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008823:Micelles; D011108:Polymers / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin; D005978:Glutathione
keywords: Anticancer drugs; Biodegradable micelles; Controlled release; Reversible crosslinking; pH-sensitive