title: Oxime linkage: a robust tool for the design of pH-sensitive polymeric drug carriers.
abstract: Oxime bonds dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their own niche. In the present work, oxime linkages were confirmed to be a robust tool for the design of pH-sensitive polymeric drug delivery systems. The triblock copolymer (PEG-OPCL-PEG) consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic oxime-tethered polycaprolactone (OPCL) was successfully prepared by aminooxy terminals of OPCL ligating with aldehyde-terminated PEG (PEG-CHO). Owing to its amphiphilic architecture, PEG-OPCL-PEG self-assembled into the micelles in aqueous media, validated by the measurement of critical micelle concentration (CMC). The MTT assay showed that PEG-OPCL-PEG exhibited low cytotoxicity against NIH/3T3 normal cells. Doxorubicin (DOX) as a model drug was encapsulated into the PEG-OPCL-PEG micelles. Drug release study revealed that the DOX release from micelles was significantly accelerated at mildly acid pH of 5.0 compared to physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery systems with oxime linkages. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. MTT assay against HeLa cancer cells showed DOX-loaded PEG-OPCL-PEG micelles had a high anticancer efficacy. All of these results demonstrate that these polymeric micelles self-assembled from oxime-tethered block copolymers are promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites,  Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jin
authors.forename: Lian
authors.initials: L
authors.lastname: Song
authors.forename: Yue
authors.initials: Y
authors.lastname: Su
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Pang
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.forename: Gangsheng
authors.initials: G
authors.lastname: Tong
authors.forename: Deyue
authors.initials: D
authors.lastname: Yan
authors.forename: Bangshang
authors.initials: B
authors.lastname: Zhu
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers / Q000032:analysis / Q000138:chemical synthesis* / Q000378:metabolism; D015195:Drug Design; D004705:Endocytosis; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism; D011091:Polyesters / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D010091:Oximes; D011091:Polyesters; C016240:polycaprolactone; D011092:Polyethylene Glycols; D004317:Doxorubicin