title: pH-triggered intracellular release from actively targeting polymer micelles.
abstract: Chemotherapy is widely applied to treat cancer patients but its application is limited due to the systemic toxicity and low efficacy. Nanocarrier system, which is capable of delivering their toxic cargos specifically into cancer cells and then greatly overcomes these disadvantages, has drawn a broad attention. Here we developed a drug-conjugated micelle for a better drug delivery in which folic acid was attached to the DOX-conjugated poly(ethylene glycol)-poly(ε-caprolactone) to target tumor; DOX was further connected with a hydrazone linker (FA-hyd) for a pH-triggered drug release. Comparing to other DOX-conjugated micelles either linked with carbamate (FA-cbm) or lacking FA(m-hyd), the developed FA-hyd demonstrated excellent biocompatibility; When analyzed with Alamar blue assays, flow cytometry and confocal laser scanning microscopy (CLSM), the pH-sensitive FA-functionalized DOX-conjugated micelles presented much better efficiency of cellular uptake and higher cytotoxicity to tumor cells. In vivo pharmacokinetics and biodistribution studies indicated that FA-hyd micelles significantly prolonged the blood circulation time of drug and enriched drug into the tumors rather than normal tissues. In vivo antitumor activity demonstrated that FA-hyd micelles had the highest safety to body and the best therapeutic efficacy to tumors. Therefore, this drug delivery system is deemed as a potential nanocarrier for cancer therapy.
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.forename: Chunli
authors.initials: C
authors.lastname: Shi
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Shubin
authors.initials: S
authors.lastname: Di
authors.forename: Shaobing
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005453:Fluorescence; D005492:Folic Acid / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D018613:Microscopy, Confocal; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D011355:Prodrugs / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011091:Polyesters; D011108:Polymers; D011355:Prodrugs; C016240:polycaprolactone; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid