title: Bioreducible core-crosslinked hyaluronic acid micelle for targeted cancer therapy.
abstract: For drug delivery nanocarriers to be a safe and effective therapeutic option, blood stability, tumor-targetability, and intracellular drug release features should be considered. In this study, to develop a potent drug delivery carrier that can meet the multiple requirements, we engineered a bioreducible core-crosslinked polymeric micelle based on hyaluronic acid (CC-HAM) by a facile method using d,l-dithiothreitol in aqueous conditions. The CC-HAM exhibited enhanced structural stability under diluted conditions with PBS containing FBS or sodium dodecyl sulfates. We also successfully encapsulated doxorubicin (DOX), chosen as a hydrophobic anti-cancer drug, in CC-HAMs with high loading efficiency (>80%). The drug release rate of CC-HAMs was rapidly accelerated in the presence of glutathione, whereas the drug release was significantly retarded in physiological buffer (pH7.4). An in vivo biodistribution study demonstrated the superior tumor targetability of CC-HAMs to that of non-crosslinked HAMs, primarily ascribed to robust stability of CC-HAMs in the bloodstream. Notably, these results correspond with the improved pharmacokinetics and tumor accumulation of DOX-loaded CC-HAMs as well as their excellent therapeutic efficacy. Overall, these results suggest that the robust, bioreducible CC-HAM can be applied as a potent doxorubicin delivery carrier for targeted cancer therapy.
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hwa Seung
authors.initials: HS
authors.lastname: Han
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Choi
authors.affiliation: Department of Health Sciences Technology, SAIHST, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Ko
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jueun
authors.initials: J
authors.lastname: Jeon
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: G
authors.initials: G
authors.lastname: Saravanakumar
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea; NanoBio Fusion Research Center, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Yung Doug
authors.initials: YD
authors.lastname: Suh
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Doo Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea; Department of Health Sciences Technology, SAIHST, Sungkyunkwan University, Suwon 440-746, Republic of Korea; NanoBio Fusion Research Center, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. Electronic address: jhpark1@skku.edu.
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D065546:Drug Liberation; D004355:Drug Stability; D005978:Glutathione / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry*; D008819:Mice, Nude; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D008823:Micelles; D004317:Doxorubicin; D006820:Hyaluronic Acid; D005978:Glutathione
keywords: Crosslinked nanoparticle; Doxorubicin; Drug delivery; Hyaluronic acid; Stability