title: Bioreducible carboxymethyl dextran nanoparticles for tumor-targeted drug delivery.
abstract: Bioreducible carboxymethyl dextran (CMD) derivatives are synthesized by the chemical modification of CMD with lithocholic acid (LCA) through a disulfide linkage. The hydrophobic nature of LCA allows the conjugates (CMD-SS-LCAs) to form self-assembled nanoparticles in aqueous conditions. Depending on the degree of LCA substitution, the particle diameters range from 163 to 242 nm. Doxorubicin (DOX), chosen as a model anticancer drug, is effectively encapsulated into the nanoparticles with high loading efficiency (>70%). In vitro optical imaging tests reveal that the fluorescence signal of DOX quenched in the bioreducible nanoparticles is highly recovered in the presence of glutathione (GSH), a tripeptide capable of reducing disulfide bonds in the intracellular compartments. Bioreducible nanoparticles rapidly release DOX when they are incubated with 10 mm GSH, whereas the drug release is greatly retarded in physiological buffer (pH 7.4). DOX-loaded bioreducible nanoparticles exhibit higher toxicity to SCC7 cancer cells than DOX-loaded nanoparticles without the disulfide bond. Confocal laser scanning microscopy observation demonstrate that bioreducible nanoparticles can effectively deliver DOX into the nuclei of SCC7 cells. In vivo biodistribution study indicates that Cy5.5-labeled CMD-SS-LCAs selectively accumulate at tumor sites after systemic administration into tumor-bearing mice. Notably, DOX-loaded bioreducible nanoparticles exhibit higher antitumor efficacy than reduction-insensitive control nanoparticles. Overall, it is evident that bioreducible CMD-SS-LCA nanoparticles are useful as a drug carrier for cancer therapy.
authors.affiliation: School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
authors.forename: Thavasyappan
authors.initials: T
authors.lastname: Thambi
authors.forename: Dong Gil
authors.initials: DG
authors.lastname: You
authors.forename: Hwa Seung
authors.initials: HS
authors.lastname: Han
authors.forename: V G
authors.initials: VG
authors.lastname: Deepagan
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Jeon
authors.forename: Yung Doug
authors.initials: YD
authors.lastname: Suh
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Choi
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.forename: Gi-Ra
authors.initials: GR
authors.lastname: Yi
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Doo Sung
authors.initials: DS
authors.lastname: Lee
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D003911:Dextrans / Q000008:administration & dosage* / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005978:Glutathione / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010316:Particle Size; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D004337:Drug Carriers; D004317:Doxorubicin; C014392:carboxymethyl dextran; D005978:Glutathione
keywords: bioreducible nanoparticle; carboxymethyl-dextran; doxorubicin; drug delivery