title: In vivo and in vitro anti-cancer activity of thermo-sensitive and photo-crosslinkable doxorubicin hydrogels composed of chitosan-doxorubicin conjugates.
abstract: Doxorubicin was chemically conjugated to acrylated chitosan in order to obtain sustained-release profiles of doxorubicin from thermo-responsive and photo-crosslinkable hydrogels. Chitooligosaccharide was acrylated with glycidyl methacrylate and subsequently conjugated to doxorubicin via an amide linkage. A mixture of doxorubicin-chitosan conjugates, acrylated Pluronic, and doxorubicin formed physical gels at 37 degrees C. Photo-irradiation was subsequently performed to chemically crosslink the physical hydrogel at 37 degrees C. Chitooligosaccharide-doxorubicin conjugates in the doxorubicin hydrogels significantly reduced burst release of free doxorubicin from doxorubicin hydrogels compared hydrogels without the conjugates. Upon incubating doxorubicin hydrogels at 37 degrees C, chitosan-doxorubicin conjugates were confirmed to be degraded into more hydrophilic oligomers by reversed-phase chromatography. In vitro cytotoxicity assay using released media from doxorubicin hydrogels showed that degraded chitosan-doxorubicin had cytotoxicity comparable to free doxorubicin. Athymic nude mice bearing human lung adenocarcinoma were subjected to intra-tumoral injections of physical hydrogels. After photo-crosslinking injected hydrogels using surgical catheters, tumor sizes, body weights, and survivals were measured for 1 month. Released media from doxorubicin hydrogels exerted similar cytotoxicities to free doxorubicin, and the tumor volume was significantly reduced for 1 month compared to other samples. Thus, doxorubicin hydrogels containing doxorubicin conjugates can be employed as a novel injectable anti-cancer drug aiming to achieve sustained release of doxorubicin for several weeks against solid tumors.
authors.affiliation: Department of Life and Nanomedcine, Kyunghee University, Seoul, Republic of Korea.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Cho
authors.forename: Shinyoung
authors.initials: S
authors.lastname: Park
authors.forename: Seo Young
authors.initials: SY
authors.lastname: Jeong
authors.forename: Hyuk Sang
authors.initials: HS
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000737:chemistry; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D004338:Drug Combinations; D006358:Hot Temperature / Q000009:adverse effects*; D006801:Humans; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry*; D008027:Light; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D020100:Hydrogels; D004317:Doxorubicin; D048271:Chitosan