In vivo and in vitro anti-cancer activity of thermo-sensitive and photo-crosslinkable doxorubicin hydrogels composed of chitosan-doxorubicin conjugates.
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.
Cho
Young Il
YI
Department of Life and Nanomedcine, Kyunghee University, Seoul, Republic of Korea.
Park
Shinyoung
S
Jeong
Seo Young
SY
Yoo
Hyuk Sang
HS
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
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D020100:Hydrogels; D004317:Doxorubicin; D048271:Chitosan