In vivo and in vitro anti-cancer activity of thermo-sensitive and photo-crosslinkable doxorubicin hydrogels composed of chitosan-doxorubicin conjugates
In vivo and in vitro anti-cancer activity of thermo-sensitive and photo-crosslinkable doxorubicin hydrogels composed of chitosan-doxorubicin conjugates
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DOI：
10.1016/j.ejpb.2009.04.010
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发表时间：
2009-09-01
影响因子：
4.9
通讯作者：
Yoo, Hyuk Sang
中科院分区：
文献类型：
--
作者：
Cho, Young Il;Park, Shinyoung;Yoo, Hyuk Sang
将阿霉素化学偶联到丙烯酸化壳聚糖上，以获得阿霉素从温敏和光交联水凝胶中的缓释特性。壳寡糖与甲基丙烯酸缩水甘油酯进行丙烯酸酯化，随后通过酰胺键与多柔比星缀合。多柔比星-壳聚糖缀合物、丙烯酸化的普朗尼克和多柔比星的混合物在37 ℃下形成物理凝胶。随后进行光照射以在37 ℃下化学交联物理水凝胶。与没有缀合物的水凝胶相比，多柔比星水凝胶中的壳寡糖-多柔比星缀合物显著降低了游离多柔比星从多柔比星水凝胶的突释。在37 ° C下孵育多柔比星水凝胶后，通过反相色谱法证实壳聚糖-多柔比星缀合物降解成更亲水的低聚物。使用从阿霉素水凝胶释放的介质的体外细胞毒性测定显示降解的壳聚糖-阿霉素具有与游离阿霉素相当的细胞毒性。对携带人肺腺癌的无胸腺裸鼠进行物理水凝胶的肿瘤内注射。在使用手术导管光交联注射水凝胶后，测量肿瘤大小、体重和存活1个月。多柔比星水凝胶释放的培养基表现出与游离多柔比星相似的细胞毒性，与其他样品相比，肿瘤体积显著减少1个月。因此，含有多柔比星缀合物的多柔比星水凝胶可用作新型可注射抗癌药物，旨在实现多柔比星针对实体瘤的持续释放数周。(c)2009爱思唯尔有限公司版权所有。
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. (c) 2009 Elsevier B.V. All rights reserved.