A pH-sensitive doxorubicin prodrug based on folate-conjugated BSA for tumor-targeted drug delivery
A pH-sensitive doxorubicin prodrug based on folate-conjugated BSA for tumor-targeted drug delivery
复制标题
基于叶酸缀合 BSA 的 pH 敏感阿霉素前药，用于肿瘤靶向药物递送
DOI：
10.1016/j.biomaterials.2013.01.041
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发表时间：
2013-04-01
期刊：
影响因子：
14
通讯作者：
Gu, Yueqing
中科院分区：
文献类型：
--
作者：
Du, Changli;Deng, Dawei;Gu, Yueqing
多柔比星（DOX）是最有效的抗癌药物之一，但其非特异性递送至靶组织以及由此产生的累积心脏毒性和肾毒性极大地阻碍了其治疗功效。为了克服这一局限性，我们制备了叶酸-牛血清白蛋白（BSA）-顺乌头酸-阿霉素前药，表示为FA-BSA-CAD。将肿瘤靶向剂叶酸连接到BSA以增加缀合物的选择性靶向能力。BSA为生物活性分子的多价偶联提供了大量的反应位点，并提高了前药的水溶性。DOX通过pH敏感性接头顺式乌头酸酐连接到BSA，顺式乌头酸酐在酸性溶酶体环境中水解以允许DOX的pH响应性释放。体外结果表明在不同pH条件下的pH响应性药物释放。此外，在体外和体内评估前药的靶向能力和治疗功效。结果表明FA-BSA-CAD前药选择性靶向肿瘤细胞和组织，对正常细胞的非特异性毒性降低。更重要的是，与未缀合的DOX相比，前药对FA阳性肿瘤的治疗功效增加。(C)2013爱思唯尔有限公司保留所有权利。
Doxorubicin (DOX) is one of the most effective anti-cancer drugs, but its therapeutic efficacy is greatly hampered by its non-specific delivery to the target tissue and the resultant cumulative cardiotoxicity and nephrotoxicity. In order to overcome this limitation, we prepared a folate-bovine serum albumin (BSA)-cis-aconitic anhydride-doxorubicin prodrug, denoted by FA-BSA-CAD. A tumor-targeting agent, folic acid, was linked to BSA to increase the selective targeting ability of the conjugate. BSA provided a large number of reactive sites for multivalent coupling of bioactive molecules and improved the water-solubility of the prodrug. DOX is attached to the BSA via a pH-sensitive linker, cis-aconitic anhydride, which hydrolyzes in the acidic lysosomal environment to allow pH-responsive release of DOX. The in vitro results demonstrate a pH-responsive drug release under different pH conditions. Furthermore, the targeting ability and therapeutic efficacy of the prodrug were assessed both in vitro and in vivo. The results demonstrate that FA-BSA-CAD prodrug selectively targeted tumor cells and tissue, with associated reduction in non-specific toxicity to the normal cells. More importantly, the therapeutic efficacy of the prodrug for FA-positive tumors increased compared to the non-conjuagted DOX. (C) 2013 Elsevier Ltd. All rights reserved.