Synergistic antitumor activity of camptothecin-doxorubicin combinations and their conjugates with hyaluronic acid.
Synergistic antitumor activity of camptothecin-doxorubicin combinations and their conjugates with hyaluronic acid.
复制标题
DOI：
10.1016/j.jconrel.2015.04.031
复制
发表时间：
2015-07-28
期刊：
影响因子：
--
通讯作者：
Mitragotri S
中科院分区：
文献类型：
--
作者：
Camacho KM;Kumar S;Menegatti S;Vogus DR;Anselmo AC;Mitragotri S
已发现拓扑异构酶抑制剂I和II的组合在体外协同抑制癌细胞生长，但这些类型的组合的临床研究尚未进展超过II期试验。拓扑异构酶（顶部）I和II抑制剂的临床组合的结果通常属于两类之一：与单一药物对应物相比，治疗功效几乎没有改善或毒性增加。因此，尽管前I和II抑制剂组合在体外具有有希望的活性，但其临床适用性尚未实现。在这里，我们报告了使用聚合物-药物缀合物作为一种手段，共同提供协同剂量的前I和II抑制剂喜树碱（CPT）和阿霉素（DOX）在体内肿瘤的4 T1乳腺癌模型。在特定的摩尔比下，发现DOX和CPT是迄今为止报道的最协同的组合，组合指数在0.01和0.1之间。将鉴定的最佳比例可控地缀合至透明质酸，并且当静脉内施用时引起鼠4 T1乳腺癌模型的显著肿瘤减少。本研究阐明了一种方法，以确定协同药物组合，并将其转化为体内通过保持协同比通过共轭载体聚合物，从而打开了一个有前途的方法，将药物组合转化为临床可行的治疗方案。
Combinations of topoisomerase inhibitors I and II have been found to synergistically inhibit cancer cell growth in vitro, yet clinical studies of these types of combinations have not progressed beyond phase II trials. The results of clinical combinations of topoisomerase (top) I and II inhibitors typically fall within one of two categories: little to no improvement in therapeutic efficacy, or augmented toxicity compared to the single drug counterparts. Hence, despite the promising activity of top I and II inhibitor combinations in vitro, their clinical applicability has not been realized. Here, we report the use of polymer-drug conjugates as a means to co-deliver synergistic doses of top I and II inhibitors camptothecin (CPT) and doxorubicin (DOX) to tumors in vivo in a 4T1 breast cancer model. At specific molar ratios, DOX and CPT were found to be among the most synergistic combinations reported to date, with combination indices between 0.01 and 0.1. The identified optimal ratios were controllably conjugated to hyaluronic acid, and elicited significant tumor reduction of murine 4T1 breast cancer model when administered intravenously. This study elucidates a method to identify synergistic drug combinations and translate them to in vivo by preserving the synergistic ratio via conjugation to a carrier polymer, thus opening a promising approach to translate drug combinations to clinically viable treatment regimens.
登录
查看更多内容
DOI：
10.1186/bcr1530
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fantozzi A;Christofori G
通讯作者：
Christofori G
影响因子：
3.8
作者：
Budman, DR;Calabro, A
通讯作者：
Calabro, A
影响因子：
3.5
作者：
Budman, DR;Calabro, A
通讯作者：
Calabro, A
影响因子：
4.8
作者：
Chen, Yunching;Bathula, Surendar Reddy;Huang, Leaf
通讯作者：
Huang, Leaf
影响因子：
15.9
作者：
Krauze, Michal T.;Noble, Charles O.;Bankiewicz, Krystof S.
通讯作者：
Bankiewicz, Krystof S.