Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy.
Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy.
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DOI：
10.1016/j.jconrel.2017.05.006
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发表时间：
2017-07-28
期刊：
影响因子：
--
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Sun J;Liu Y;Chen Y;Zhao W;Zhai Q;Rathod S;Huang Y;Tang S;Kwon YT;Fernandez C;Venkataramanan R;Li S
设计了两种新型的前药聚合物POEG-b-PSSDas（氧化还原敏感型）和POEG-b-PCCDas（氧化还原不敏感型），它们分别由聚（低聚乙二醇）甲基丙烯酸酯（POEG）亲水性嵌段和达沙替尼（DAS，一种致癌酪氨酸激酶抑制剂）结合的疏水性嵌段组成，作为与阿霉素（DOX）共递送的双功能载体。两种载体均保留了DAS的抗肿瘤活性，并能与DOX形成混合胶束。与POEG-b-PCCDas胶束相比，POEG-b-PSSDas胶束中二硫键的引入促进了DAS在肿瘤细胞/组织中从前药胶束中的有效切割，从而导致更高水平的体外和体内抗肿瘤活性。此外，DOX负载的POEG-b-PSSDas胶束在氧化还原环境（10 mM谷胱甘肽，GSH）下表现出触发DOX释放，并表现出与DOX和DOX负载的POEG-b-PCCDas胶束相比增强的对4T1.2和PC 3细胞系的细胞毒性。更重要的是，与DOX-负载的POEG-b-PCCDas胶束和DOX和DAS共负载的胶束制剂相比，DOX-负载的POEG-b-PSSDas胶束在抑制肿瘤生长和延长侵袭性鼠乳腺癌模型（4T1.2）中的存活率方面更有效。这种对氧化还原反应敏感的前药胶束系统为肿瘤靶向治疗和传统化疗的有效结合提供了一种有吸引力的策略，值得进一步研究。
Two novel prodrug polymers POEG-b-PSSDas (redox-sensitive) and POEG-b-PCCDas (redox-insensitive), which consist of poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic blocks and dasatinib (DAS, an oncogenic tyrosine kinases inhibitor) conjugated hydrophobic blocks, were designed as dual-functional carriers for codelivery with doxorubicin (DOX). Both carriers retained antitumor activity of DAS and could form mixed micelles with DOX. Compared to POEG-b-PCCDas micelles, incorporation of disulfide linkage into POEG-b-PSSDas micelles facilitated efficient cleavage of DAS from prodrug micelles in tumor cells/tissues, leading to a higher level of anti-tumor activity in vitro and in vivo. In addition, DOX-loaded POEG-b-PSSDas micelles exhibited triggered DOX release under a redox environment (10 mM glutathione, GSH), and demonstrated enhanced cytotoxicity against 4T1.2 and PC3 cell lines compared to DOX and DOX-loaded POEG-b-PCCDas micelles. More importantly, DOX-loaded POEG-b-PSSDas micelles were more effective in inhibiting the tumor growth and prolonging the survival rate in an aggressive murine breast cancer model (4T1.2) compared to DOX-loaded POEG-b-PCCDas micelles and a micellar formulation co-loaded with DOX and DAS. This redox-responsive prodrug micellar system provides an attractive strategy for effective combination of tumor targeted therapy and traditional chemotherapy, which warrants further investigation.
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影响因子：
8.8
作者：
通讯作者：
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影响因子：
5.8
作者：
Li, Qingqing;Lai, Ka Lun;Lee, Thomas W. Y.
通讯作者：
Lee, Thomas W. Y.
影响因子：
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作者：
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通讯作者：
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DOI：
10.1016/j.jconrel.2015.01.026
发表时间：
2015-03-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
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通讯作者：
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影响因子：
9.7
作者：
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通讯作者：
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