A surface charge-switchable and folate modified system for co-delivery of proapoptosis peptide and p53 plasmid in cancer therapy
A surface charge-switchable and folate modified system for co-delivery of proapoptosis peptide and p53 plasmid in cancer therapy
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表面电荷可切换和叶酸修饰系统，用于在癌症治疗中共同递送促凋亡肽和 p53 质粒
DOI：
10.1016/j.biomaterials.2015.11.013
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发表时间：
2016-01-01
期刊：
影响因子：
14
通讯作者：
Zhang, Xian-Zheng
中科院分区：
文献类型：
--
作者：
Chen, Si;Rong, Lei;Zhang, Xian-Zheng
为了提高肿瘤治疗效率并减少不良副作用，设计了具有可分离表面屏蔽层的三元FK/p53/PEG - PLL(DA)复合物。FK/p53/PEG - PLL(DA)复合物是通过静电作用，用电荷可转换的PEG屏蔽层（PEG - PLL(DA)）包裹结合了叶酸的带正电荷的FK/p53复合物而制成的。在血液中生理pH值为7.4的条件下，PEG - PLL(DA)可通过屏蔽带正电荷的FK/p53复合物来延长循环时间。在FK/p53/PEG - PLL(DA)复合物在肿瘤部位聚集后，肿瘤酸性触发的电荷转换导致PEG - PLL(DA)从FK/p53复合物上脱离，并通过叶酸介导的摄取和静电吸引实现高效的肿瘤细胞进入。在细胞质中高含量谷胱甘肽（GSH）的刺激下，二硫键的断裂导致促凋亡肽C - KLA(TPP)和p53基因的释放，通过调节内源性和外源性凋亡途径发挥联合肿瘤治疗作用。体外和体内研究均证实，三元可分离复合物FK/p53/PEG - PLL(DA)能够提高抗肿瘤疗效并减少对正常细胞的不良影响。这些发现表明，肿瘤触发的FK/p53/PEG - PLL(DA)解复合为协同抗癌治疗中不同治疗药物的靶向递送提供了一种有用的策略。（C）2015爱思唯尔有限公司。保留所有权利。
To improve the tumor therapeutic efficiency and reduce undesirable side effects, ternary FK/p53/PEG-PLL(DA) complexes with a detachable surface shielding layer were designed. The FK/p53/PEG-PLL(DA) complexes were fabricated by coating the folate incorporated positively charged FK/p53 complexes with charge-switchable PEG-shield (PEG-PLL(DA)) through electrostatic interaction. At the physiological pH 7.4 in the bloodstream, PEG-PLL(DA) could extend the circulating time by shielding the positively charged FK/p53 complexes. After the accumulation of the FK/p53/PEG-PLL(DA) complexes in tumor sites, tumor-acidity-triggered charge switch led to the detachment of PEG-PLL(DA) from the FK/p53 complexes, and resulted in efficient tumor cell entry by folate-mediated uptake and electrostatic attraction. Stimulated by the high content glutathione (GSH) in cytoplasm, the cleavage of disulfide bond resulted in the liberation of proapoptosis peptide C-KLA(TPP) and the p53 gene, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. Both in vitro and in vivo studies confirmed that the ternary detachable complexes FK/p53/PEG-PLL(DA) could enhance antitumor efficacy and reduce adverse effects to normal cells. These findings indicate that the tumor-triggered decomplexation of FK/p53/PEG-PLL(DA) supplies a useful strategy for targeting delivery of different therapeutic agents in synergetic anticancer therapy. (C) 2015 Elsevier Ltd. All rights reserved.