Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly.
Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly.
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DOI：
10.1038/srep12023
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发表时间：
2015-07-13
影响因子：
4.6
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Fu Q;Wang Y;Ma Y;Zhang D;Fallon JK;Yang X;Liu D;He Z;Liu F
递送前药的纳米载体是提高体内有效性和效率的一种方式。为了治疗功效，前药必须在给药后水解成其母体药物。基于空间位阻对水解的阻碍作用和足够的极性对水解的促进作用，本研究提出了紫杉醇（PTX）与维生素E（VE）通过二硫键连接的方法，即PTX-S-S-VE。该偶联物具有以下优点：（1）由于良好的疏水相互作用，可将其包封在VE/VE 2-PEG 2000/水纳米乳中;最后，肿瘤微环境中的浓缩谷胱甘肽可切割二硫键，从而削弱空间位阻并增加极性，促进水解为PTX，提高抗癌活性。体外实验表明，PTX-S-S-VE的水解作用增强，细胞毒性增强。此外，PTX-S-S-VE对KB-3-1细胞系肿瘤异种移植物具有更大的抗癌活性，并且在第4次注射后肿瘤尺寸更小。目前的结果表明，一种新的方法，使用还原，以提高体内抗癌活性的前药的纳米载体交付通过解除屏蔽酯键和起飞的空间位阻。
Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4th injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.
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影响因子：
5.8
作者：
Jiang, Tao;Li, You-Mei;Zhuo, Ren-Xi
通讯作者：
Zhuo, Ren-Xi
DOI：
10.1073/pnas.97.2.745
发表时间：
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影响因子：
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作者：
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