Balancing the stability and drug release of polymer micelles by the coordination of dual-sensitive cleavable bonds in cross-linked core
Balancing the stability and drug release of polymer micelles by the coordination of dual-sensitive cleavable bonds in cross-linked core
复制标题
通过交联核心中双敏感可裂解键的协调来平衡聚合物胶束的稳定性和药物释放。
DOI：
10.1016/j.actbio.2014.09.047
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发表时间：
2015-01-01
影响因子：
9.7
通讯作者：
Dong, Anjie
中科院分区：
文献类型：
--
作者：
Deng, Hongzhang;Zhang, Yumin;Dong, Anjie
如何优化纳米载体的结构设计，抑制药物在血液循环中的提前释放，提高药物在肿瘤细胞内的释放，是聚合物胶束应用于抗肿瘤药物缓释的一个重要问题。为了平衡聚合物胶束稳定性和药物释放之间的矛盾，在两亲性共聚物胶束的核中引入了双敏感的可裂解的苯甲酰亚胺共轭二硫键交联，形成核交联胶束。首先，合成了可生物降解的聚（乙二醇）-B-（聚己内酯-g-聚（甲基丙烯酸-对羟基苯甲醛-胱胺）），即mPEG-B-（PCL-g-P（MAA-Hy-Cys））（PECMHC）共聚物，并组装成PECMHC胶束（PECMHC Ms）。然后，简单地通过向PECMHC Ms分散体中引入H2 O2以氧化核心中的胱胺部分的硫醇基团，在水中容易地获得尺寸类似于100 nm的核心交联的PECMHC胶束（cc-PECMHC Ms）。体外研究表明，由于胶束对广泛的稀释和盐浓度的高稳定性，交联的核心阻碍了药物在物理条件下的释放，而它大大加速了DOX在弱酸性条件下的释放。（pH类似于5.0-6.0）介质中的谷胱甘肽，由于苯甲酸亚胺键的pH敏感性裂解和二硫键的还原敏感性裂解的协调。通过DOX的荧光图像监测DOX负载的α-PECMHC M的体内组织分布和肿瘤积累。由于其在血液循环中的高稳定性和较少的DOX过早释放，负载DOX的α-PECMHC Ms表现出增强的肿瘤积累。因此，在交联核心中具有双敏感可裂解键的cc-PECMHC Ms具有优异的生物相容性、高细胞外稳定性和智能细胞内药物释放特性，表明有望作为抗癌药物递送的候选物。(C)2014 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
The optimal structure design of nanocarriers to inhibit premature release of anticancer drugs from nanocarriers during blood circulation and improve drug release inside tumor cells is still a significant issue for polymer micelles applied to antitumor drug delivery. Herein, in order to balance the contradiction between polymer micellar stability and drug release, dual-sensitive cleavable cross-linkages of benzoic imine conjugated disulfide bonds were introduced into the core of the amphiphilic copolymer micelles to form core-cross-linked micelles. First, biodegradable poly(ethylene glycol)-b-(polycaprolactone-g-poly(methacrylic acid-p-hydroxy benzaldehyde-cystamine)), i.e. mPEG-b-(PCL-g-P(MAA-Hy-Cys)) (PECMHC) copolymers were synthesized and assembled into PECMHC micelles (PECMHC Ms). Then, simply by introducing H2O2 to the PECMHC Ms dispersions to oxidate the thiol groups of cystamine moieties in the core, core-cross-linked PECMHC micelles (cc-PECMHC Ms) similar to 100 nm in size were readily obtained in water. In vitro studies of doxorubicin (DOX)-loaded cc-PECMHC Ms show that the cross-linked core impeded the drug release in the physical conditions, owing to the high stability of the micelles against both extensive dilution and salt concentration, while it greatly accelerated DOX release in mildly acidic (pH similar to 5.0-6.0) medium with glutathione, owing to the coordination of the pH-sensitive cleaving of benzoic imine bonds and the reduction-sensitive cleaving of disulfide bonds. The in vivo tissue distribution and tumor accumulation of the DOX-loaded cc-PECMHC Ms were monitored via fluorescence images of DOX. DOX-loaded cc-PECMHC Ms exhibited enhanced tumor accumulation because of their high stability in blood circulation and less DOX premature release. Therefore, the cc-PECMHC Ms with dual-sensitive cleavable bonds in the cross-linked core were of excellent biocompatibility, high extracellular stability and had intelligent intracellular drug release properties, indicating promise as candidates for anticancer drug delivery. (C) 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.