Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.
Tianjin Key Laboratory of Radiation Molecular and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.
Acta Biomater. 2015 Jan;11:126-36. doi: 10.1016/j.actbio.2014.09.047. Epub 2014 Oct 5.
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) ∼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 ∼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.
为了平衡聚合物胶束的稳定性与药物释放之间的矛盾，将苯亚胺共轭二硫键的双敏感可裂解交联键引入两亲性共聚物胶束的核心，以形成核交联胶束。首先，合成可生物降解的聚乙二醇-b-（聚己内酯-g-聚（甲基丙烯酸-p-羟基苯甲醛-胱胺）），即 mPEG-b-（PCL-g-P（MAA-Hy-Cys））（PECMHC）共聚物，并将其组装成 PECMHC 胶束（PECMHC Ms）。然后，只需将 H2O2 引入 PECMHC Ms 分散体中以氧化核心中胱胺部分的巯基，即可在水中轻易获得尺寸约为 100nm 的核交联 PECMHC 胶束（cc-PECMHC Ms）。载阿霉素（DOX）的 cc-PECMHC Ms 的体外研究表明，交联核阻碍了物理条件下的药物释放，这是由于胶束对广泛稀释和盐浓度都具有很高的稳定性，而在具有谷胱甘肽的轻度酸性（pH ∼5.0-6.0）介质中，由于苯亚胺键的 pH 敏感裂解和二硫键的还原敏感裂解的协调，DOX 释放大大加速。通过 DOX 的荧光图像监测载 DOX 的 cc-PECMHC Ms 的体内组织分布和肿瘤积累。载 DOX 的 cc-PECMHC Ms 由于在血液循环中具有高稳定性和较少的 DOX 过早释放，因此表现出增强的肿瘤积累。因此，具有交联核中双敏感可裂解键的 cc-PECMHC Ms 具有优异的生物相容性、高细胞外稳定性和智能的细胞内药物释放特性，有望成为抗癌药物输送的候选物。
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