School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
Biomacromolecules. 2011 Oct 10;12(10):3460-8. doi: 10.1021/bm200956u. Epub 2011 Sep 7.
Oxime bonds dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their own niche. In the present work, oxime linkages were confirmed to be a robust tool for the design of pH-sensitive polymeric drug delivery systems. The triblock copolymer (PEG-OPCL-PEG) consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic oxime-tethered polycaprolactone (OPCL) was successfully prepared by aminooxy terminals of OPCL ligating with aldehyde-terminated PEG (PEG-CHO). Owing to its amphiphilic architecture, PEG-OPCL-PEG self-assembled into the micelles in aqueous media, validated by the measurement of critical micelle concentration (CMC). The MTT assay showed that PEG-OPCL-PEG exhibited low cytotoxicity against NIH/3T3 normal cells. Doxorubicin (DOX) as a model drug was encapsulated into the PEG-OPCL-PEG micelles. Drug release study revealed that the DOX release from micelles was significantly accelerated at mildly acid pH of 5.0 compared to physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery systems with oxime linkages. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. MTT assay against HeLa cancer cells showed DOX-loaded PEG-OPCL-PEG micelles had a high anticancer efficacy. All of these results demonstrate that these polymeric micelles self-assembled from oxime-tethered block copolymers are promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.
肟键分散在合成聚合物的主链中，虽然在当前的生物医学应用中还处于起步阶段，但正在迅速扩展到自己的领域。在本工作中，肟键被证实是设计 pH 敏感型聚合物药物传递系统的一种稳健工具。三嵌段共聚物（PEG-OPCL-PEG）由亲水性聚乙二醇（PEG）和疏水性肟键合的聚己内酯（OPCL）组成，通过 OPCL 的氨氧基末端与醛基封端的 PEG（PEG-CHO）连接成功制备。由于其两亲性结构，PEG-OPCL-PEG 在水介质中自组装成胶束，通过临界胶束浓度（CMC）的测量得到验证。MTT 测定表明，PEG-OPCL-PEG 对 NIH/3T3 正常细胞的细胞毒性较低。阿霉素（DOX）作为模型药物被包封到 PEG-OPCL-PEG 胶束中。药物释放研究表明，与生理 pH 值 7.4 相比，在温和酸性 pH 值 5.0 下，DOX 从胶束中的释放明显加快，表明具有肟键的药物传递系统具有 pH 响应特性。流式细胞术和共聚焦激光扫描显微镜（CLSM）测量表明，这些载 DOX 的胶束很容易被活细胞内化。针对 HeLa 癌细胞的 MTT 测定表明，载 DOX 的 PEG-OPCL-PEG 胶束具有很高的抗癌功效。所有这些结果表明，由肟键合嵌段共聚物自组装而成的这些聚合物胶束是用于 pH 触发的疏水性抗癌药物细胞内传递的有前途的载体。
