Chen Yi-Chun, Chang Chang-Jung, Hsiue Ging-Ho, Chiang Yi-Ting
Department of Forestry, National Chung Hsing University, Taichung City 402, Taiwan.
Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
Cancers (Basel). 2021 Jul 29;13(15):3816. doi: 10.3390/cancers13153816.
In this study, a graft copolymer, poly(-(2-hydroxypropyl) methacrylamide dilactate)--(-(2-hydroxypropyl) methacrylamide--histidine)-graft-poly(d,l-lactide), and a diblock copolymer, methoxy poly(ethylene glycol)--poly(d,l-lactide), were assembled into a mixed micellar system to encapsulate the anticancer drug doxorubicin (Dox). This mixed micellar system possesses the hydrophobic lactide segment of both copolymers, which reinforces its stability in physiological milieus; the histidine molecules appended on the graft copolymer provide the desired pH-responsive behavior to release Dox during internalization in cancer cells. The results demonstrate that the two copolymers were successfully prepared, and their ratios in the mixed micelles were optimized on the basis of the results of the stability tests. Under acidic conditions, the mixed micelles swell and are able to release their payloads. Therefore, the in vitro results indicate that the Dox in the mixed micelles is released effectively in response to the environmental pH of the mimetic internalization process, increasing cancer cells' sensitivity toward Dox. The mixed micelles display low cytotoxicity due to the degradability of the polymers. The in vivo images show that the high stability of the mixed micelles ensures a high tumor accumulation. This selective tumor accumulation results in an excellent inhibition of in vivo tumor growth and a high rate of apoptosis in cancerous tissues, with low toxicity. This highly stable, mixed micellar system with a pH-dependent drug release, which enables the precise delivery of drugs to the tumor lesions, is feasible to employ clinically in cancer therapy.
在本研究中，将接枝共聚物聚（-（2-羟丙基）甲基丙烯酰胺二乳酸）-（-（2-羟丙基）甲基丙烯酰胺-组氨酸）-接枝-聚（d，l-丙交酯）和二嵌段共聚物甲氧基聚（乙二醇）-聚（d，l-丙交酯）组装成混合胶束系统，用于包封抗癌药物阿霉素（Dox）。该混合胶束系统具有两种共聚物的疏水丙交酯链段，这增强了其在生理环境中的稳定性；接枝共聚物上连接的组氨酸分子提供了所需的pH响应行为，以便在癌细胞内化过程中释放Dox。结果表明，成功制备了两种共聚物，并根据稳定性测试结果优化了它们在混合胶束中的比例。在酸性条件下，混合胶束膨胀并能够释放其负载物。因此，体外结果表明，混合胶束中的Dox能有效地响应模拟内化过程的环境pH值而释放，从而提高癌细胞对Dox的敏感性。由于聚合物的可降解性，混合胶束显示出低细胞毒性。体内成像表明，混合胶束的高稳定性确保了高肿瘤蓄积。这种选择性肿瘤蓄积导致体内肿瘤生长受到出色抑制，癌组织中凋亡率高，且毒性低。这种具有pH依赖性药物释放的高度稳定的混合胶束系统能够将药物精确递送至肿瘤病灶，在癌症治疗中临床应用是可行的。
