Doxorubicin-Loaded Mixed Micelles Using Degradable Graft and Diblock Copolymers to Enhance Anticancer Sensitivity.
Doxorubicin-Loaded Mixed Micelles Using Degradable Graft and Diblock Copolymers to Enhance Anticancer Sensitivity.
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使用可降解接枝和二嵌段共聚物的载阿霉素混合胶束以提高抗癌敏感性
DOI：
10.3390/cancers13153816
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发表时间：
2021-07-29
期刊：
影响因子：
5.2
通讯作者：
Chiang YT
中科院分区：
文献类型：
--
作者：
Chen YC;Chang CJ;Hsiue GH;Chiang YT
在这项研究中，一种可降解接枝共聚物聚（N -（2 - 羟丙基）甲基丙烯酰胺二乳酸酯） - 共 -（N -（2 - 羟丙基）甲基丙烯酰胺 - 共 - 组氨酸） - 接枝 - 聚（D，L - 丙交酯）和一种二嵌段共聚物甲氧基聚（乙二醇） - b - 聚（D，L - 丙交酯）被组装成一种长循环且pH响应的混合胶束系统，用于负载抗癌药物阿霉素。体外实验结果表明，该胶束系统在癌细胞中显示出高生物安全性和细胞内药物释放行为。此外，体内实验结果显示，混合胶束的高稳定性导致其在肿瘤部位的高聚集，从而对肿瘤生长有出色的抑制作用。这种由可降解二嵌段和接枝共聚物组成的混合胶束系统能够提高癌细胞对阿霉素的敏感性，在癌症治疗中进一步临床应用是可行的。
在这项研究中，一种接枝共聚物聚（N -（2 - 羟丙基）甲基丙烯酰胺二乳酸酯） - 共 -（N -（2 - 羟丙基）甲基丙烯酰胺 - 共 - 组氨酸） - 接枝 - 聚（D，L - 丙交酯）和一种二嵌段共聚物甲氧基聚（乙二醇） - b - 聚（D，L - 丙交酯）被组装成一种混合胶束系统以包封抗癌药物阿霉素（Dox）。这种混合胶束系统具有两种共聚物的疏水性丙交酯链段，这增强了它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，两种共聚物制备成功，并且根据稳定性测试结果对它们在混合胶束中的比例进行了优化。在酸性条件下，混合胶束膨胀并能够释放其负载物。因此，体外实验结果表明，混合胶束中的Dox能够有效响应模拟内化过程的环境pH而释放，提高了癌细胞对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。体内成像显示，混合胶束的高稳定性确保了在肿瘤部位的高聚集。这种选择性的肿瘤聚集导致体内肿瘤生长得到出色抑制，癌组织中的细胞凋亡率高，且毒性低。这种高度稳定、具有pH依赖性药物释放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。
In this study, a long-circulating and pH responsive mixed micellar system was assembled with a degradable graft copolymer, poly(N-(2-hydroxypropyl) methacrylamide dilactate)-co-(N-(2-hydroxypropyl) methacrylamide-co-histidine)-graft-poly(d,l-lactide), and a diblock copolymer, methoxy poly(ethylene glycol)-b-poly(d,l-lactide) to load with the anticancer agent doxorubicin. The in vitro results indicate that the micellar system display high biosafety and intracellular drug-releasing behavior in cancer cells. Furthermore, the in vivo results show that the high stability of the mixed micelles leads to a high tumor accumulation and hence an excellent inhibition of tumor growth. This mixed micellar system, comprising degradable diblock and graft copolymers enables one to increase cancer cells’ sensitivity toward doxorubicin (Dox) and is feasible for further clinical use in cancer therapy. In this study, a graft copolymer, poly(N-(2-hydroxypropyl) methacrylamide dilactate)-co-(N-(2-hydroxypropyl) methacrylamide-co-histidine)-graft-poly(d,l-lactide), and a diblock copolymer, methoxy poly(ethylene glycol)-b-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.
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