Abstract

Development of new drugs are confronted with some barriers and challenges, since these projects are mainly expensive, complex, time consuming with lack of success, there is an urgent need to reformulate the current poorly water soluble anti-cancer drugs. In this study, a new type of polymer–curcumin conjugates based on glycidyl azide polymer (GAP) was developed for cancer therapy. The copolymer was used for delivery of curcumin (CUR) as an anticancer drug to cancer cells. Our method is based on the facile conjugation of CUR to amine-containing polymeric vehicles through imine linkage bonds, which could remain stable in normal physiological condition while readily dissociate by an acidic environment and make the prodrug active to liberate its payload CUR to inhibit cell growth. The results demonstrated that fabricated amphiphilic PDCs were self-assembled into nanosized micelles in aqueous solution and the micelles showed an average size of 180 nm with a good polydispersity index. Drug release studies demonstrated that this nano-conjugate is fairly stable at physiologic environments but prone to mild acidic conditions which would trigger the release of conjugated CUR. Moreover, the PDCs micelles exhibited excellent cytotoxicity effect on 4T1 mouse breast cancer cell line but no significant toxicity was observed for the copolymer. In addition, the copolymer did not display remarkable toxicity against A. salina even at high doses of copolymer. In addition, the synthesized PDCs exhibited hemolysis lowers than 6%. The safety of copolymers as a drug vehicle was also confirmed by LD₅₀, since all mice which treated with 5000 mg/Kg (limited dose) were still alive after one week. Our findings revealed that these unique pH-sensitive PDCs may provide a promising approach for delivery of the anticancer drugs to cancer cells.

摘要

新药开发面临一些障碍和挑战，由于这些项目主要是昂贵、复杂、耗时且缺乏成功的，迫切需要重新配制目前水溶性差的抗癌药物。在这项研究中，开发了一种基于缩水甘油叠氮化物聚合物 (GAP) 的新型聚合物 - 姜黄素偶联物用于癌症治疗。该共聚物用于将姜黄素 (CUR) 作为抗癌药物输送到癌细胞。我们的方法基于 CUR 通过亚胺键与含胺聚合物载体的轻松缀合，亚胺键可以在正常生理条件下保持稳定，同时容易被酸性环境解离并使前药具有活性以释放其有效负载 CUR 以抑制细胞生长. 结果表明，制备的两亲 PDCs 在水溶液中自组装成纳米级胶束，胶束的平均粒径为 180 nm，具有良好的多分散指数。药物释放研究表明，这种纳米偶联物在生理环境中相当稳定，但容易出现温和的酸性条件，这会触发偶联 CUR 的释放。此外，PDCs胶束对4T1小鼠乳腺癌细胞系表现出优异的细胞毒性作用，但没有观察到共聚物的显着毒性。此外，共聚物没有表现出显着的毒性 药物释放研究表明，这种纳米偶联物在生理环境中相当稳定，但容易出现温和的酸性条件，这会触发偶联 CUR 的释放。此外，PDCs胶束对4T1小鼠乳腺癌细胞系表现出优异的细胞毒性作用，但没有观察到共聚物的显着毒性。此外，共聚物没有表现出显着的毒性 药物释放研究表明，这种纳米偶联物在生理环境中相当稳定，但容易出现温和的酸性条件，这会触发偶联 CUR 的释放。此外，PDCs胶束对4T1小鼠乳腺癌细胞系表现出优异的细胞毒性作用，但没有观察到共聚物的显着毒性。此外，共聚物没有表现出显着的毒性A. salina即使在高剂量的共聚物下。此外，合成的 PDCs 的溶血率低于 6%。LD ₅₀也证实了共聚物作为药物载体的安全性，因为所有用 5000 mg/Kg（有限剂量）治疗的小鼠在一周后仍然活着。我们的研究结果表明，这些独特的 pH 敏感 PDC 可能为将抗癌药物递送至癌细胞提供了一种有前景的方法。