Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague 6, Czech Republic.
Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague 6, Czech Republic.
Nanomedicine. 2022 Nov;46:102597. doi: 10.1016/j.nano.2022.102597. Epub 2022 Sep 5.
Polymer nanomedicines with anti-tumor activity should exhibit sufficient stability during systemic circulation to the target tissue; however, they should release the active drug selectively in the tumor. Thus, choice of a tumor-specific stimuli-sensitive spacer between the drug and the carrier is critical. Here, a series of polymer conjugates of anti-cancer drugs doxorubicin and pirarubicin covalently bound to copolymers based on N-(2-hydroxypropyl)methacrylamide via various enzymatically cleavable oligopeptide spacers were prepared and characterized. The highest rate of the drug release from the polymer carriers in presence of the lysosomal protease cathepsin B was determined for the copolymers with Val-Cit-Aba spacer. Copolymers containing pirarubicin were more cytotoxic and showed higher internalization rate than the corresponding doxorubicin counterparts. The conjugates containing GFLG and Val-Cit-Aba spacers exhibited the highest anti-tumor efficacy in vivo against murine sarcoma S-180, the highest rate of the enzymatically catalyzed drug release, and the highest cytotoxicity in vitro.
具有抗肿瘤活性的聚合物纳米药物在向靶组织的全身循环中应表现出足够的稳定性;然而，它们应该在肿瘤中选择性地释放活性药物。因此，在药物和载体之间选择肿瘤特异性刺激敏感间隔物至关重要。在这里，通过各种酶可裂解的寡肽间隔物，将抗癌药物阿霉素和吡柔比星共价结合到基于 N-(2-羟丙基)甲基丙烯酰胺的共聚物上，制备并表征了一系列聚合物缀合物。在溶酶体蛋白酶组织蛋白酶 B 的存在下，从聚合物载体中释放药物的最高速率是用 Val-Cit-Aba 间隔物的共聚物确定的。含有吡柔比星的共聚物比相应的阿霉素类似物具有更高的细胞毒性和更高的内化率。含有 GFLG 和 Val-Cit-Aba 间隔物的缀合物在体内对 S-180 肉瘤具有最高的抗肿瘤功效，酶促药物释放的最高速率以及体外的最高细胞毒性。
