Key Laboratory of Functional Polymer Materials (Ministry of Education), College of Chemistry, Nankai University, Tianjin, 300071, China.
Key Laboratory of Functional Polymer Materials (Ministry of Education), College of Chemistry, Nankai University, Tianjin, 300071, China; Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300071, China.
Colloids Surf B Biointerfaces. 2021 Jul;203:111752. doi: 10.1016/j.colsurfb.2021.111752. Epub 2021 Apr 7.
The severe side-effects and drug resistance development of conventional chemotherapy are mainly caused by poor tumor penetration as well as nonspecific biodistribution and insufficient cellular uptake of drugs. Herein a branched arginine-rich polymer was synthesized and co-administration of this polymer with doxorubicin, a model drug of chemotherapeutic agents, overcame simultaneously the three obstacles shown above. Co-incubation of the polymer promoted doxorubicin penetration deeply into multicellular tumor spheroids and internalization into cancer cells. Upon co-injection of the polymer with doxorubicin into tumor-bearing mice, the enhanced drug accumulation in and deep penetration into tumor tissue were observed compared to injection of doxorubicin alone. A combined therapy of doxorubicin and the polymer in the treatment of tumor-bearing mice showed a marked enhancement in anticancer efficacy compared to doxorubicin alone. Notably, the treatment with the combination regime reduced the doxorubicin dose to one fifth without reducing the antitumor efficacy compared to the treatment with doxorubicin alone. The possible mechanism of action of the polymer was postulated, in which the guanidinium groups of arginine residues in the polymer may play a pivotal role in the action.
常规化疗的严重副作用和耐药性发展主要是由于肿瘤穿透性差、药物非特异性生物分布和细胞摄取不足所致。本文合成了一种支链精氨酸聚合物，并将其与多柔比星（一种化疗药物的模型药物）联合给药，同时克服了上述三个障碍。聚合物的共孵育促进了多柔比星深入穿透多细胞肿瘤球体并进入癌细胞内。将聚合物与多柔比星共同注射到荷瘤小鼠体内后，与单独注射多柔比星相比，观察到药物在肿瘤组织中的蓄积和深层穿透增强。与单独使用多柔比星相比，多柔比星和聚合物联合治疗荷瘤小鼠的抗癌疗效明显增强。值得注意的是，与单独使用多柔比星相比，联合治疗方案将多柔比星的剂量减少到五分之一，而没有降低抗肿瘤疗效。推测了聚合物的作用机制，其中聚合物中精氨酸残基的胍基可能在作用中起关键作用。
