Department of Chemical and Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
ACS Appl Mater Interfaces. 2021 Apr 7;13(13):14866-14874. doi: 10.1021/acsami.0c20050. Epub 2021 Mar 24.
Multidrug resistance (MDR) of cancer cells reduces chemotherapeutic efficacy by preventing drug accumulation in the cells through a drug efflux pump and lysosomal sequestration/exocytosis. Herein, to overcome such anticancer resistance, lysosome-targeted self-assembly of perylene diimide (PDI) derivatives is presented as a powerful strategy for effective and selective anticancer therapy. Stimulated by the lysosomal low pH, the amphiphilic PDI derivatives functionalized with amino acids (PDI-AAs) construct fibrous self-assembled structures inside the lysosomes, causing cancer cell apoptosis by lysosomal rupture. In contrast, negligible apoptosis was observed from normal cells by PDI-AA. The agglomerated fibrous assemblies were not removed by lysosomal exocytosis, thereby displaying a 10.7-fold higher anticancer efficacy on MDR cancer cells compared to a doxorubicin chemotherapeutic agent. The MDR-circumventing capability, along with high selectivity toward cancer cells, supports PDI-AAs as potential candidates for the treatment of MDR cancer cells by lysosome-targeted self-assembly.
癌细胞的多药耐药性（MDR）通过药物外排泵和溶酶体隔离/胞吐作用阻止药物在细胞内积累，从而降低了化疗的疗效。在此，为了克服这种抗癌耐药性，本文提出了一种将苝二酰亚胺（PDI）衍生物靶向溶酶体自组装作为有效和选择性抗癌治疗的强大策略。在溶酶体低 pH 的刺激下，用氨基酸（PDI-AAs）功能化的两亲性 PDI 衍生物在溶酶体内构建纤维状自组装结构，通过溶酶体破裂导致癌细胞凋亡。相比之下，PDI-AA 对正常细胞几乎没有引起凋亡。聚集的纤维状组装物不能通过溶酶体胞吐作用去除，因此与多柔比星化疗药物相比，对多药耐药癌细胞的抗癌功效提高了 10.7 倍。PDI-AAs 绕过多药耐药性的能力以及对癌细胞的高选择性，支持其作为通过溶酶体靶向自组装治疗多药耐药癌细胞的潜在候选药物。
