Liu Yupeng, Yu Fangying, Dai Suhuan, Meng Tingting, Zhu Yun, Qiu Guoxi, Wen Lijuan, Zhou Xueqing, Yuan Hong, Hu Fuqiang
College of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
Department of Clinical Pharmacology, Affiliated Hangzhou First People's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China.
Mol Pharm. 2021 Nov 1;18(11):3966-3978. doi: 10.1021/acs.molpharmaceut.1c00220. Epub 2021 Sep 27.
Stemness and metastasis are the two main challenges in cancer therapy and are related to disease relapse post-treatment. They both have a strong correlation with chemoresistance and poor prognosis, ultimately leading to treatment failure. It has been reported that chemotherapy can induce stemness and metastasis in many cancer types, especially treatment with the chemotherapeutic agent doxorubicin (DOX) in breast cancer. A combination treatment is an efficient and elegant approach in cancer therapy through simultaneous delivery of two or more drugs with a delivery system for its synergistic effect, which is not an additive of two individual drugs. Herein, we report a combinatorial system with DOX and all-trans retinoic acid (ATRA) to address both of the above issues. As a common critical regulatory factor for oncogenic signal transduction pathways, Pin1 is a specific isomerase highly expressed within various tumor cells. ATRA, a newly identified Pin1 inhibitor, can abolish several oncogenic pathways by effectively inhibiting and degrading overexpressed Pin1. We successfully developed a folic acid (FA)-modified chitosan (CSO)-derived polymer (FA-CSOSA) and obtained FA-CSOSA/DOX and FA-CSOSA/ATRA drug-loaded micelles. FA modification can improve the uptake of the nanoparticles in tumor cells and tumor sites via folate receptor-mediated cell internalization. Compared to treatment with DOX alone, the combined treatment induced 4T1 cell apoptosis in a synergistic manner. Reduced stemness-related protein expression and inhibited metastasis were observed during treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA and were found to be associated with Pin1. Further experiments showed that treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA resulted in 85.5% tumor inhibition, which was 2.5-fold greater than that of cells treated with DOX·HCl alone. This work presents a new paradigm for addressing chemotherapy-induced side effects via degradation of Pin1 induced by tumor-targeted delivery of DOX and ATRA.
干性和转移是癌症治疗中的两大主要挑战，且与治疗后的疾病复发相关。它们都与化疗耐药性和不良预后密切相关，最终导致治疗失败。据报道，化疗可在多种癌症类型中诱导干性和转移，尤其是乳腺癌中使用化疗药物阿霉素（DOX）进行治疗时。联合治疗是癌症治疗中的一种有效且精妙的方法，通过用递送系统同时递送两种或更多种药物以产生协同效应，而不是两种单独药物的简单相加。在此，我们报道了一种含有DOX和全反式维甲酸（ATRA）的组合系统，以解决上述两个问题。作为致癌信号转导通路的常见关键调节因子，Pin1是一种在各种肿瘤细胞中高表达的特异性异构酶。ATRA是一种新发现的Pin1抑制剂，可通过有效抑制和降解过表达的Pin1来消除多种致癌通路。我们成功开发了一种叶酸（FA）修饰的壳聚糖（CSO）衍生聚合物（FA-CSOSA），并获得了负载FA-CSOSA/DOX和FA-CSOSA/ATRA的药物胶束。FA修饰可通过叶酸受体介导的细胞内化作用提高纳米颗粒在肿瘤细胞和肿瘤部位的摄取。与单独使用DOX治疗相比，联合治疗以协同方式诱导4T1细胞凋亡。在用FA-CSOSA/DOX和FA-CSOSA/ATRA治疗期间，观察到干性相关蛋白表达降低和转移受到抑制，并且发现这与Pin1有关。进一步的实验表明，用FA-CSOSA/DOX和FA-CSOSA/ATRA治疗导致肿瘤抑制率达到85.5%，这比单独用盐酸阿霉素处理的细胞高出2.5倍。这项工作通过肿瘤靶向递送DOX和ATRA诱导Pin1降解，为解决化疗引起的副作用提供了一种新的范例。
