Wang Yonghui, Ma Xiaodong, Zhou Wenhui, Liu Chang, Zhang Hongbo
Pharmaceutical Sciences Laboratory Åbo Akademi University Turku Finland.
Turku Bioscience Centre University of Turku and Åbo Akademi University Turku Finland.
Smart Med. 2022 Dec 22;1(1):e20220013. doi: 10.1002/SMMD.20220013. eCollection 2022 Dec.
Chemotherapy is one of the most basic and important treatments for malignant tumors. However, most chemotherapeutic drugs suffer from the resistance of tumor cells and lead to chemotherapy failure. Multidrug resistance (MDR) of tumor cells is the main obstacle to chemotherapy failure. The generation of MDR is not only the result of the performance of tumor cells, but the tumor microenvironment (TEM) also plays an important role in this process. The simultaneous dual intervention of cancer cells and the TEM has the potential to provide surprising results in overcoming MDR tumor therapy. Therefore, in this study, we designed a folate acid ligand-modified nanoparticle (FA-NPs) with a size of about 145 nm targeting multidrug-resistant colorectal cancer and successfully co-loaded cisplatin and Tris(2-chloroisopropyl) phosphate (TCPP). FA-NPs can enrich tumor sites through receptor-mediated endocytosis. In vitro mechanism studies have shown that nanoparticles can reverse cisplatin resistance mainly by further increasing the level of reactive oxygen species in tumor cells, breaking the homeostasis of the internal environment, then trigging mitochondrial stress, regulating drug resistance-related pathways, and improving the tumor drug resistance microenvironment; finally, the cisplatin recovers the antitumor effect with assistance from TCPP.
化疗是恶性肿瘤最基本且重要的治疗方法之一。然而，大多数化疗药物会遭遇肿瘤细胞耐药问题，导致化疗失败。肿瘤细胞的多药耐药性（MDR）是化疗失败的主要障碍。MDR的产生不仅是肿瘤细胞表现的结果，肿瘤微环境（TEM）在此过程中也起着重要作用。对癌细胞和TEM同时进行双重干预，在克服MDR肿瘤治疗方面有可能产生惊人的效果。因此，在本研究中，我们设计了一种靶向多药耐药性结直肠癌的、尺寸约为145纳米的叶酸配体修饰纳米颗粒（FA-NPs），并成功共负载了顺铂和磷酸三（2-氯异丙基）酯（TCPP）。FA-NPs可通过受体介导的内吞作用富集于肿瘤部位。体外机制研究表明，纳米颗粒主要通过进一步提高肿瘤细胞内活性氧水平、打破内环境稳态、引发线粒体应激、调节耐药相关通路以及改善肿瘤耐药微环境来逆转顺铂耐药性；最后，顺铂在TCPP的协助下恢复抗肿瘤作用。
