National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China; College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China.
National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China; College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China; Sichuan Testing Centre for Biomaterials and Medical Devices, No.29 Wangjiang Road, Chengdu, Sichuan 610064, China.
Acta Biomater. 2022 Oct 15;152:380-392. doi: 10.1016/j.actbio.2022.08.024. Epub 2022 Aug 23.
The abnormal activation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in drug-resistant tumor cells and cancer stem cells (CSCs) stimulate tumor metastasis and recurrence. Here, a promising combined chemotherapeutic strategy of salinomycin (SL) and doxorubicin (DOX) with specific inhibition of tumor stemness by a targeted co-delivery nanosystem was developed to overcome this abnormal progression. This strategy could be benefit drugs to effectively penetrate and infiltrate into spheres of 3D-cultured breast cancer stem cells (BCSCs). The expression of the Wnt/β-catenin signaling pathway-related genes (β-catenin, LRP6, LEF1, and TCF12) and target genes (Cyclin D1, Cmyc, and Fibronectin) as well as CSC stemness-related genes (Oct4, Nanog, and Hes1) was downregulated by redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety. The changes in EMT-associated gene expression (E-cadherin and Vimentin) in vitro showed that the EMT process was also effectively inverted. This strategy achieved a strong inhibitory effect on solid tumor growth and an effective reduction in the risk of tumor metastasis in 4T1 tumor-bearing mice in vivo and effectively alleviated splenomegaly caused by the malignant tumor. Immunohistochemical staining analysis of E-cadherin, Vimentin, and β-catenin confirmed that the inversion of the EMT was also achieved in solid tumors. These results highlight the potential of SL and DOX combined chemotherapeutic strategy for eliminating breast carcinoma. STATEMENT OF SIGNIFICANCE: Cancer stem cells (CSCs), as an important part of tumor heterogeneity, can survive against conventional chemotherapy and initiate tumorigenesis, recurrence, and metastasis. Moreover, non-CSCs can convert into the CSC state through the abnormal Wnt/β-catenin pathway, which is closely related to the epithelial-mesenchymal transition (EMT) process. Here, redox-degradable binary drug-loaded micelles (PPH/DOX+SL) were designed to target CSCs and overcome drug resistance of breast cancer cells. The combined chemotherapy of salinomycin (SL) and doxorubicin (DOX) reversed drug resistance, while the PPH/DOX+SL micelles enhanced the intracellular accumulation and drug penetration of BCSC spheres. The introduction of SL downregulated the expression of tumor stemness genes and the Wnt/β-catenin pathway-related genes and inverted the EMT process. PPH/DOX+SL continuously inhibited tumor growth and invasion in vivo.
异常激活耐药肿瘤细胞和癌症干细胞（CSC）中的 Wnt/β-连环蛋白信号通路和上皮-间充质转化（EMT）会刺激肿瘤转移和复发。在这里，开发了一种有前途的联合化疗策略，即使用青蒿琥酯（SL）和多柔比星（DOX），并通过靶向共递送纳米系统特异性抑制肿瘤干性，以克服这种异常进展。这种策略可以使药物有效地穿透并渗透到 3D 培养的乳腺癌干细胞（BCSC）球体中。Wnt/β-连环蛋白信号通路相关基因（β-连环蛋白、LRP6、LEF1 和 TCF12）和靶基因（Cyclin D1、Cmyc 和 Fibronectin）以及 CSC 干性相关基因（Oct4、Nanog 和 Hes1）的表达通过被修饰为主动靶向部分的具有氧化还原敏感性的共递药胶束下调。体外 EMT 相关基因表达（E-钙粘蛋白和波形蛋白）的变化表明 EMT 过程也得到了有效逆转。该策略在体内 4T1 荷瘤小鼠中对实体瘤生长具有很强的抑制作用，并有效降低了肿瘤转移的风险，有效缓解了恶性肿瘤引起的脾肿大。E-钙粘蛋白、波形蛋白和 β-连环蛋白的免疫组织化学染色分析证实，实体瘤中 EMT 的逆转也得到了证实。这些结果突出了 SL 和 DOX 联合化疗策略在消除乳腺癌方面的潜力。
意义声明：癌症干细胞（CSC）作为肿瘤异质性的重要组成部分，可以抵抗常规化疗并引发肿瘤发生、复发和转移。此外，非 CSC 可以通过异常的 Wnt/β-连环蛋白途径转化为 CSC 状态，这与上皮-间充质转化（EMT）过程密切相关。在这里，设计了氧化还原可降解二元药物负载胶束（PPH/DOX+SL）以靶向 CSC 并克服乳腺癌细胞的耐药性。青蒿琥酯（SL）和多柔比星（DOX）的联合化疗逆转了耐药性，同时 PPH/DOX+SL 胶束增强了 BCSC 球体的细胞内积累和药物渗透。SL 的引入下调了肿瘤干性基因和 Wnt/β-连环蛋白通路相关基因的表达，并逆转了 EMT 过程。PPH/DOX+SL 在体内持续抑制肿瘤生长和侵袭。
