School of Nursing, Weifang Medical University, Weifang 261053, P. R. China.
School of Bioscience and Technology, Weifang Medical University, Weifang 261053, P. R. China.
ACS Appl Mater Interfaces. 2021 Apr 14;13(14):16019-16035. doi: 10.1021/acsami.0c23137. Epub 2021 Apr 5.
Recent research studies have shown that the low survival rate of liver cancer is due to drug resistance and metastasis. In the tumor microenvironment (TME), activated hepatic stellate cells (aHSCs) have been proven to favor the development of liver cancer. Hence, the combination therapy dual-targeting aHSCs and tumor cells might be an effective strategy for treatment of liver cancer. In this study, the novel multifunctional liposomes (CAPS-CUR/GA&Gal-Lip) were prepared for co-delivery of curcumin (CUR) and capsaicin (CAPS), in which glycyrrhetinic acid (GA) and galactose (Gal) were chosen as targeting ligands to modify the liposomes (Lip) for dual-targeting liver cancer. To mimic TME, a novel HSCs+HepG2 (human hepatoma cell line) cocultured model was established for the antitumor effect . The results showed that, compared to HepG2 cells alone, the cocultured model promoted drug resistance and migration by upregulating the expression of P-glycoprotein (P-gp) and Vimentin, which were effectively inhibited by CAPS-CUR/GA&Gal-Lip. The efficacy of the antitumor was evaluated by three mice models: subcutaneous H22 (mouse hepatoma cell line) tumor-bearing mice, H22+m-HSC (mouse hepatic stellate cell) tumor-bearing mice, and orthotopic H22 cells-bearing mice. The results showed that CAPS-CUR/GA&Gal-Lip exhibited lesser extracellular matrix (ECM) deposition, lesser tumor angiogenesis, and superior antitumor effect compared with the no- and/or Gal-modified Lip, which was attributed to the simultaneous blocking of the activation of HSCs and inhibition of the metastasis of tumor cells. The dual-targeting method using Lip is thus a potential strategy for liver cancer treatment.
最近的研究表明，肝癌的低存活率是由于耐药性和转移。在肿瘤微环境（TME）中，已证实激活的肝星状细胞（aHSCs）有利于肝癌的发展。因此，双重靶向 aHSCs 和肿瘤细胞的联合治疗可能是治疗肝癌的有效策略。在这项研究中，制备了新型多功能脂质体（CAPS-CUR/GA&Gal-Lip），用于共同递送姜黄素（CUR）和辣椒素（CAPS），其中甘草酸（GA）和半乳糖（Gal）被选为靶向配体来修饰脂质体（Lip），以双重靶向肝癌。为了模拟 TME，建立了新型 HSCs+HepG2（人肝癌细胞系）共培养模型，以评估其抗肿瘤效果。结果表明，与单独的 HepG2 细胞相比，共培养模型通过上调 P-糖蛋白（P-gp）和波形蛋白的表达促进了耐药性和迁移，而这两种表达均被 CAPS-CUR/GA&Gal-Lip 有效抑制。通过三种小鼠模型评估了抗肿瘤效果：皮下 H22（小鼠肝癌细胞系）荷瘤小鼠、H22+m-HSC（小鼠肝星状细胞）荷瘤小鼠和原位 H22 细胞荷瘤小鼠。结果表明，与无修饰和/或 Gal 修饰的 Lip 相比，CAPS-CUR/GA&Gal-Lip 表现出较少的细胞外基质（ECM）沉积、较少的肿瘤血管生成和更好的抗肿瘤效果，这归因于同时阻断 HSCs 的激活和抑制肿瘤细胞的转移。因此，使用 Lip 的双重靶向方法是治疗肝癌的一种有潜力的策略。
