Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Mol Biol Rep. 2023 Dec;50(12):10047-10059. doi: 10.1007/s11033-023-08888-2. Epub 2023 Oct 30.
Single-target inhibitors have not been successful in cancer treatment due to the development of drug resistance. Nevertheless, therapeutic agents capable of simultaneously inhibiting multiple targets have revealed encouraging results in inducing apoptosis and overcoming drug resistance in cancerous cells. Here, we designed a composite liposomal nano-carrier co-loading 5-Fluorouracil (5-FU) with all-trans retinoic acid (ATRA) to assess anticancer efficacy of the combined drugs in colorectal cancer (CRC).
A PEGylated liposomal nano-carrier with phospholipid/cholesterol/DSPE-PEG (2000) was synthesized by the thin film hydration technique for co-delivery of ATRA and 5-FU. After characterizing, the role of 5-FU and ATRA co-loaded liposomal nano-carrier in proliferation, epithelial-mesenchymal transition (EMT), apoptosis, and cancer stem cells (CSCs) were investigated by using colony forming and MTT assay, RT-qPCR and Annexin V/PI kit.
The average size of liposomes (LPs) was < 150 nm with uniform size distribution. Drug release analyses indicated that both ATRA and 5-FU could simultaneously release from LPs in a sustained release manner. The synergistic inhibitory effects of ATRA and 5-FU loaded in LPs were verified with a combination index of 0.43. Dual drug LPs showed the highest cytotoxicity, enhanced inhibition of cell proliferation, increased apoptotic potential, decreased CSCs, and attenuated EMT-associated biomarkers. Also, dual drug LPs decreased β-catenin gene expression more than other liposomal formulations.
These findings suggest that using LPs to achieve a synergistic effect of ATRA and 5-FU is an effectual approach to increase the therapeutic effect of 5-FU toward CRC cells.
由于耐药性的发展，单靶点抑制剂在癌症治疗中并未取得成功。然而，能够同时抑制多个靶点的治疗剂已在诱导癌细胞凋亡和克服耐药性方面显示出令人鼓舞的结果。在这里，我们设计了一种复合脂质体纳米载体，共同装载 5-氟尿嘧啶（5-FU）和全反式视黄酸（ATRA），以评估联合药物在结直肠癌（CRC）中的抗癌疗效。
通过薄膜水化技术合成了一种具有磷脂/胆固醇/DSPE-PEG（2000）的 PEG 化脂质体纳米载体，用于共递送 ATRA 和 5-FU。在表征后，通过集落形成和 MTT 分析、RT-qPCR 和 Annexin V/PI 试剂盒研究了 5-FU 和 ATRA 共载脂质体纳米载体在增殖、上皮-间充质转化（EMT）、凋亡和癌症干细胞（CSCs）中的作用。
脂质体（LPs）的平均粒径<150nm，粒径分布均匀。药物释放分析表明，ATRA 和 5-FU 均可从 LPs 中以持续释放的方式同时释放。载药 LPs 的协同抑制作用通过组合指数 0.43 得到验证。双药 LPs 显示出最高的细胞毒性，增强了对细胞增殖的抑制作用，增加了凋亡潜能，减少了 CSCs，并减弱了 EMT 相关生物标志物。此外，双药 LPs 降低了β-连环蛋白基因的表达，比其他脂质体制剂更有效。
这些发现表明，使用 LPs 实现 ATRA 和 5-FU 的协同作用是提高 5-FU 对 CRC 细胞治疗效果的有效方法。
