Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Med Oncol. 2023 Jul 29;40(9):255. doi: 10.1007/s12032-023-02120-8.
The high incidence rate coupled with significant mortality makes colorectal cancer one of the most prevalent and devastating cancers worldwide. Research is currently underway to explore new forms of treatment that could potentially maximize treatment outcomes while minimizing the side effects associated with conventional chemotherapy. Metformin, a natural biguanide drug, has anti-cancer properties that can inhibit the growth and proliferation of cancer cells. However, due to its short half-life and low bioavailability, the efficacy of Metf as an anti-cancer agent is limited. The purpose of this research is to assess the potency of PEGylated niosomes as a nano-delivery system for Metf, with the aim of increasing its anti-cancer effects on CaCo2 colorectal cancer cells through the effect on the expression of genes, including GPR75, hTERT, Bax, Bcl2, and Cyclin D1. Metf-loaded niosomal NPs (N-Metf) were synthesized using the thin-film hydration method and then characterized using SEM, FTIR, AFM, and DLS techniques. The release pattern of the drug from the nanoparticles (NPS) was determined using the dialysis membrane method. Furthermore, the cytotoxic effect of the metformin-loaded PEGylated niosome on the CaCo2 cell line was evaluated by the MTT test. Additionally, an apoptosis assay was conducted to assess the effect of free Metf and Metf-loaded NPS on the programmed death of the CaCo2 cells, and the impact on the cell cycle was studied through a cell cycle test. Finally, the expression levels of hTERT, Cyclin D1, BCL2, GPR75, and BAX genes were assessed in the presence of free Metf and Metf-loaded NPs by RT-PCR. Characterization experiments showed successful loading of metformin into PEGylated niosomes. The results of cytotoxicity evaluation showed that Metf-NPs had more cytotoxicity than free Metf in a dose-dependent manner. Furthermore, nuclear fragmentation and the percentage of apoptotic cells induced by Metf-NPs were significantly higher than those induced by free Metf. Additionally, Metf-NPs were found to induce more cell cycle arrest at the sub-G1 checkpoint than free Metf did. Compared with Metf-treated cells, the mRNA expression levels of GPR75, Cyclin D1, and hTERT were significantly changed in cells treated with Metf-NPs. Ultimately, it is hypothesized the nano-encapsulation of Metf into PEGylated niosomal NPs could be a worthwhile drug delivery system to enhance its effectiveness in treating colorectal cancer cells.
高发病率加上显著的死亡率使得结直肠癌成为全球最普遍和最具破坏性的癌症之一。目前正在研究新的治疗形式，这些治疗形式可能在最大限度地提高治疗效果的同时最大限度地减少与传统化疗相关的副作用。二甲双胍是一种天然的双胍类药物，具有抗癌特性，可以抑制癌细胞的生长和增殖。然而，由于其半衰期短和生物利用度低，二甲双胍作为抗癌药物的疗效有限。本研究旨在评估聚乙二醇化的尼奥斯omes作为二甲双胍的纳米递药系统的效力，目的是通过对 GPR75、hTERT、Bax、Bcl2 和 Cyclin D1 等基因表达的影响，增加其对 CaCo2 结直肠癌细胞的抗癌作用。二甲双胍负载的尼奥斯ome NPs（N-Metf）通过薄膜水化法合成，然后使用 SEM、FTIR、AFM 和 DLS 技术进行表征。使用透析膜法测定药物从纳米颗粒（NPS）中的释放模式。此外，通过 MTT 试验评估载有二甲双胍的聚乙二醇化尼奥斯ome 对 CaCo2 细胞系的细胞毒性作用。此外，通过凋亡试验评估游离 Metf 和载有 Metf 的 NPS 对 CaCo2 细胞程序性死亡的影响，并通过细胞周期试验研究对细胞周期的影响。最后，通过 RT-PCR 评估游离 Metf 和载有 Metf 的 NPs 存在时 hTERT、Cyclin D1、BCL2、GPR75 和 BAX 基因的表达水平。表征实验表明成功地将二甲双胍载入聚乙二醇化尼奥斯ome 中。细胞毒性评价结果表明，Metf-NPs 具有比游离 Metf 更高的细胞毒性，且呈剂量依赖性。此外，Metf-NPs 诱导的核碎片和凋亡细胞的百分比明显高于游离 Metf 诱导的核碎片和凋亡细胞的百分比。此外，与游离 Metf 相比，Metf-NPs 诱导更多的细胞周期阻滞在 sub-G1 检查点。与 Metf 处理的细胞相比，用 Metf-NPs 处理的细胞中 GPR75、Cyclin D1 和 hTERT 的 mRNA 表达水平发生了显著变化。最终，假设将 Metf 纳米封装到聚乙二醇化的尼奥斯ome NPs 中可能是一种有价值的药物传递系统，可增强其治疗结直肠癌细胞的效果。
