Myeloid cell leukemia 1 (Mcl-1) overexpression is found in various human tumors and has emerged as a promising new target for pancreatic cancer treatment. Recent research has found that most pancreatic cancers develop resistance to the current first-line chemotherapeutic drug, gemcitabine (Gem), and high expression of Mcl-1 can reduce the sensitivity of pancreatic cancer cells to Gem chemotherapy. Therefore, novel strategies, such as combination therapy, to overcome resistance of Gem chemotherapy are needed urgently. Here, we employed a lipid-based delivery system (LPs) to codeliver Mcl-1 siRNA and Gem for pancreatic cancer treatment, named LP-Gem-siMcl-1. LP-Gem-siMcl-1 exhibited an increased cellular uptake, enhanced Mcl-1 down-regulation efficacy, and significant cytotoxicity in the human pancreatic carcinoma cell lines PANC-1 and BxPC-3. Furthermore, tumor inhibition in vivo proved that LP-Gem-siMcl-1 has higher anti-tumor efficiency than LP-siMcl-1 plus LP-Gem, indicating the synergistic anti-tumor effects of Gem and siMcl-1. Meanwhile, histological analysis demonstrated that LPs could efficiently co-deliver Gem and Mcl-1 siRNA to cancerous cells and overcome the resistance of Gem. Taken together, our results offer proof that LP-Gem-siMcl-1 is an effective co-delivery system to treat pancreatic cancers and may serve as a valuable tool for developing new strategies for cancer therapy.

中文翻译：

---

通过基于阳离子脂质体的系统共同递送吉西他滨和Mcl-1 SiRNA可增强胰腺癌化学疗法的疗效。

在各种人类肿瘤中发现了髓样细胞白血病1（Mcl-1）过表达，并且已经成为胰腺癌治疗的有希望的新靶标。最近的研究发现，大多数胰腺癌对当前的一线化疗药物吉西他滨（Gem）产生抗药性，而Mcl-1的高表达可降低胰腺癌细胞对Gem化疗的敏感性。因此，迫切需要新的策略，例如联合疗法，以克服宝石化学疗法的耐药性。在这里，我们采用了基于脂质的递送系统（LP）来编码Mcl-1 siRNA和Gem以治疗胰腺癌，命名为LP-Gem-siMcl-1。LP-Gem-siMcl-1在人胰腺癌细胞系PANC-1和BxPC-3中显示出增加的细胞摄取，增强的Mcl-1下调功效以及显着的细胞毒性。体内实验证明，LP-Gem-siMcl-1具有比LP-siMcl-1加LP-Gem更高的抗肿瘤效果，表明Gem与siMcl-1具有协同的抗肿瘤作用。同时，组织学分析表明，LPs可以有效地将Gem和Mcl-1 siRNA共递送至癌细胞，并克服Gem的耐药性。综上所述，我们的结果提供了证据，证明LP-Gem-siMcl-1是治疗胰腺癌的有效共同递送系统，并且可以作为开发新的癌症治疗策略的宝贵工具。