Purpose

KRAS is the most frequently mutated gene in human cancers, and ~ 90% of pancreatic cancers exhibit KRAS mutations. Despite the well-known role of KRAS in malignancies, directly inhibiting KRAS is challenging.

Methods

In this study, we successfully synthesized apolipoprotein E3-based liposomes for the co-delivery of gemcitabine (GEM) and a small interfering RNA targeting KRAS (KRAS-siRNA) to improve the efficacy of pancreatic cancer treatment.

Results

Apolipoprotein E3 self-assembly on the liposome surface led to a substantial increase in its internalization in PANC1 human pancreatic cancer cells. KRAS-siRNA led to downregulated KRAS protein expression and KRAS-dependent carcinogenic pathways, resulting in the inhibition of cell proliferation, cell cycle arrest, increased apoptosis, and suppression of tumor progression. The combination of KRAS-siRNA and GEM induced a synergistic improvement in cell apoptosis and significantly lower cell viability compared with single-agent therapy. The low IC₅₀ value of A3-SGLP might be attributed to potentiation of the anticancer effect of GEM by siRNA-mediated silencing of KRAS mutations, thereby inducing synergistic effects on cancer cells.

Conclusion

A3-SGLP led to a marked decrease in the overall tumor burden and did not show any signs of toxicity. Therefore, the combination of KRAS-siRNA and GEM holds great potential for the treatment of pancreatic cancer.

中文翻译：

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载脂蛋白 E3 标记的脂质体纳米颗粒的纳米制剂用于联合递送 KRAS-siRNA 和吉西他滨以治疗胰腺癌

目的

KRAS 是人类癌症中最常发生突变的基因，约 90% 的胰腺癌表现出 KRAS 突变。尽管 KRAS 在恶性肿瘤中的作用众所周知，但直接抑制 KRAS 具有挑战性。

方法

在这项研究中，我们成功合成了基于载脂蛋白 E3 的脂质体，用于共同递送吉西他滨 (GEM) 和靶向 KRAS 的小干扰 RNA (KRAS-siRNA)，以提高胰腺癌治疗的疗效。

结果

载脂蛋白 E3 在脂质体表面的自组装导致其在 PANC1 人胰腺癌细胞中的内化显着增加。KRAS-siRNA 导致 KRAS 蛋白表达下调和 KRAS 依赖性致癌途径，导致细胞增殖抑制、细胞周期停滞、细胞凋亡增加和肿瘤进展抑制。与单药治疗相比，KRAS-siRNA 和 GEM 的组合可协同改善细胞凋亡并显着降低细胞活力。A3-SGLP的低 IC ₅₀值可能归因于通过 siRNA 介导的 KRAS 突变沉默增强 GEM 的抗癌作用，从而诱导对癌细胞的协同作用。

结论

A3-SGLP 导致整体肿瘤负荷显着降低，并且没有显示出任何毒性迹象。因此，KRAS-siRNA与GEM联合治疗胰腺癌具有巨大潜力。