Pancreatic cancer (PC) stands for the most intractable malignancy. Gemcitabine (GEM) is one of the few approved first-line treatments for PC patients. The fast clearance, demanded high dosage, and existence of drug resistance have, nevertheless, posed not only a significant limitation to its clinical efficacy but also serious toxicity concerns. KRAS^G12D mutation is identified as a key driver in many PC patients, and its expression level shows a correlation with drug resistance and mortality. Here, we explored KRAS^G12D siRNA-gemcitabine oligonucleotide chimeras (siKRAS-G_n) as a dual prodrug that was designed to specifically silence KRAS^G12D gene and sensitize PC cells to GEM for the synergistic treatment of PC. siKRAS-G_n conjugates with 1, 2, 3, 4, or 5 units of GEM were synthesized and delivered using cRGD-decorated polymersomes. Interestingly, the proapoptotic activity of siKRAS-G_n was shown to highly depend on the number of GEM, in which three GEM units (siKRAS-G₃) were found to be optimal and induced strong apoptosis of PANC-1 cells (apoptosis rate: 64.2%). In contrast, minimal cell apoptosis was discerned for siKRAS, siKRAS-G₁, siKRAS-G₂, and free GEM (9-fold of that in siKRAS-G₃). siKRAS-G₃, while showing similar KRAS mRNA silencing ability to siKRAS, markedly enhanced the downregulation of KRAS protein in vitro and in vivo. Accordingly, siKRAS-G₃ significantly outperformed siKRAS and siScramble-G₃ in both tumor inhibition and survival benefits. The targeted delivery of the siKRAS-gemcitabine prodrug conjugate has emerged as an appealing treatment for pancreatic cancer.

中文翻译：

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靶向递送 siRNA-吉西他滨寡核苷酸嵌合体用于胰腺癌的高效协同治疗


胰腺癌 （PC） 代表最难治的恶性肿瘤。吉西他滨 （GEM） 是为数不多的获批用于 PC 患者的一线治疗药物之一。然而，快速清除、高剂量要求和耐药性的存在不仅对其临床疗效构成了重大限制，还引起了严重的毒性问题。KRAS^G12D 突变被确定为许多 PC 患者的关键驱动因素，其表达水平与耐药和死亡率相关。在这里，我们探索了 KRAS^G12D siRNA-吉西他滨寡核苷酸嵌合体 （siKRAS-G _n） 作为一种双重前药，旨在特异性沉默 KRAS^G12D 基因并使 PC 细胞对 GEM 敏感，以协同治疗 PC。使用 cRGD 修饰的聚合物体合成和递送具有 1、2、3、4 或 5 个 GEM 单位的 siKRAS-G _n 偶联物。有趣的是，siKRAS-G _n 的促凋亡活性被证明高度依赖于 GEM 的数量，其中三个 GEM 单元 （siKRAS-G ₃） 被发现是最佳的，并诱导 PANC-1 细胞的强烈凋亡 （细胞凋亡率：64.2%）。相比之下，siKRAS、siKRAS-G ₁、siKRAS-G ₂ 和游离 GEM 的细胞凋亡最小（是 siKRAS-G ₃ 的 9 倍）。siKRAS-G ₃ 虽然显示出与 siKRAS 相似的 KRAS mRNA 沉默能力，但在体外和体内显着增强了 KRAS 蛋白的下调。 因此，siKRAS-G ₃ 在肿瘤抑制和生存获益方面均显著优于 siKRAS 和 siScramble-G ₃。siKRAS-吉西他滨前药偶联物的靶向递送已成为胰腺癌的一种有吸引力的治疗方法。