Targeted Delivery of siRNA-Gemcitabine Oligonucleotide\nChimeras for High-Efficacy Synergistic Treatment of Pancreatic Cancer

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