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

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 -G 3 ) 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 -G 1, siKRAS -G 2, and free GEM (9-fold of that in siKRAS -G 3 ). siKRAS -G 3, while showing similar KRAS mRNA silencing ability to siKRAS, markedly enhanced the downregulation of KRAS protein in vitro and in vivo . Accordingly, siKRAS -G 3 significantly outperformed siKRAS and siScramble -G 3 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.