Co-delivery of gemcitabine and Mcl-1 SiRNA via cationic liposome-based system enhances the efficacy of chemotherapy in pancreatic cancer

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.