Gemcitabine and miRNA34a mimic codelivery with magnetic nanoparticles enhanced anti-tumor effect against pancreatic...

Pancreatic ductal adenocarcinoma is a highly aggressive cancer with a low survival rate. Thus, efforts are needed to develop more effective treatments. Herein, we propose utilizing magnetic nanoparticles (MNP) for the concurrent delivery of gemcitabine and miRNA34a mimic to target pancreatic cancer cells. The MNP were functionalized with disulfide bonds to selectively release their cargo inside tumor cells. The incorporation of the miRNA34a mimic increased the sensitivity of cells to gemcitabine, especially in BxPC-3 cells. Additionally, the miRNA34a sequence was modified with locked nucleic acids (LNA) to increase stability. The resulting LNA34a showed a stronger cytotoxic effect when combined with gemcitabine, even in PANC-1 cells, which are resistant to the drug. Notably, the modified MNP exhibited less toxicity than their free counterparts when incubated with HaCaT cells, a model of healthy keratinocytes. Additionally, the combined delivery of miRNA34a mimics and gemcitabine using MNP elicited a synergistic cytotoxic effect against pancreatic cancer cells through magnetic hyperthermia. The intratumoral administration of the modified MNP in subcutaneous xenografts of BxPC-3 cells resulted in a sustained increase in temperature when an alternating magnetic field was applied. Notably, the treatment with the MNP functionalized with GEM and LNA34a led to significant changes in the expression of NOTCH1 and NOTCH2 in the tumor, which are direct targets of miRNA34a, as well as HSP70, which is related to the cellular response to stressors like heat.