In vivo imaging and targeted siRNA delivery using superparamagnetic nanoparticles (MNPs) in pancreatic ductal adenocarcinoma
Aim: Pancreatic ductal adenocarcinoma is one of the most aggressive and deadly malignancies. Despite considerable knowledge about the cell biology and the genetic changes of malignant cells, therapeutic options for pancreatic adenocarcinoma remain ineffective. One plausible explanation for the poor tumor response to therapy is an insufficient delivery of anticancer drugs to the tumour site. Superparamagnetic nanoparticles (MNPs) could serve a dual purposes: the can delivery antiproliferative substances to turmour cells and they allow for noninvasive assessment of this delivery by in vivo MRI.
Results: We synthesized and characterized dual purpose MNPs for the in vivo application of siRNA with simultaneous imaging of its accumulation in the tumour. MNPs were designed with a membrane translocation peptide (MPAP-) and with tumour selective peptides (EPPT-) to increase intracellular delivery and tumour specificity, respectively. In vitro and in vivo experiments using a syngenic murine orthotopic pancreatic cancer model revealed significant accumulation of MNPs in pancreatic cancer as well as efficient protein silencing. When we silenced the PLK1, a serine-threonine-kinase, this resulted in a highly significant reduction in tumour size when applied i.v. twice weekly. Significant systemic side effects were not observed.
Conclusion: Superparamagnetic nanoparticles with dual specificity residues for tumour targeting and membrane translocation represent an exciting opportunity for overcoming treatment resistance in pancreatic cancer. Carrying siRNA directed against PLK1 they are well tolerated, can be monitored by MRI, and reduce tumour size.