Targeting Pancreatic Cancer with a Polymeric Nanocarrier and an Anticancer MicroRNA Polyplex

The highly aggressive pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 5%, therefore new treatment approaches are urgently needed. MicroRNAs are now being explored as new therapeutic targets for cancer treatment. Importantly, the heterogeneity and complexity of cancer suggests that the only way to successful treatment might lie with the simultaneous targeting of multiple genes, further emphasizing the therapeutic potential of miRNAs. However, efficient delivery of miRNA for therapeutic purposes is extremely challenging due to low cellular uptake, RNases degradation and rapid renal clearance. We developed a novel polymeric nanocarrier to deliver miRNAs to tumors and their vasculature. Our therapeutic candidate miRNA was miR-34a, a tumor suppressor downregulated in PDAC and inhibits malignant growth. Our biodegradable nanocarrier was able to complex electrostatically with miR-34a and form nano-scaled polyplexes. The polymer enhanced the internalization of miR-34a into human PDAC cells, as it was capable of downregulating four of its direct target genes and could also inhibit their growth, clonogenicity and cell cycle. Systemic administration of polymer-miRNA nanoplexes to orthotopically-inoculated pancreatic tumors was not toxic at the relevant dose and accumulated selectively at the tumor site warranting their potential as a novel therapeutic for PDAC.