Targeting Pancreatic Ductal Adenocarcinoma with a Polymeric Nanocarrier and an Anticancer miRNA Polyplex

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy and currently the fourth leading cause of cancer death in the United States. The high mortality and poor prognosis are due to extensive metastasis and lack of early diagnostic markers and symptoms. In spite of advances in chemo therapies, the 5-year survival rate is still less than 5%, indicating the ineffectiveness of current approaches to treatment.

MicroRNAs, after being demonstrated as deregulated in cancer, are now being explored as therapeutic targets for cancer treatment. Reversion of miRNA expression to normal levels can restore perturbed cellular homeostasis. 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. miR-34a, a master regulator of tumor suppression, is downregulated in numerous cancers including PDAC and inhibits malignant growth by repressing oncogenic genes.

Efficient delivery of miRNA for therapeutic purposes is extremely challenging due to low cellular uptake, RNases degradation and rapid renal clearance. Therefore, we synthesized a novel polymeric nanocarrier to deliver microRNAs to tumors and their vasculature. Our nanocarrier was able to complex electrostatically with miR-34a and form therapeutically active nano-scaled polyplexes. The polymer enhanced the internalization of miR-34a in its active form into human PDAC cells, as the miR was capable of downregulating four of its direct target genes. miR-34a delivered by the nanocarrier could also inhibit growth, clonogenicity and cell cycle of PDAC cells. Systemic administration of polymer-siRNA nanoplexes to orthotopically-inoculated pancreatic tumors showed no toxicity and accumulated selectively at the tumor site warranting its potential as a novel therapeutic for PDAC.

Key words: microRNA, pancreatic cancer, polymer therapeutics, nanomedicine.