MR Molecular Image Guided Treatment of Pancreatic Cancer with Targeted ECO/miR-200c Nanoparticles in Immunocompetent Mouse Tumor Models

Abstract

Objective Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplasia due to increased deposition of extracellular matrix (ECM) proteins. This work investigates the efficacy of targeted ECO/miR-200c nanoparticles (ELNP) on ECM remodeling in PDAC and tumor proliferation with MR molecular imaging (MRMI) with MT218 in immunocompetent mouse models. Methods The miR-200c mediated regulation of EMT markers was measured in PDAC cells in vitro . Wild-type mice bearing mutated KRAS-driven KPC subcutaneous or orthotopic tumors were dosed weekly with RGD-ELNP/miR-200c at 1 mg-RNA/kg for a total of 4 doses. We utilized MT218-MRMI to non-invasively monitor the alteration of tumor ECM EDN-FN levels by miR-200c and tumor response to the treatment. The changes were also validated by posthumous histopathology. Results Transfection of PDAC cells with ELNP/miR-200c downregulated the expression of FN1 and EDB-FN and some mesenchymal markers, inhibiting 3D spheroid formation and migration of KPC PDAC cells. RGD-ELNP/miR-200c treatment resulted in significant signal reduction in the MT218 enhanced MRMI images of both subcutaneous and orthotopic KPC tumors compared to those prior to treatment and treated with a non-specific control. MT218-MRMI results were suggestive of EDB-FN downregulation in tumors, which was later confirmed by immunohistochemistry. Tumor growth in subcutaneous tumors was significantly attenuated with RGD-ELNP/miR-200c and was an observed trend in orthotopic tumors. Substantial necrosis and remodeling were observed in both models treated with RGD-ELNP/miR-200c based on H&E staining. Conclusion These results demonstrate the feasibility of RGD-ELNP/miR-200c in modulating PDAC ECM and restraining tumor growth and the utility of MT218-MRMI for non-invasively monitoring miR-200c efficacy.

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