Local Chemotherapy for Pancreatic Cancer: Potential of Injectable Drug-Loaded Microparticles

Abstract

Introduction: A key limitation of systemic delivery of chemotherapy in pancreatic adenocarcinoma (PDAC) is poor drug penetrance to the tumor due to the surrounding desmoplastic reaction. Systemic side effects also interfere with treatment continuity. These can be circumvented with a local delivery method via endoscopic ultrasound (EUS) fine needle injection. Poly(lactic-co-glycolic acid) (PLGA) is an FDA-approved polymer that can be utilized to create spherical microparticles (MPs) containing encapsulated chemotherapy that is slowly eluted with particle degradation. Methods: Local delivery of gemcitabine encapsulated within MPs (GMPs) to the the pancreas was previously explored by our lab in a 3-phase experiment. In phase I, blank MPs were injected into mouse pancreata to assess for adverse effects from the polymer and none were noted. In phase II, GMPs were injected into pancreatic tumors grown in nude mice. Injected tumors showed evidence of apoptosis compared to control pancreatic tumors. In Phase III, EUS-guided fine needle injection of GMPs into the porcine pancreas was performed. Survival was assessed for 14 days. GMPs were not localized in pancreatic tissue, calling into question if GMPs entered pancreatic tissue upon injection. This study evaluates if MPs containing fluorescently labelled protein can be localized in porcine pancreatic tissue after direct needle injection. We also present a methodology of simultaneous fluorescent labeling of PLGA and encapsulation of gemcitabine. Pancreata were harvested from pigs within 1 hour of euthanasia and placed in PBS for transport. MPs were injected into the pancreas aiming to approximate EUS conditions. Results: The tissue was H&E stained for light microscope visualization and MPs were visualized in the parenchyma and within interlobular septae. MPs were not visualized in control sections of porcine pancreatic tissue. Albumin-fluorescein isothiocyanate (BSA-FITC) was encapsulated in MPs and the injection experiments were repeated to confirm localization. Conclusion: This provided preliminary evidence that MPs enter the pancreatic tissue after injection and can be visualized. Thereafter, BSA-FITC was covalently bonded to the PLGA polymer allowing concurrent fluorescence and gemcitabine encapsulation. Visualization of the MPs in the porcine pancreas is rationale for repeating EUS fine needle injection into the pig pancreas, with the goal of developing a versatile and practical methodology for localized chemotherapy delivery to human pancreatic tumors.