title: Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma.
abstract: Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.
authors: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors: James D
authors: JD
authors: Byrne
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors: Mohammad R N
authors: MR
authors: Jajja
authors: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors: Allison N
authors: AN
authors: Schorzman
authors: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors: Amanda W
authors: AW
authors: Keeler
authors: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors: J Christopher
authors: JC
authors: Luft
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors: William C
authors: WC
authors: Zamboni
authors: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695; desimone@unc.edu jen_jen_yeh@med.unc.edu.
authors: Joseph M
authors: JM
authors: DeSimone
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 desimone@unc.edu jen_jen_yeh@med.unc.edu.
authors: Jen Jen
authors: JJ
authors: Yeh
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D015918:Infusion Pumps, Implantable; D007478:Iontophoresis / Q000295:instrumentation; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: FOLFIRINOX; chemotherapy; device delivery; iontophoresis; pancreatic cancer