Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 6, pp 991–998 | Cite as

Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer

  • James D. ByrneEmail author
  • Mohammad R. N. Jajja
  • Adrian T. O’Neill
  • Allison N. Schorzman
  • Amanda W. Keeler
  • J. Christopher Luft
  • William C. Zamboni
  • Joseph M. DeSimone
  • Jen Jen Yeh
Original Article



Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer.


Three formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer.


Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations.


Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.


Iontophoresis FOLFIRINOX Pancreatic cancer Device delivery Chemotherapy 



Folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin


University of North Carolina


Liquid chromatography–mass spectrometry


Quality controls


Inductively-coupled plasma mass spectroscopy



We would like to thank X. Wang, C. Santos, S. Herrera-Loeza, UNC Animal Studies Core, PDX Program, and the Tissue Procurement Facility for their contributions to this work.


University Cancer Research Fund at the University of North Carolina. J. D. B. was supported by a National Defense Science and Engineering Graduate Fellowship, UNC Medical Scientists Training Program NIGMS-2-T32-GM008719, and PhRMA Foundation Fellowship.

Compliance with ethical standards

Conflict of interest

J. D. B., J. M. D., and J. J. Y. hold equity in the start-up company, Advanced Chemotherapy Technologies L.L.C.

Supplementary material

280_2018_3570_MOESM1_ESM.docx (205 kb)
Iontophoretic transport of the FOLFIRINOX formulations characterized according to liver and kidney exposure after a single device treatment. (DOCX 205 kb)


  1. 1.
    Garrido-Laguna I, Hidalgo M (2015) Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol 12:319–334CrossRefPubMedGoogle Scholar
  2. 2.
    Kleef J, Reiser C, Hinz U, Bachmann J, Debus J, Jaeger D, Friess H, Büchler MW (2007) Surgery for recurrent pancreatic ductal adenocarcinoma. Ann Surg 245:566–572CrossRefGoogle Scholar
  3. 3.
    Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA (2009) Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Neesse A, Algül H, Tuveson DA, Gress TM (2015) Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 64:1476–1484CrossRefPubMedGoogle Scholar
  5. 5.
    Byrne JD, Jajja MR, O’Neill AT, Bickford LR, Keeler AW, Hyder N, Wagner K, Deal A, Little RE, Moffitt RA, Stack C, Nelson M, Brooks CR, Lee W, Luft JC, Napier ME, Darr D, Anders CK, Stack R, Tepper JE, Wang AZ, Zamboni WC, Yeh JJ, DeSimone JM (2015) Local iontophoretic administration of cytotoxic therapies to solid tumors. Sci Transl Med 7:273ra14CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Byrne JD, Jajja MR, Schorzman AN, Keeler AW, Luft JC, Zamboni WC, DeSimone JM, Yeh JJ (2016) Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci 113:2200–2205CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kalia YN, Naik A, Garrison J, Guy RH (2004) Iontophoretic drug delivery. Adv Drug Deliv Rev 56:619–658CrossRefPubMedGoogle Scholar
  8. 8.
    Gratieri T, Kalia YN (2014) Targeted local simultaneous iontophoresis of chemotherapies for topical therapy of head and neck cancers. Int J Pharm 460:24–27CrossRefPubMedGoogle Scholar
  9. 9.
    Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer, PRODIGE Intergroup (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–1825CrossRefPubMedGoogle Scholar
  10. 10.
    Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, Smyla JK, Anderson JM, Kim HJ, Bentrem DJ, Talamonti MS, Iacobuzio-Donahue CA, Hollingsworth MA, Yeh JJ (2015) Virtual microdissection identifies distinct tumor- and stroma specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 47:1168–1178CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Na YS, Kim SM, Jung KA, Yang SJ, Hong YS, Ryu MH, Ro S, Cho DH, Kim JC, Jin DH, Lee JS, Kim TW (2010) Effects of the HDAC inhibitor CG2 in combination with irinotecan, 5-fluorouracil, or oxaliplatin on HCT116 colon cancer cells and xenografts. Oncol Rep 24:1509–1514PubMedGoogle Scholar
  12. 12.
    Azrak RG, Cao S, Slocum HK, Tóth K, Durrani FA, Yin MB, Pendyala L, Zhang W, McLeod HL, Rustum YM (2004) Therapeutic synergy between irinotecan and 5-fluorouracil against human tumor xenografts. Clin Cancer Res 10:1121–1129CrossRefPubMedGoogle Scholar
  13. 13.
    Louvet C, Coudray AM, Tournigand C, Prévost S, Raymond E, de Gramont A, Chazard M, Gespach C (2000) Synergistic antitumoral activity of combined UFT, folinic acid and oxaliplatin against human colorectal HT29 cell xenografts in athymic nude mice. Anticancer Drugs 11:579–582CrossRefPubMedGoogle Scholar
  14. 14.
    Wallace BD, Roberts AB, Pollet RM, Ingle JD, Biernat KA, Pellock SJ, Venkatesh MK, Guthrie L, O’Neal SK, Robinson SJ, Dollinger M, Figueroa E, McShane SR, Cohen RD, Jin J, Frye SV, Zamboni WC, Pepe-Ranney C, Mani S, Kelly L, Redinbo MR (2015) Structure and inhibition of microbiome β-glucuronidases essential to the alleviation of cancer drug toxicity. Chem Biol 22:1238–1249CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Büchel B, Rhyn P, Schürch S, Bühr C, Amstutz U, Largiadèr CR (2013) LC–MS/MS method for simultaneous analysis of uracil, 5,6-dihydrouracil, 5-fluorouracil and 5-fluoro-5,6-dihydrouracil in human plasma for therapeutic drug monitoring and toxicity prediction in cancer patients. Biomed Chromatogr 27:7–16CrossRefPubMedGoogle Scholar
  16. 16.
    Kai MP, Keeler AW, Perry JL, Reuter KG, Luft JC, O’Neal SK, Zamboni WC, DeSimone JM (2015) Evaluation of drug loading, pharmacokinetic behavior, and toxicity of a cisplatin-containing hydrogel nanoparticle. J Control Release 204:70–77CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C, LAP07 Trial Group (2016) Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 315:1844–1853CrossRefPubMedGoogle Scholar
  18. 18.
    Heestan GM, Murphy JD, Lowy AM (2015) Approach to patients with pancreatic cancer without detectable metastases. J Clin Oncol 33:1770–1778CrossRefGoogle Scholar
  19. 19.
    Indolfi L, Ligorio M, Ting DT, Xega K, Tzafriri AR, Bersani F, Aceto N, Thapar V, Fuchs BC, Deshpande V, Baker AB, Ferrone CR, Haber DA, Langer R, Clark JW, Edelman ER (2016) A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma. Biomaterials 93:71–82CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yi HG, Choi YJ, Kang KS, Hong JM, Pati RG, Shim IK, Lee CM, Kim SC, Cho DW (2016) A 3D-printed local drug delivery patch for pancreatic cancer growth suppression. J Control Release 238:231–241CrossRefPubMedGoogle Scholar
  21. 21.
    Wu H, Infante JR, Keedy VL, Jones SF, Chan E, Bendell JC, Lee W, Kirschbrown WP, Zamboni BA, Ikeda S, Kodaira H, Rothenberg ML, Burris HA, Zamboni WC (2015) Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors. Int J Nanomed 10:1201–1209CrossRefGoogle Scholar
  22. 22.
    Pikal MJ (2001) The role of electroosmotic flow in transdermal iontophoresis. Adv Drug Deliv Rev 46:281–305CrossRefPubMedGoogle Scholar
  23. 23.
    Leucovorin [package insert] (2012) Sagent Pharmaceuticals, Schaumburg, IL, USAGoogle Scholar
  24. 24.
    5-Fluorouracil [package insert] (2000) APP Pharmaceuticals, Schaumburg, IL, USAGoogle Scholar
  25. 25.
    Irinotecan [package insert] (2008) Sun Pharmaceuticals, Gujarat, IndiaGoogle Scholar
  26. 26.
    Oxaliplatin [package insert] (2009) Hospira, Gujarat, IndiaGoogle Scholar
  27. 27.
    Melisi D, Xia Q, Paradiso G, Ling J, Moccia T, Carbone C, Budillon A, Abbruzzese JL, Chiao PJ (2011) Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. JNCI 103:1190–1204CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kurata N, Fujita H, Ohuchida K, Mizumoto K, Mahawithitwong P, Sakai H, Onimaru M, Manabe T, Ohtsuka T, Tanaka M (2011) Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil. Int J Oncol 39:473–482PubMedGoogle Scholar
  29. 29.
    Cui Y, Brosnan JA, Blackford A, Sur S, Hruban RH, Kinzler KW, Vogelstein B, Maitra A, Diaz LA, Iacobuzio-Donahue CA, Eshleman JR (2012) Genetically defined subsets of human pancreatic cancer demonstrate unique in vitro chemosensitivity. Clin Cancer Res 18:6519–6530CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • James D. Byrne
    • 1
    • 2
    Email author
  • Mohammad R. N. Jajja
    • 3
  • Adrian T. O’Neill
    • 3
  • Allison N. Schorzman
    • 4
  • Amanda W. Keeler
    • 4
  • J. Christopher Luft
    • 1
    • 3
  • William C. Zamboni
    • 3
    • 4
  • Joseph M. DeSimone
    • 1
    • 3
    • 5
    • 6
    • 7
  • Jen Jen Yeh
    • 3
    • 6
    • 8
  1. 1.Division of Molecular Pharmaceutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  5. 5.Department of ChemistryUniversity of North Carolina at Chapel HillChapel HillUSA
  6. 6.Department of PharmacologyUniversity of North Carolina at Chapel HillChapel HillUSA
  7. 7.Department of Chemical and Biomolecular EngineeringNorth Carolina State UniversityRaleighUSA
  8. 8.Division of Surgical Oncology, Department of SurgeryUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations