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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

FOLFIRINOX:

Folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin

UNC:

University of North Carolina

LC–MS:

Liquid chromatography–mass spectrometry

QC:

Quality controls

ICP-MS:

Inductively-coupled plasma mass spectroscopy

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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    James D. Byrne, J. Christopher Luft & Joseph M. DeSimone

  2. School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    James D. Byrne

  3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Mohammad R. N. Jajja, Adrian T. O’Neill, J. Christopher Luft, William C. Zamboni, Joseph M. DeSimone & Jen Jen Yeh

  4. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Allison N. Schorzman, Amanda W. Keeler & William C. Zamboni

  5. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Joseph M. DeSimone

  6. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Joseph M. DeSimone & Jen Jen Yeh

  7. Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, 27695, USA

    Joseph M. DeSimone

  8. Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Jen Jen Yeh

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  1. James D. Byrne
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Corresponding author

Correspondence to James D. Byrne.

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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.

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280_2018_3570_MOESM1_ESM.docx

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

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Byrne, J.D., Jajja, M.R.N., O’Neill, A.T. et al. Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer. Cancer Chemother Pharmacol 81, 991–998 (2018). https://doi.org/10.1007/s00280-018-3570-3

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