Local iontophoretic administration of cytotoxic therapies to solid tumors

James D Byrne; Mohammad R N Jajja; Adrian T O'Neill; Lissett R Bickford; Amanda W Keeler; Nabeel Hyder; Kyle Wagner; Allison Deal; Ryan E Little; Richard A Moffitt; Colleen Stack; Meredith Nelson; Christopher R Brooks; William Lee; J Chris Luft; Mary E Napier; David Darr; Carey K Anders; Richard Stack; Joel E Tepper; Andrew Z Wang; William C Zamboni; Jen Jen Yeh; Joseph M DeSimone

doi:10.1126/scitranslmed.3009951

Local iontophoretic administration of cytotoxic therapies to solid tumors

Sci Transl Med. 2015 Feb 4;7(273):273ra14. doi: 10.1126/scitranslmed.3009951.

Authors

James D Byrne¹, Mohammad R N Jajja², Adrian T O'Neill², Lissett R Bickford², Amanda W Keeler³, Nabeel Hyder⁴, Kyle Wagner⁴, Allison Deal⁵, Ryan E Little⁶, Richard A Moffitt², Colleen Stack⁷, Meredith Nelson², Christopher R Brooks⁸, William Lee⁹, J Chris Luft¹⁰, Mary E Napier², David Darr², Carey K Anders¹¹, Richard Stack¹², Joel E Tepper¹³, Andrew Z Wang¹³, William C Zamboni¹⁴, Jen Jen Yeh¹⁵, Joseph M DeSimone¹⁶

Affiliations

¹ Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Lineberger Comprehensive Cancer Center Biostatistics and Clinical Data Management Core, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. School of Medicine, Duke University, Durham, NC 27708, USA. Synecor LLC, Chapel Hill, NC 27517, USA.
⁸ Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁰ Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Synecor LLC, Chapel Hill, NC 27517, USA. Division of Cardiology, Department of Medicine, Duke University, Durham, NC 27708, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. jen_jen_yeh@med.unc.edu desimone@unc.edu.
¹⁶ Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA. jen_jen_yeh@med.unc.edu desimone@unc.edu.

Abstract

Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of -0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Cell Death / drug effects
Cell Proliferation / drug effects
Cisplatin / administration & dosage
Cisplatin / pharmacokinetics
Cisplatin / pharmacology
Cisplatin / therapeutic use
Combined Modality Therapy
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacokinetics
Deoxycytidine / pharmacology
Deoxycytidine / therapeutic use
Disease Models, Animal
Dogs
Drug Delivery Systems*
Equipment Design
Female
Gemcitabine
Humans
Injections, Intravenous
Iontophoresis*
Mice, Inbred BALB C
Neoplasms / drug therapy*
Neoplasms / pathology
Neoplasms / radiotherapy
Skin / drug effects
Survival Analysis
Tissue Distribution / drug effects
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Deoxycytidine
Cisplatin
Gemcitabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding