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

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Local iontophoretic administration of cytotoxic therapies to solid tumors

Journal article

Open access

Peer reviewed

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, …

Science translational medicine, Vol.7(273), pp.273ra14-ra14

02/04/2015

DOI: 10.1126/scitranslmed.3009951

PMCID: PMC4545246

PMID: 25653220

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https://doi.org/10.1126/scitranslmed.3009951View

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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.

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

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

Details

Title: Subtitle: Local iontophoretic administration of cytotoxic therapies to solid tumors
Creators: James D Byrne - University of North Carolina at Chapel Hill
Mohammad R N Jajja - University of North Carolina at Chapel Hill
Adrian T O'Neill - University of North Carolina at Chapel Hill
Lissett R Bickford - University of North Carolina at Chapel Hill
Amanda W Keeler - University of North Carolina at Chapel Hill
Nabeel Hyder - University of North Carolina at Chapel Hill
Kyle Wagner - University of North Carolina at Chapel Hill
Allison Deal - University of North Carolina at Chapel Hill
Ryan E Little - University of North Carolina at Chapel Hill
Richard A Moffitt - University of North Carolina at Chapel Hill
Colleen Stack - University of North Carolina at Chapel Hill
Meredith Nelson - University of North Carolina at Chapel Hill
Christopher R Brooks - University of North Carolina at Chapel Hill
William Lee - University of North Carolina at Chapel Hill
J Chris Luft - University of North Carolina at Chapel Hill
Mary E Napier - University of North Carolina at Chapel Hill
David Darr - University of North Carolina at Chapel Hill
Carey K Anders - University of North Carolina at Chapel Hill
Richard Stack - Duke University
Joel E Tepper - University of North Carolina at Chapel Hill
Andrew Z Wang - University of North Carolina at Chapel Hill
William C Zamboni - University of North Carolina at Chapel Hill
Jen Jen Yeh - University of North Carolina at Chapel Hill
Joseph M DeSimone - University of North Carolina at Chapel Hill
Resource Type: Journal article
Publication Details: Science translational medicine, Vol.7(273), pp.273ra14-ra14
DOI: 10.1126/scitranslmed.3009951
PMID: 25653220
PMCID: PMC4545246
NLM abbreviation: Sci Transl Med
ISSN: 1946-6234
eISSN: 1946-6242
Grant note: R01CA178748-01 / NCI NIH HHS P30 ES010126 / NIEHS NIH HHS T32-CA009156 / NCI NIH HHS T32-GM008719 / NIGMS NIH HHS T32 CA009156 / NCI NIH HHS DP1 OD006432 / NIH HHS R01 CA178748 / NCI NIH HHS T32 GM008719 / NIGMS NIH HHS
Language: English
Date published: 02/04/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiation Oncology
Record Identifier: 9984274756002771

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