title: Local iontophoretic administration of cytotoxic therapies to solid tumors.
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.
authors: 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.
authors: James D
authors: JD
authors: Byrne
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Mohammad R N
authors: MR
authors: Jajja
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Adrian T
authors: AT
authors: O'Neill
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Lissett R
authors: LR
authors: Bickford
authors: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Amanda W
authors: AW
authors: Keeler
authors: Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Nabeel
authors: N
authors: Hyder
authors: Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Kyle
authors: K
authors: Wagner
authors: Lineberger Comprehensive Cancer Center Biostatistics and Clinical Data Management Core, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Allison
authors: A
authors: Deal
authors: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Ryan E
authors: RE
authors: Little
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Richard A
authors: RA
authors: Moffitt
authors: 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.
authors: Colleen
authors: C
authors: Stack
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Meredith
authors: M
authors: Nelson
authors: Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Christopher R
authors: CR
authors: Brooks
authors: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: William
authors: W
authors: Lee
authors: 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.
authors: J Chris
authors: JC
authors: Luft
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Mary E
authors: ME
authors: Napier
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: David
authors: D
authors: Darr
authors: 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.
authors: Carey K
authors: CK
authors: Anders
authors: 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.
authors: Richard
authors: R
authors: Stack
authors: 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.
authors: Joel E
authors: JE
authors: Tepper
authors: 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.
authors: Andrew Z
authors: AZ
authors: Wang
authors: 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.
authors: William C
authors: WC
authors: Zamboni
authors: 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.
authors: Jen Jen
authors: JJ
authors: Yeh
authors: 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.
authors: Joseph M
authors: JM
authors: DeSimone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004285:Dogs; D016503:Drug Delivery Systems; D004867:Equipment Design; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007478:Iontophoresis; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D012867:Skin / Q000187:drug effects; D016019:Survival Analysis; D014018:Tissue Distribution / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine
references: Ophthalmology. 2012 Jan;119(1):66-73
references: 22115712
references: Clin Cancer Res. 2008 Oct 15;14(20):6456-68
references: 18927285
references: BMC Urol. 2005;5:14
references: 16300684
references: Ann Intern Med. 1987 Oct;107(4):459-65
references: 2957943
references: J Control Release. 2013 Jun 28;168(3):298-306
references: 23562634
references: Adv Drug Deliv Rev. 2004 Mar 27;56(5):619-58
references: 15019750
references: Clin Cancer Res. 1999 Jun;5(6):1583-6
references: 10389947
references: N Engl J Med. 2008 Jan 3;358(1):36-46
references: 18172173
references: Cancer Cell. 2014 Apr 14;25(4):516-29
references: 24684846
references: Nat Rev Clin Oncol. 2012 Jun;9(6):338-50
references: 22508028
references: Clin Cancer Res. 2006 Aug 1;12(15):4652-61
references: 16899615
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2006 May 1;835(1-2):136-42
references: 16584929
references: N Engl J Med. 2011 May 12;364(19):1817-25
references: 21561347
references: N Engl J Med. 2010 Apr 29;362(17):1605-17
references: 20427809
references: Clin Cancer Res. 2002 Mar;8(3):878-84
references: 11895922
references: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19372-7
references: 19050074
references: Nat Rev Cancer. 2006 Aug;6(8):583-92
references: 16862189
references: J Am Med Assoc. 1946 Sep 21;132:126-32
references: 20997191
references: Lancet. 2004 Mar 27;363(9414):1049-57
references: 15051286
references: Cancer Res. 1998 Feb 15;58(4):672-84
references: 9485020
references: N Engl J Med. 2005 Aug 18;353(7):701-11
references: 16107623
references: Lancet Oncol. 2011 Sep;12(9):871-9
references: 21831711
references: Arch Surg. 2006 Jun;141(6):567-72; discussion 572-3
references: 16785357
references: PLoS Med. 2010 Apr;7(4):e1000267
references: 20422030
references: J Pharmacol Exp Ther. 2013 Dec;347(3):599-606
references: 24042160
references: Liver Cancer. 2012 Nov;1(3-4):144-58
references: 24159579
references: Mol Cancer Ther. 2014 Jan;13(1):122-33
references: 24222664
references: J Am Acad Dermatol. 1997 Jun;36(6 Pt 1):956-8
references: 9204062
references: Arch Dermatol. 1993 Apr;129(4):425-7
references: 8466212
references: J Control Release. 2012 Apr 10;159(1):14-26
references: 22154931
references: Clin Cancer Res. 2004 Mar 1;10(5):1633-44
references: 15014014
references: J Thorac Dis. 2014 May;6 Suppl 3:S289-97
references: 24876933
references: Pharm Res. 1999 May;16(5):758-61
references: 10350021
references: Br J Surg. 1997 Oct;84(10):1474-8
references: 9361617
references: Int J Pharm. 2014 Jan 2;460(1-2):24-7
references: 24219856
references: Clin Cancer Res. 2013 Sep 1;19(17):4889-99
references: 23780888
references: Nat Biotechnol. 2010 Jun;28(6):585-93
references: 20495549
references: N Engl J Med. 2004 Oct 21;351(17):1731-40
references: 15496622
references: Science. 2009 Jun 12;324(5933):1457-61
references: 19460966
references: J Gastrointest Surg. 2008 Apr;12(4):701-6
references: 18027062
references: Thorax. 1998 Jun;53(6):445-9
references: 9713441
references: PLoS One. 2014;9(2):e89474
references: 24586805
references: N Engl J Med. 2004 Mar 18;350(12):1200-10
references: 15028824
references: N Engl J Med. 2006 Jul 6;355(1):11-20
references: 16822992
references: Radiat Res. 2007 Jan;167(1):12-42
references: 17214511
references: Clin Cancer Res. 2009 Nov 1;15(21):6639-48
references: 19825949