Research ArticleDrug Delivery

Local iontophoretic administration of cytotoxic therapies to solid tumors

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Science Translational Medicine  04 Feb 2015:
Vol. 7, Issue 273, pp. 273ra14
DOI: 10.1126/scitranslmed.3009951

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Electric field drives drugs into tumors

Maintaining a high local concentration of anticancer drug may be key to killing tumors, but sometimes, therapeutics need an extra “push” to fully penetrate cancer tissues. Byrne and colleagues created a new implantable device that relies on iontophoresis—or, the flow of charged molecules in an electric field—to drive drugs into tumors. In doing so, the device, lodged in the tumor, enables local delivery of cytotoxic therapies. The authors tested their iontophoretic devices in mouse models of human pancreatic and breast cancers, using the standard drugs gemcitabine and cisplatin. The device enhanced the therapeutic efficacy of the drugs, slowing tumor growth in all animals and prolonging survival in the breast cancer models, especially when in combination with radiotherapy. In dogs, the device showed favorable pharmacokinetic profiles, indicating that, if implanted in humans, drugs would be retained primarily at the site of the tumor rather than traveling throughout the body, damaging healthy tissues. By maintaining high local drug concentrations and low systemic exposure, the iontophoretic device could improve long-term patient outcomes compared with intravenous injection of cytotoxic therapies. Currently, there are iontophoretic catheters (for bladder) and pumps (for arteries) being tested in patients, thus paving the way for this device to move into human 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.

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