Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma

Abstract

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patientderived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, K i -67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.iontophoresis | FOLFIRINOX | pancreatic cancer | device delivery | chemotherapy

Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy

“…GEM (Mylan) (80 mg/kg), JNK-IN-8 (30 mg/kg), and 15% Tween80 + 5% DMSO (both from Fisher) vehicle treatments were administered IP 2×/week. FOLFOX and GEM dosing was based on prior pharmacokinetics analyses (48). Animal body weights and tumor volumes (V) were both measured 1×/week, with V = (length × width 2 )/2.…”

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

“…The fabrication and testing of the device have been previously described [5–6]. Briefly, 5 millimeter (mm) disks were cut from 0.1 mm thick platinum foil using a 5 mm hole punch.…”

“…Stroma acts as a major resistance mechanism to systemically administered cytotoxic treatments [4]. To circumvent the problems associated with limited drug transport into pancreatic tumors, we have designed an implantable iontophoretic device that can be adapted to deliver cytotoxic chemotherapies directly to pancreatic tumors [5–6]. The application of an electrical potential can drive drug molecules into poorly vascularized tissues, including tumors, at higher concentrations than achievable by systemic administration [7–8].…”

Neutron‐activatable needles for radionuclide therapy of solid tumors

“…In order to deliver therapeutic agents to solid tumors, approaches which have been successfully used in the transdermal drug delivery field that do not involve simple passive diffusion have been investigated for intra‐tumoral delivery of drugs, proteins and other therapeutics. These approaches include the use of focused ultrasound, iontophoresis and electroporation . One approach that has not been previously explored is utilizing microneedle technology.…”

“…These approaches include the use of focused ultrasound, iontophoresis and electroporation. [1][2][3] One approach that has not been previously explored is utilizing microneedle technology. Microneedles have been fabricated in solid form to allow transport of therapeutics across the stratum corneum, in hollow form to allow delivery of drugs through a small orifice in the tip of the needle, and in a form composed of dissolvable materials that permit extended release of therapeutics.…”