Localized delivery of heparin to angioplasty sites with iontophoresis

Drug delivery by iontophoresis involves the application of an electric field to move selectively charged drug molecules across biological membranes. The purpose of this study was to assess the efficacy of intravascular iontophoresis in the local delivery of heparin to balloon angioplasty sites by using a recently designed iontophoretic catheter. In vivo heparin iontophoresis was assessed in 33 rats and 21 pigs in four protocols designed to measure the technical determinants of intramural drug deposition, the pharmacokinetics and localization of coronary delivery, and the effect of this technique on platelet deposition following balloon injury. First, iontophoresis of 3H-heparin into the aorta of 33 rats was performed to determine the effects of iontophoretic current, iontophoretic membrane balloon initiation pressure, iontophoresis time, and heparin concentration on intramural drug deposition. Second, iontophoresis of 3H-heparin was performed in 16 porcine coronary arteries to quantitate immediate drug delivery and subsequent wash-out over 24 h. Third, iontophoresis of fluorescent heparin was performed in 8 porcine coronary arteries to define intramural localization of locally delivered drug. Fourth, 111In-labeled platelet deposition was measured 1 h following balloon angioplasty and local iontophoretic heparin delivery in 16 porcine carotid and iliac vessels. Contralateral control vessels that were dilated with the same size balloon and treated with iontophoresis of saline served as controls. Rat aortic studies demonstrated that iontophoresis resulted in 13 times more intramural heparin deposition than passive delivery (passive: 0.3 +/- 0.4 microgram, iontophoresis: 4.6 +/- 1.6 micrograms, P < 0.0004). Iontophoretic membrane balloon inflation pressure had no significant effect on intramural drug deposition, but longer iontophoresis times and higher heparin concentrations resulted in higher levels of intramural heparin (P < 0.05). Porcine coronary studies demonstrated successful intramural deposition of heparin in all arteries without adverse electrical or hemodynamic sequelae, with persistence of the drug for at least 24 h. Localization studies demonstrated immediate deposition of fluorescent heparin in the intima and internal elastic lamina, with subsequent rapid diffusion of the drug into the media. Porcine platelet studies demonstrated that heparin iontophoresis decreased platelet deposition following balloon injury by approximately 66% compared with saline-treated control vessels (heparin-treated: 1.46 +/- 2.51 x 10(8), control: 4.27 +/- 7.02 x 10(8), P = 0.001). This study has demonstrated that local intramural heparin delivery is feasible with an intravascular iontophoretic catheter. Following intracoronary heparin iontophoresis in the porcine model, intramural drug is detected for at least 24 h. Local delivery of heparin with this technique significantly decreases early platelet deposition following balloon injury in peripheral porcine arteries.