Transscleral Iontophoresis for Noninvasive Ocular Drug Delivery of Macromolecules

Abstract

<b><i>Purpose:</i></b> The objectives were to investigate the effect of transscleral iontophoresis of macromolecules <i>in vitro</i> and <i>in vivo</i>, to study the importance of electroosmosis on macromolecules of low charge to mass ratio, and to evaluate transscleral iontophoresis efficacy in a choroidal neovascularization (CNV) animal model. <b><i>Methods:</i></b> Through <i>in vitro</i> transport experiments, the permeability coefficients of macromolecules [eg, immunoglobulin G (IgG), dextran 70 kDa] were determined under different conditions. The effect of ionic strength formulations and iontophoretic conditions was studied on the distribution of IgG and bevacizumab into the eye <i>in vivo</i>. Magnetic resonance imaging (MRI) was utilized to evaluate <i>in vivo</i> real time distribution of gadolinium-labeled albumin (Galbumin) following iontophoresis. The efficacy between no treatment, intravitreal injection (IVT), and iontophoresis of bevacizumab on a CNV model of subretinal injection of adeno-associated virus encoding human VEGF-165 was investigated. <b><i>Results:</i></b> The permeability data suggested a significant effect of ionic strength on the iontophoretic transport of macromolecules. Transscleral iontophoresis of IgG at 4 mA with a low ionic strength formulation was about 600 times greater than passive diffusion and 14-fold over a conventional formulation <i>in vitro</i>. Approximately 0.6 mg of bevacizumab can be delivered into the rabbit eye <i>in vivo</i> with a 20-min treatment of iontophoresis. MRI showed that Galbumin was in the posterior tissues after iontophoresis. In the CNV model, the iontophoresis and IVT methods of bevacizumab delayed retinal neovascularization by 4 and 8 weeks, respectively. <b><i>Conclusions:</i></b> Transscleral iontophoresis is capable of delivering macromolecule drugs through the conjunctiva and sclera, eventually exposing the retina/choroid to the drugs.