Protein Transport to Choroid and Retina following Periocular Injection: Theoretical and Experimental Study

Abstract

Ocular neovascularization is a major cause of blindness in several diseases including age-related macular degeneration (choroidal neovascularization) and diabetic retinopathy (retinal neovascularization). Antiangiogenic agents with clinically significant effects exist, but a key question remains: how to effectively deliver drugs to the site of neovascularization. Periocular delivery of drugs or proteins is less invasive and safer than intravitreous delivery, but little is known regarding how and to what extent agents access intraocular tissues after periocular injection. We present a computational model of drug or protein transport into the eye following periocular injection to quantify movement of macromolecules across the sclera of the mouse eye. We apply this model to the movement of green fluorescent protein (GFP) across the mouse eye and fit the results of in vivo experiments to find transport parameters. Using these parameters, the model gives the profile of interstitial GFP concentration across the sclera, choroid and retina. We compare this to predictions of transport following intravitreous injections. We then scale up the model to estimate the transport of GFP into the human choroid and retina; the thicker sclera decreases transscleral delivery. This is the first model of ocular drug delivery to explicitly account for transport properties of each eye layer.

Computer Modeling of Drug Delivery to the Posterior Eye: Effect of Active Transport and Loss to Choroidal Blood Flow

“…5b) because the effect of k act is felt less immediately after systemic injection and it increases as the vitreous concentrations increase. More detailed experimental evaluation of the permeability of fluorescein and FG through the blood-vitreous barrier is needed to get a better estimate of k act from the model, and a more detailed view of transport in the retina, choroid, and sclera [e.g., (58)] may also be necessary.…”

Sustained Subconjunctival Protein Delivery Using a Thermosetting Gel Delivery System

“…The ReGel release system seems less traumatic than insertion of a solid implant and can still give prolonged and ample delivery. Mac Gabhann and colleagues 21 measured GFP in rat ocular tissue after a single subconjunctival dose and correlated his data with a one-dimensional distributed mathematical model of the eye tissue. These studies did not attempt long-term trans-scleral delivery with a sustained delivery biodegradable polymer.…”

Ocular delivery of macromolecules

“…Subconjunctival routes can be used for sustained-release delivery because a drug depot can be formed in these spaces. Subconjunctival administration is a potential way of delivering drugs to targets in the anterior segment and/or posterior segment [59] [80]. In vivo, proteins as large as 145 kDa were shown to penetrate though the sclera and were detected in the choroid, but mostly cleared by the systemic circulation and, thus, very small and well below the therapeutic concentration was detected in the retina [48, 49].…”