Although intravitreal injections place the entire dose in the vitreous humor, only a small fraction of the dose is expected to reach the target tissues such as choroid and retina for treating back of the eye diseases. Additionally, monthly repeated intravitreal injections carry the risk of endophthalmitis. The long-term goal of this project is to develop alternative routes of drug administration that are less or minimally invasive to the retina, while allowing targeted delivery to the affected tissues. In recent years, suprachoroidal route of drug administration not only proved to be a viable and reliable method for drug administration, but also showed promising efficacy in initial clinical studies. This route of administration offers greater choroid-retina:vitreous humor exposure of drug, when compared to intravitreal injections. Drug removal, however, is rapid from the suprachoroidal site of administration, necessitating the use of slow release dosage forms such as drug suspensions in the clinical studies. The objective of the present study is to evaluate the fate of slow release, injectable implant delivery systems in the suprachoroidal space using primarily noninvasive techniques. Noninvasive approaches will allow monitoring of the delivery system in the same animal over prolonged periods, as opposed to traditional pharmacokinetic studies that use multiple animals at discrete time points. Additionally, noninvasive approaches are likely to reduce variability, thereby improving the reliability of the data. The overall hypothesis of this study is that the dimensions and solute release characteristics of suprachoroidally injected implants can be monitored using noninvasive fundus imaging, optical coherence tomography (OCT), and fluorophotometry. This hypothesis will be tested using the following two specific aims.
Specific Aim 1 : To determine whether measures of implant location, length, diameter, and volume in the suprachoroidal space can be obtained for 2 months using noninvasive fundus imaging and optical coherence tomography.
Specific Aim 2 : To determine whether release of fluorescently labeled solutes with different lipophilicities from suprachoroidal implants can be monitored up to 2 months using noninvasive fluorophotometry. Pigmented and albino rabbits will be used in this study. At the end of the study, eye tissues will be isolated and analyzed for histological changes or solute levels in the dosed- and opposite- sides of various eye tissues. This study will provide proof of concept for the suitability of noninvasive methods to monitor slow release delivery systems and their drug release in the suprachoroidal space in the whole animal, and potentially in humans in the long-run. The findings of this study will lay a foundation for understanding the suitability of suprachoroidal space for dosing injectable, preformed implants to achieve sustained drug delivery to the back of the eye tissues. Further, this study will inform regarding the influence of solute lipophilicity and eye pigmentation on back of the eye drug delivery from a suprachoroidal implant.
This project will advance the suitability of monitoring suprachoroidally injected implants for a few months to facilitate development and assessment of novel slow release systems administered by this route. While the noninvasive monitoring approaches may allow robust human pharmacokinetic studies with a few subjects in the long run, the implants will allow reduced frequency of injections to the suprachoroidal space.