A novel lipid prodrug strategy for sustained delivery of hexadecyloxypropyl 9-[2-(phosphonomethoxy)ethyl]guanine (HDP-PMEG) on unwanted ocular proliferation

Abstract

Proliferative vitreoretinopathy (PVR) is a blinding eye disease and there is no effective pharmacological measure to prevent PVR development. The difficulty comes from lack of potent antiproliferative agent and lack of sustained delivery to cover high-risk time window for PVR to develop. Lipid prodrug of PMEG, hexadecyloxypropyl 9-[(2-phosphonomethoxy)ethyl]guanine (HDP-PMEG), was prepared and was evaluated as a pharmacological adjuvant to surgical management of PVR. A dose-escalation study determined that the highest nontoxic dose for intravitreal use in pigmented rabbits was 3 µg per eye. The genotoxicity of HDP-PMEG was harnessed as a perioperative preventative measure against PVR in a rabbit eye model while the sustained intravitreal pharmacological effect was evaluated on a laser-induced fibrovascular model in rat eye. After intravitreal 3 µg, HDP-PMEG particles in the rabbit vitreous was visible for at least 6 weeks. A single 50-min intravitreal infusion of HDP-PMEG demonstrated significant inhibition of PVR formation when compared with the eyes infused with only BSS (BSS vs. HDP-PMEG: estimate = 1.14, OR = 3.1, p = .027). A single intravitreal 104 ng (equivalent to 3 µg for rabbit eye) of HDP-PMEG significantly inhibit laser-induced fibrovascular proliferation in rat eye by 55% (least square mean pixel, BSS = 4763569.5 vs. HDP-PMEG = 2148129.7, p < .0001, generalized estimating equation [GEE]). Retinal fluorescein angiography showed the odds for BSS intervened eyes to have higher-rated FA leaking grades were 38.5 times compared with HDP-PMEG treated eyes (p < .0001, GEE). Our study results indicate that single intravitreal HDP-PMEG may be a promising ocular drug delivery as a perioperative intervention to prevent PVR reoccurrence following primary surgical management.

Prodrug Approach for Posterior Eye Drug Delivery: Synthesis of Novel Ganciclovir Prodrugs and in Vitro Screening with Cassette Dosing

“…In clinical applications, a strategy for substantial prolongation of ocular retention is needed, such as using a controlled release polymeric drug delivery system, 47 utilizing melanin binding 7,8 or exploiting solubility-limited drug release. 14 In fact, rapid physical clearance from the vitreous will probably contribute to the total clearance more than the enzymatic hydrolysis in the vitreous. Therefore, the enzymatic stabilities of the prodrugs in the vitreous are likely not a limiting factor for prodrug entry into the RPE.…”

“…Hypothetically, the increased lipophilicity could also increase drug uptake in the retina and RPE. In clinical applications, a strategy for substantial prolongation of ocular retention is needed, such as using a controlled release polymeric drug delivery system, utilizing melanin binding , or exploiting solubility-limited drug release . In fact, rapid physical clearance from the vitreous will probably contribute to the total clearance more than the enzymatic hydrolysis in the vitreous.…”

“…For example, for prodrug bioconversion studies in the vitreous humor, the increase of vitreal pH to >8 upon isolation and handling should be counteracted, , but only a few studies have attempted to overcome this problem. , This was one reason for developing a novel setup, suitable for small molecular weight compounds, where the physiological pH of the vitreous homogenate could be maintained. Lastly, intravitreal prodrugs have been studied to some extent, ,,− yet, compared to topical prodrugs, the reports are rather sparse. Some of these have reported in vitro or ex vivo methods for studying the prodrugs’ biopharmaceutical properties, ,− but the field would still benefit from further methodological development.…”

Experimental Models to Study Epithelial-Mesenchymal Transition in Proliferative Vitreoretinopathy

“…These cells will then induce subsequent epiretinal membranes, surface wrinkling retinopathy and star-fold-like configurations 4 weeks after surgery [87]. Nonetheless, as rabbit retinas are less vascularized compared to human, these models are not ideal to study the actual impact of BRB disruption and subsequent ERM formation [65,88]. In fact, rabbit retinal vascularization pattern (merangiotic) is different compared to humans (euangiotic/holangiotic) with PVR in rabbits beginning on or around the medullary rays where retinal vasculature is present, the rest of the rabbit retina being avascular [133].…”