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.
Highlights
Unwanted cell proliferation is a hallmark of many human diseases, including various tumors and cancers
The analysis revealed that intraocular pressure (IOP) was not significantly different among the checking points but IOP was significantly different among the dose groups (p 1⁄4 .0029)
proliferative vitreoretinopathy (PVR) is a blinding eye disease which is responsible for 10%–20% failure of retinal detachment repair, (Heimann et al, 2007) and PVR is responsible for over 21% of severe vision loss after open globe eye trauma (Cardillo et al, 1997)
Summary
Unwanted cell proliferation is a hallmark of many human diseases, including various tumors and cancers. In the arena of visual science, intraocular cellular proliferation is a prominent feature of several ocular disorders, including proliferative vitreoretinopathy (PVR), one of the most common causes of retinal re-detachment (Cardillo et al, 1997; Asaria & Charteris, 2006; Klein et al, 2008; Wang et al, 2009). PVR can arise from various pathologic conditions such as diabetic retinopathy, ocular trauma, and rhegmatogenous retinal detachment, as well as intraocular surgical procedure itself. The current available treatment for PVR is vitreoretinal surgical approach (vitrectomy); recurrent membrane formation can lead to retinal re-detachment and permanent impairment of vision (Asaria & Charteris, 2006). It has been reported that a median time to develop PVR after an intraocular procedure or ocular trauma is about
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