A novel lipid prodrug strategy for sustained delivery of hexadecyloxypropyl 9-[2-(phosphonomethoxy)ethyl]guanine (HDP-PMEG) on unwanted ocular proliferation. (1st January 2017)

• Record Type: Journal Article
• Authors: Chen, Mei; Hou, Jiangping; Tan, Guilin; Xie, Peng; Freeman, William R.; Beadle, James R.; Hostetler, Karl Y.; Cheng, Lingyun
• Is Part Of: Drug delivery. Volume 24:Number 1(2017)
• Page Start: 1703
• Page End: 1712
• Publication Date: 2017-01-01
• Subjects: Intravitreal drug delivery -- hexadecyloxypropyl 9-[2-(phosphonomethoxy) ethyl]guanine (HDP-PMEG) -- ocular toxicity -- rabbit PVR model -- rat CNV model -- lipid prodrug -- UHR-OCT -- retina fluorescein angiography; Drug delivery systems -- Periodicals; Drug targeting -- Periodicals; 615.05
• DOI: 10.1080/10717544.2017.1399303
• Languages: English
• ISSNs: 1071-7544

Abstract

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.