Cheng L, Hostetler K Y, Chaidhawangul S, Gardner M F, Beadle J R, Keefe K S, Bergeron-Lynn G, Severson G M, Soules K A, Mueller A J, Freeman W R
Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
Invest Ophthalmol Vis Sci. 2000 May;41(6):1523-32.
To evaluate the intraocular safety and antiviral treatment efficacy of the sustained lipid prodrug of ganciclovir, 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV), as an intravitreal injectable drug system for viral retinitis.
HDP-P-GCV was synthesized by coupling 1-O-hexadecyl-propanediol-3-phosphate to either free hydroxyl of ganciclovir in pyridine with dicyclohexylcarbodiimide as catalyst. The compound was formulated into liposomes. The antiviral activity was assessed by DNA reduction in vitro, and intraocular safety was assessed by ophthalmoscopy, electrophysiology, and histology after intravitreal injections, with resultant intravitreal concentrations of 0.2, 0.632, 1.12, and 2 mM. The treatment efficacy was evaluated by simultaneous intravitreal injection of HDP-P-GCV and herpes simplex virus type 1 (HSV-1) or by intravitreal injection of HDP-P-GCV at various times before HSV-1 intravitreal inoculation. Retinitis was scored with ophthalmoscopy and compared with controls.
In vitro, the IC50 of HDP-P-GCV against HSV-1 and human cytomegalovirus (HCMV) infected cells was 0.02 and 0.6 microM, respectively. In rabbits in vivo, HDP-P-GCV dispersed evenly and maintained a good vitreous clarity at all doses except 2 mM final intravitreal concentration. Although cataracts were observed in some eyes at the higher doses, they were not observed in eyes with 0.2 mM final intravitreal concentration. No other indications of ocular toxicity were observed. Intravitreal injection of HDP-P-GCV with resultant 0.2 mM intravitreal concentration in the HSV-1 retinitis rabbit model demonstrated a complete protection of the retina with the simultaneous treatment strategy and a 4 (P = 0.03) to 6-(P = 0.058) week significant protection of retina with the pretreatment strategies when compared with ganciclovir or blank liposome controls.
In the rabbit model of HSV-1 retinitis HDP-P-GCV acts as a long-lasting intravitreal injectable anti-CMV or anti-HSV compound. This self-assembling liposome system could be applicable for many compounds available for intraocular diseases.
评估更昔洛韦的持续脂质前药1-O-十六烷基丙二醇-3-磷酸更昔洛韦（HDP-P-GCV）作为玻璃体内注射用药物系统治疗病毒性视网膜炎的眼内安全性和抗病毒治疗效果。
以二环己基碳二亚胺为催化剂，在吡啶中将1-O-十六烷基丙二醇-3-磷酸与更昔洛韦的游离羟基偶联合成HDP-P-GCV。将该化合物制成脂质体。通过体外DNA减少评估抗病毒活性，通过玻璃体腔内注射后进行检眼镜检查、电生理学和组织学评估眼内安全性，最终玻璃体腔内浓度分别为0.2、0.632、1.12和2 mM。通过同时玻璃体腔内注射HDP-P-GCV和1型单纯疱疹病毒（HSV-1）或在HSV-1玻璃体腔内接种前不同时间玻璃体腔内注射HDP-P-GCV来评估治疗效果。用检眼镜检查对视网膜炎进行评分并与对照组比较。
在体外，HDP-P-GCV对HSV-1和人巨细胞病毒（HCMV）感染细胞的IC50分别为0.02和0.6 microM。在兔体内，除最终玻璃体腔内浓度为2 mM外，所有剂量的HDP-P-GCV均均匀分散并保持良好的玻璃体清晰度。虽然在较高剂量时在一些眼中观察到白内障，但在最终玻璃体腔内浓度为0.2 mM的眼中未观察到。未观察到其他眼毒性迹象。在HSV-1视网膜炎兔模型中，玻璃体腔内注射HDP-P-GCV使最终玻璃体腔内浓度达到0.2 mM，与更昔洛韦或空白脂质体对照组相比，同时治疗策略可完全保护视网膜，预处理策略可使视网膜在4（P = 0.03）至6（P = 0.058）周内得到显著保护。
在HSV-1视网膜炎兔模型中，HDP-P-GCV可作为一种长效的玻璃体内注射用抗CMV或抗HSV化合物。这种自组装脂质体系统可适用于许多用于眼内疾病的化合物。
