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H. Takahashi, N. Yagi, M. Yamauchi, Y. Yanagi, Y. Tamaki, I. Manabe, R. Nagai; Effects of Wrapped Liposome Encapsulating siRNA Targeting VEGF and VEGF Receptors in a Mouse Model of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2009;50(13):791.
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© ARVO (1962-2015); The Authors (2016-present)
Wrapped Liposome (WL) in the current study is composed of a core complex of cationic lipid bilayer and siRNA and an enveloping lipid bilayer with a neutral lipid and polyethylene glycol on the surface. The current study was performed to investigate whether intravenous administration of WL encapsulating siRNA targeting VEGF and its receptors (VEGFRs) is effective in suppressing choroidal neovascularization (CNV) in a mouse model.
Ten- to twelve-week old C57Bl/6J male mice were used. Firstly, to investigate the accumulation of siRNA/WL to the CNV lesion, mice received intravenous injection of fluorescein-conjugated siRNA/WL two days after laser photocoagulation and fundus photograph was taken 1, 2, 4, 8 hours and 1, 2, 4 days after the injection. Next, to examine the effects of siRNA/WL targeting to VEGF and VEGFRs on CNV, thirty mice were divided into the following 6 groups. Group 1: saline Group2: siRNA targeting luciferase. Group3: siRNA targeting VEGFA. 4: siRNA targeting VEGFR1. Group5: siRNA targeting VEGFR2. In all siRNA groups 5 mg/kg 21 to 23 base pair siRNA/WL was injected intravenously every other day. As a control, Group6 consisted of mice that orally received VEGFR2 inhibitor SU11248 150 mg/kg daily. Fluorescein angiography was performed to investigate the leakage from the CNV lesion. CNV area measurements were also performed using choroidal flatmounts seven days after laser photocoagulation. To determine the systemic side effects, body weight measurements, serum biochemistry and histological analysis of the intestine, brain and heart were performed 14 days after laser photocoagulation.
Fundus fluorescence was clearly detected at the CNV lesion 8 to 24 hours after the siRNA administration. The leakage from the CNV lesion in Groups 3 to 5 was reduced to 62 to 72 % of the control (Group2)(p<0.0001). CNV area was 40 to 52 % smaller in Groups 3 to 5 (p<0.05) than Group 2. In Group6, body weight was reduced by 17% (p<0.0001) compared to Group 2. In Group3, body weight was reduced by 5% (p<0.05) compared to Group 2. In Group 6, serum aspartate amino transferase, alanine amino transferase, alkaline phosphatase, creatinine was significantly increased (p<0.01), whereas serum biochemical analysis demonstrated no abnormalities in Groups 1 to 5. Histological analysis demonstrated the shortening of the microvilli of small interstitine in Group6. No other abnormalities were found.
WL encapsulating siRNA targeting VEGFA and its receptors may be useful in the treatment of CNV.
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