1. Academic Validation
  2. Efficacy of Lenvatinib, a multitargeted tyrosine kinase inhibitor, on laser-induced CNV mouse model of neovascular AMD

Efficacy of Lenvatinib, a multitargeted tyrosine kinase inhibitor, on laser-induced CNV mouse model of neovascular AMD

  • Exp Eye Res. 2018 Mar;168:2-11. doi: 10.1016/j.exer.2017.12.009.
Xian Wei 1 Ting Zhang 2 Yuqin Yao 3 Shaoxue Zeng 4 Min Li 2 Haotian Xiang 4 Chengjian Zhao 2 Guiqun Cao 5 Minhui Li 1 Ran Wan 6 Ping Yang 7 Jinliang Yang 8
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Chengdu Medical College, Chengdu, PR China.
  • 2 State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.
  • 3 Research Center for Public Health and Preventive Medicine, West China School of Public Health, No.4 West China Teaching Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: yuqin_yao@scu.edu.cn.
  • 4 Ophthalmic Laboratories & Department of Ophthalmology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, PR China.
  • 5 Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, PR China.
  • 6 Liverpool Hospital, Liverpool, NSW, 2170, Australia.
  • 7 School of Basic Medical Sciences, Chengdu Medical College, Chengdu, PR China. Electronic address: yangping1996@cmc.edu.cn.
  • 8 Guangdong Zhongsheng Pharmaceutical Co., Ltd, Guangdong, PR China.
Abstract

Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Although intravitreal injection of anti-VEGF Antibodies and VEGF Trap have significant clinical benefits, the complications of intravitreal injection, drug resistance and patient compliance still need to be concerned. In this study, the effects of an orally administered multi-targeted tyrosine kinase inhibitor (Lenvatinib, E7080) were evaluated in vitro and in vivo on neovascular AMD mouse model. The results showed that E7080 effectively inhibited the proliferation, migration and tubule formation of human choroidal microvascular endothelial cells (HCMECs), and suppressed the angiogenesis of zebrafish subintestinal vessels without causing malformation. The anti-angiogenic effect of E7080 on the laser-induced choroidal neovascularization (CNV) mouse model by oral administration of 10 mg/kg/day was observed. The fluorescein angiography showed CNV leakage area in treatment group vs control group was 3.407 ± 0.2939 vs 5.202 ± 0.9001 (P = .0133) at day 7th post laser-induced CNV, 1.138 ± 0.4334 vs 3.122 ± 0.3466 (P = .0064) at day 14th, 1.401 ± 0.6577 vs 2.781 ± 0.9815 (P = .00262) at day 21th respectively. Moreover, pharmacokinetics analysis in rat retina showed that E7080 rapidly penetrated the blood-retina barrier to retina through oral administration. The T1/2 in retina was 3.81 ± 0.77 h, the Tmax was 4.60 ± 0.73 h, the AUC0-∞ was 110448.51 ± 18532.51 h*ng/g after a single dose administration analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In conclusion, our study suggested that orally administered E7080 can be a novel therapeutic strategy for neovascular AMD.

Keywords

Angiogenesis; Choroidal neovascularization; LC/MS/MS; Lenvatinib; Neovascular AMD; Retina; tyrosine kinase inhibitor.

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