The Effect of CM082, an Oral Tyrosine Kinase Inhibitor, on Experimental Choroidal Neovascularization in Rats

Abstract

The aims of this study were to evaluate the effects of CM082 on the development of choroidal neovascularization (CNV) in a laser-induced CNV rat model and to determine the drug concentration in the ocular tissues. After the laser-induced CNV model was established in rats, CM082 was orally administered. The effects of CM082 on the CNV lesions were assessed using fundus fluorescein angiography (FFA), CNV histology, and retinal pigment epithelium- (RPE-) choroid-sclera eyecup analysis. The concentrations of CM082 in the plasma and eye tissues were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results of FFA, histology, and RPE-choroid-sclera eyecup analysis demonstrated that the CM082-treated (10 mg/kg/d or 30 mg/kg/d) rats exhibited significantly less neovascularization than did the control group. The total concentration of CM082 in the eyes (172.86 ± 57.11 ng/g) was similar to that in the plasma (196.87 ± 73.13 ng/ml). Within the eye, the concentrations of CM082 and its metabolites were highest in the retina-sclera. The orally administered CM082 thus effectively passed through the blood-retina barrier (BRB) to reach the retina in the Brown Norway rats. Therefore, at both 10 mg/kg/d and 30 mg/kg/d, CM082 was able to reduce CNV lesions in the laser-induced CNV rat model.

Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity

“…Preclinical studies in rats revealed that an oral administration of vorolanib could reduce CNV lesions in a laser-induced CNV rat model. 9 In this study, vorolanib dose-dependently inhibited the KDR phosphorylation of HUVECs, thus notably repressed VEGF-induced proliferation of HUVECs. Moreover, vorolanib was found to inhibit the tube formation of HUVECs, further suggesting its role in inhibiting angiogenesis.…”

“…Vorolanib (CM082) is a TKI that targets all VEGFR and plateletderived growth factor receptor (PDGFR) isoforms. 9 It has a shorter half-life and limited tissue accumulation compared with other TKIs. 10 Enhanced chemotherapeutic drug efficacy has also been shown by inhibition of the drug efflux function of ABCG2, a potential ATP-binding cassette transporter.…”

Vorolanib, an oral VEGFR/PDGFR dual tyrosine kinase inhibitor for treatment of patients with advanced solid tumors: An open-label, phase I dose escalation and dose expansion trial

“…Preclinical studies have indicated that vorolanib has a shorter half-life than approved TKIs for advanced RCC sunitinib and pazopanib. Furthermore, vorolanib is known to exert substantial inhibitory effects on VEGFR, PDGFR, c-KIT, and FLT-3, thus leading to the inhibition of vascular endothelial cell proliferation and lumen formation in vitro ( 16 , 17 ). The inhibition of VEGF signaling has been shown to induce the regression of choroidal neovascularization in a rat model treated with vorolanib ( 17 ).…”

“…Furthermore, vorolanib is known to exert substantial inhibitory effects on VEGFR, PDGFR, c-KIT, and FLT-3, thus leading to the inhibition of vascular endothelial cell proliferation and lumen formation in vitro ( 16 , 17 ). The inhibition of VEGF signaling has been shown to induce the regression of choroidal neovascularization in a rat model treated with vorolanib ( 17 ). A subsequent phase I dose-escalation trial in patients with neovascular age-related macular degeneration showed a favorable toxicity profile when administered with a daily dose of 200 mg of vorolanib in the vast majority of patients who completed 24-week treatment reported maintained or improved visual acuity ( 18 ).…”

Fluorescein Sodium Loaded By Polyethyleneimine for Fundus Fluorescein Angiography Improves Adhesion

“…All animals received were cared for in strict accordance with the Association for Research in Vision and Ophthalmology Statement for the use of animals in vision and ophthalmic research and the Shanghai Tenth People's Hospital Guidelines for the Use of Animals in Research. Brown Norway rats (6-8 w, 180-200 g, male) were used to establish CNV models, and laser photocoagulation-induced CNV models were established as previously described [32]. Intraperitoneal injection of 1% pentobarbital sodium (40 mg/kg, Sigma-Aldrich) was used to anesthetize the animals, a topical application of 0.5% tropicamide (Mydrin-P, Santen Pharmaceutical Co., Osaka, Japan) was used to dilate the pupil, and 0.5% Alcaine (Alcon [China] Ophthalmic Product Co., Beijing, China) was used to anesthetize the ocular surface.…”