The inhibition of retinal neovascularization by gold nanoparticles via suppression of VEGFR-2 activation Jin Hyoung Kim a , Myung Hun Kim b , Dong Hyun Jo a , Young Suk Yu a , Tae Geol Lee c, * , Jeong Hun Kim a, ** a Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Department of Ophthalmology, College of Medicine, Seoul National University & Seoul Artificial Eye Center Clinical Research Institute, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea b Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea c Center for Nano-BioTechnology, Division of Convergence Technology, Korea Research Institute of Standards and Science (KRISS),102 Yuseong, Daejeon 305-340, Republic of Korea article info Article history: Received 28 October 2010 Accepted 14 November 2010 Available online 9 December 2010 Keywords: Gold nanoparticle Retinal neovascularization Retinal microvascular endothelial cell Vascular endothelial growth factor receptor-2 ERK 1/2 abstract The pathological angiogenesis in the retina is the major cause of vision loss at all ages. In particular, reti- nopathy of prematurity (ROP) is a leading cause of blindness in children. This study investigated whether gold nanoparticle (GNP) could inhibit retinal neovascularization in the animal model of ROP. Intravitreal injection of GNP significantly inhibited retinal neovascularization in the mouse model of ROP. In addition, GNP effectively suppressed VEGF-induced in vitro angiogenesis of retinal microvascular endothelial cells including proliferation, migration and capillary-like networks formation. GNP blocked VEGF-induced auto- phosphorylation of VEGFR-2 to inhibit consequently ERK 1/2 activation. GNP never affected on the cellular viability of retinal microvascular endothelial cells and induced no retinal toxicity. Our data suggest that GNP could be a potent inhibitor to retinal neovascularization without retinal toxicity. Furthermore, GNP could be extensively applied to variable vaso-proliferative retinopathies mediated by VEGF. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Angiogenesis is a strictly-controlled process that plays a central role in the physiological condition of development and tissue repair which is regulated by the balance of many stimulating or inhibiting factors [1]. In the pathological condition when the balance is dis- rupted, angiogenic factors such as vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) lead to robust proliferation and migration of vascular endothelial cellsdthe pathological angiogenesis. These newly formed blood vessels are so fragile to be easily ruptured, and hemorrhagic which could result in fibrous proliferation [2]. In particular, this pathological angiogen- esis also occurs in the retina, which leads to retinal edema, retinal or vitreous hemorrhage, and finally traction retinal detachment, which might result in catastrophic loss of vision [3]. The patho- logical angiogenesis in the retina is the major cause of vision loss at all ages including retinopathy of prematurity (ROP) in children, diabetic retinopathy (DR) in young adults, and age-related macular degeneration (AMD) in the elderly [4]. ROP is a leading cause of blindness in children [5]. Although the detail mechanism of molecular processes remains to be elucidated, ROP is known to be a biphasic vaso-proliferative retinopathy, which occurs through the pathological angiogenesis following the vaso- obliteration in developing retinal vasculature [6]. The retinal neo- vascularization followed by the vaso-obliteration appears to be driven by relative tissue hypoxia. The hypoxia induces VEGF production in the retina, which finally leads to pathological retinal angiogenesis [3]. The oxygen-induced retinopathy (OIR) in the mouse is an animal model of ROP, which is induced by hyperoxia- induced vaso-obliteration of capillaries in mouse pups and their subsequent return to room air. This triggers retinal neo- vascularization starting from the inner retina, characterized by growing into the vitreous [7]. Therefore, OIR reflects the current understanding of the pathogenesis of ROP. VEGF, originally isolated as a vascular permeability factor, is the best known pro-angiogenic factor to involve in the initiation and development of variable retinopathies [4]. It has been known that VEGF could induce vascular abnormalities including vascular leakage and neovascularization [8]. In addition, VEGF and VEGFR system is known to play a critical role in retinal neovacularization, where VEGF interacts with the tyrosine kinase receptors, VEGFR-1 or VEGFR-2 [9]. In particular, signaling via VEGFR-2 is prerequisite for all processes of angiogenesis including vascular endothelial * Corresponding author. Tel.: þ82 42 868 5080; fax: þ82 42 868 5444. ** Corresponding author. Tel.: þ82 2 2072 2438; fax: þ82 2 741 3187. E-mail addresses: trglee@kriss.re.kr (T.G. Lee), steph25@snu.ac.kr (J.H. Kim). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2010.11.030 Biomaterials 32 (2011) 1865e1871