Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles
Hiroki Tsujinaka, Jie Fu, Jikui Shen, Yun Yu, Zibran Hafiz, Joshua Kays, David McKenzie, Delia Cardona, David A. Culp, Ward Peterson, Brian C. Gilger, Christopher Crean, Jin Z. Zhang, Yogita Kanan, Weiling Yu, Jeffrey L. Cleland, Ming Yang, Justin Hanes, Peter A. Campochiaro
Abstract
Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.