Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles

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.

A 60% Edible Ethanolic Extract of Ulmus davidiana Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis

“…Bevacizumab, a VEGF protein-neutralizing antibody, is known to effectively inhibit angiogenesis in various cancers and DR [37][38][39]. In addition, tyrosine kinase inhibitors such as sunitinib and sorafenib inhibit angiogenesis by suppressing VEGF receptor tyrosine kinases and are also known to be effective against various cancers and ocular diseases [40][41][42][43][44][45]. However, these drugs are expensive or cause serious toxicities [46].…”

Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives

“…Previously, some pre-clinical studies with sunitinib malate suggested its anti-angiogenesis effects in vitro and in vivo as well as the minor ocular toxicity that it induces [ 75 , 76 , 77 ]. The latest investigation by Tsujinaka et al proposed that biodegradable polymer sunitinib microparticles self-aggregate into a depot formulation in the vitreous and maintain a steady therapeutic effect in the retinal pigment epithelium/choroid and retina for more than 6 months in an ocular neovascularization minipig model [ 78 ].…”

Emerging therapies and their delivery for treating age‐related macular degeneration

“…Acrizanib (LHA510; Alcon) is a low molecular weight VEGFR2 inhibitor which was delivered as a topical formulation but failed to show efficacy compared to anti-VEGF injections (Poor et al, 2018) These microparticles bind to melanin granules in the RPE and promote a depot for sustained release. They also have a surface treatment to promote self-aggregation in the vitreous to prevent interference with vision (Bhatt et al, 2019;GraybugVision, 2019aGraybugVision, , 2019bTsujinaka et al, 2020;Ying et al, 2016). Furthermore, pazopanib is a multitargeted TKI which inhibits VEGFR 1, 2, 3 and platelet derived growth factor (PDGF) signalling and has been developed as a topical formulation, with a reduction in CNV size in pre-clinical models (Takahashi et al, 2009;Yafai et al, 2011).…”