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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.

SUBMITTER: Tsujinaka H

PROVIDER: S-EPMC7000758 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Tsujinaka Hiroki H Fu Jie J Shen Jikui J Yu Yun Y Hafiz Zibran Z Kays Joshua J McKenzie David D Cardona Delia D Culp David D Peterson Ward W Gilger Brian C BC Crean Christopher S CS Zhang Jin-Zhong JZ Kanan Yogita Y Yu Weiling W Cleland Jeffrey L JL Yang Ming M Hanes Justin J Campochiaro Peter A PA

Nature communications 20200204 1

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 s ...[more]

PMID: 32019921

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Project description:BackgroundRetinal vascular diseases, including diabetic macular edema (DME), neovascular age-related macular degeneration (nAMD), myopic choroidal neovascularization (mCNV), and branch and central retinal vein occlusion (BRVO/CRVO), are considered vision-threatening eye diseases. However, accurate diagnosis depends on multimodal imaging and the expertise of retinal ophthalmologists.ObjectiveThe aim of this study was to develop a deep learning model to detect treatment-requiring retinal vascular diseases using multimodal imaging.MethodsThis retrospective study enrolled participants with multimodal ophthalmic imaging data from 3 hospitals in Taiwan from 2013 to 2019. Eye-related images were used, including those obtained through retinal fundus photography, optical coherence tomography (OCT), and fluorescein angiography with or without indocyanine green angiography (FA/ICGA). A deep learning model was constructed for detecting DME, nAMD, mCNV, BRVO, and CRVO and identifying treatment-requiring diseases. Model performance was evaluated and is presented as the area under the curve (AUC) for each receiver operating characteristic curve.ResultsA total of 2992 eyes of 2185 patients were studied, with 239, 1209, 1008, 211, 189, and 136 eyes in the control, DME, nAMD, mCNV, BRVO, and CRVO groups, respectively. Among them, 1898 eyes required treatment. The eyes were divided into training, validation, and testing groups in a 5:1:1 ratio. In total, 5117 retinal fundus photos, 9316 OCT images, and 20,922 FA/ICGA images were used. The AUCs for detecting mCNV, DME, nAMD, BRVO, and CRVO were 0.996, 0.995, 0.990, 0.959, and 0.988, respectively. The AUC for detecting treatment-requiring diseases was 0.969. From the heat maps, we observed that the model could identify retinal vascular diseases.ConclusionsOur study developed a deep learning model to detect retinal diseases using multimodal ophthalmic imaging. Furthermore, the model demonstrated good performance in detecting treatment-requiring retinal diseases.

Project description:PurposeTo describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling.DesignObservational case review.ParticipantsThree patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate.MethodsPatient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits.Main outcome measuresVisual acuity, size of RCH, and degree of exudation.ResultsThree patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction.ConclusionsSystemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other medications in the same class or drugs directed at multiple targets in the tumor, may be safer and more effective for the treatment of advanced VHL-associated RCH.

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

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

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