title: Safety profile of topical VEGF neutralization at the cornea.
abstract: OBJECTIVE
  Bevacizumab eyedrops inhibit corneal neovascularization. The purpose of this study was to analyze the safety profile of VEGF-A neutralization at the ocular surface.
  
  
  METHODS
  Bevacizumab eyedrops (5 mg/mL) and an antimurine VEGF-A antibody (250 microg/mL) were applied to normal murine corneas five times a day for 7 and 14 days. Subsequently, corneas were analyzed for morphologic changes by light and electron microscopy. In a mouse model of corneal epithelial abrasion, the effects of topically applied anti-VEGF antibodies on epithelial wound healing were analyzed: the treatment group received bevacizumab (5 mg/mL) or the antimurine VEGF-A antibody (250 microg/mL) as eyedrops, and the control group received an equal volume of saline solution. After 12, 18, and 24 hours, corneas were photographed in vivo with and without fluorescein staining for morphometry. Afterwards the mice were killed, and eyes were removed for histology, immunohistochemistry with Ki67/DAPI, and electron microscopy. The effect of midterm anti-VEGF therapy on corneal nerve density was assessed by staining corneas treated with an FITC-conjugated anti-neurofilament antibody and morphometric analysis.
  
  
  RESULTS
  Murine corneas treated with two different types of anti-VEGF antibody eyedrops did not show obvious corneal morphologic changes at the light and electron microscopic levels. Furthermore, anti-VEGF antibody eyedrops had no significant impact on the wound healing process after corneal epithelial injury or on normal murine corneal nerve fiber density.
  
  
  CONCLUSIONS
  Topical neutralization of VEGF-A at the corneal surface does not have significant side effects on normal corneal epithelial wound healing, normal corneal integrity, or normal nerve fiber density. Therefore, anti-VEGF eyedrops seem to be a relatively safe option to treat corneal neovascularization.
authors.affiliation: Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bock
authors.forename: Jasmine
authors.initials: J
authors.lastname: Onderka
authors.forename: Carmen
authors.initials: C
authors.lastname: Rummelt
authors.forename: Tina
authors.initials: T
authors.lastname: Dietrich
authors.forename: Björn
authors.initials: B
authors.lastname: Bachmann
authors.forename: Friedrich E
authors.initials: FE
authors.lastname: Kruse
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
mesh_terms: D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002452:Cell Count; D003315:Cornea / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000648:ultrastructure; D016510:Corneal Neovascularization / Q000188:drug therapy; D019573:Epithelium, Corneal / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D015590:Fluorophotometry; D007211:Indoles / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009412:Nerve Fibers / Q000187:drug effects; D016900:Neurofilament Proteins / Q000378:metabolism; D009882:Ophthalmic Nerve / Q000187:drug effects / Q000378:metabolism; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D019394:Ki-67 Antigen; D016900:Neurofilament Proteins; D009883:Ophthalmic Solutions; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab; C007293:DAPI