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L. C. Berglin, L. Bergman, E. S. Kim, S. Kang, W. Gao, G. Holley, I. Schmack, K. J. Mandell, H. E. Grossniklaus, H. F. Edelhauser; Transscleral Uptake and Diffusion of Bevacizumab (AvastinTM) and Ranibizumab (LucentisTM). Invest. Ophthalmol. Vis. Sci. 2007;48(13):5788.
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To explore the in vitro, and in vivo transscleral-retinal pigment epithelium (RPE) uptake and diffusion of Avastin and Lucentis and structurally related immunoglobulins to investigate a possible alternative to intravitreal injection for retinal delivery.
Human scleral donor tissues were perfused at 15 mmHg in a Lucite block system for 24 hours with 200 µL FITC conjugated IgG (150-160 kD), FITC conjugated Fab Fragment (52 kD), Avastin (149 kD) or Lucentis (48 kD). After perfusion the drugs were tagged with a FITC or CY3 conjugated Goat Anti Human, F(ab')2 Fragment Specific IgG. The perfusate and scleral washout was analyzed for protein content by fluorometry or ELISA. Protein uptake in the sclera was analyzed by epifluorescence and confocal microscopy. Transscleral-retinal pigment epithelium (RPE) uptake and diffusion of Avastin and Lucentis were analyzed in both euthanized and living C57/BL6 mice and Dutch belted rabbits up to 24 hours after a subconjunctival drug injection.
Human scleral tissue was permeable to all studied immunoglobulins, often with a visible intrascleral fluorescent gradient. Washout for the different immunoglobulins was maximal after 2 hours. Human sclera also showed uptake of Avastin and Lucentis when exposed on the episcleral surface. In living mice Avastin and Lucentis were detectable in the sclera and retina after 1 hour with increasing intensity after three hours. The drugs were minimally visible after 24 hours. In situ rabbit sclera at 24 hrs also showed a progressive uptake of both Avastin and Lucentis from a 50 µL subconjunctival injection.
Human and rabbit sclera are permeable to Avastin and Lucentis. In mice the drugs can permeate both sclera and retina within an hour. The drugs were minimally detected in the mouse eye after 24 hours following a 10 µL subconjunctival injection. These results indicate that transscleral drug delivery of Avastin and Lucentis, possibly with a sustained release, could be a viable alternative to intravitreal drug injection.
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