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Novel Therapeutic Gene Regulation by Genetic Biosensor Tethered to Magnetic Nanoparticles for the Detection and Treatment of Retinopathy of Prematurity

¹ Ophthalmology, Johns Hopkins Univ/Wilmer Eye Inst, Baltimore, MD
² Internal Medicine, University of Texas Medical Branch, Galveston, TX

Commercial Relationships: T.W. Prow, None; R. Grebe, None; C. Merges, None; D.S. McLeod, None; J.F. Leary, None; G. Lutty, None.

Support: R03EY013744, T32HL007525, R01EY09357, EY01765

Abstract

Purpose: To develop a novel system, based on a biosensor tethered nanoparticle agent, for the treatment of retinopathy of prematurity. Methods: The construction of a five–layered nanoparticle was visualized with gel electrophoresis. Transcriptionally active PCR products (TAPs) containing the biosensor, were bioconjugated to the surface of magnetic nanoparticles yielding biosensor tethered magnetic nanoparticles (MNP). These MNPs were then used to transfect adult dog retinal endothelial cells in culture. Results: The MNPs penetrated dividing and migrating cells more often than quiescent cells in a wound–healing in vitro assay. Comparison of the presence of nanoparticle cores, MNPs, and transfected cells showed a decrease in activity with the addition of layers. When compared to naked TAPs alone, MNPs transfected more cells in a dose dependant manner. The biosensor was based on a EGFP reporter gene driven by an enhanced antioxidant response element. Both the biosensor alone and MNP with biosensor induced EGFP reporter gene expression in the presence of hyperoxia, greater than 1.5 fold over control. Conclusions: These data also show that the MNP had a signal to noise ratio of 0.5 greater than the plasmid form of the biosensor. In theory, this approach has the potential to allow the endothelial cells of the retinal vasculature to prevent or treat themselves after hyperoxic insult, rather than systemic treatment to protect or treat the retina. This could be an excellent strategy for the vaso–obliterative stage of oxygen induced retinopathy.

Key Words: gene transfer/gene therapy • oxidation/oxidative or free radical damage • retinopathy of prematurity

© 2005, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. For permission to reproduce any part of this abstract, contact the ARVO Office at arvo{at}arvo.org.