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Treatment of hypoxia-induced retinopathy with targeted proapoptotic peptidomimetic in a mouse model of disease

Johanna Lahdenranta^*,1, Richard L. Sidman, Renata Pasqualini^*,2 and Wadih Arap^*,2

^* The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA; and

Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts, USA

²Correspondence: The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA. E-mail: rpasqual{at}mdanderson.org or warap{at}mdanderson.org

We have previously identified ligands from combinatorial peptide libraries that target tumor vasculature after in vivo selection. These ligands bind to differentially expressed receptors in angiogenic vasculature such as _vß₃/_vß₅ integrins, aminopeptidase N, and aminopeptidase A. We hypothesized that we can use these ligands to target angiogenic vasculature in retinopathies. Pathological retinal angiogenesis in conditions such as diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration is a major cause of blindness for which current treatments are inadequate. Here we tested whether known tumor vasculature targeting peptide ligands displayed on bacteriophage particles would home to the proliferating blood vessels of the retina in a standard mouse model of retinopathy of prematurity. We found that activated retinal blood vessels share many of the endothelial and periendothelial cell receptors expressed in tumor vasculature. Furthermore, these vascular receptors—_v integrins and aminopeptidases—are accessible through the circulation and mediate phage homing and internalization to endothelial and periendothelial cells. Treatment of mice with a peptide containing a _vß₃/_vß₅-integrin targeting domain fused to a proapoptotic domain significantly reduced oxygen-induced retinal angiogenesis by selectively inducing activated endothelial cell apoptosis. Targeted proapoptotic peptides may prove useful in the management of angiogenic retinal diseases.—Lahdenranta, J., Sidman, R. L., Pasqualini, R., Arap, W. Treatment of hypoxia-induced retinopathy with targeted proapoptotic peptidomimetic in a mouse model of disease.

Key Words: aminopeptidases • angiogenesis • peptide ligand • targeted therapy

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				A. Corti, F. Curnis, W. Arap, and R. Pasqualini The neovasculature homing motif NGR: more than meets the eye Blood, October 1, 2008; 112(7): 2628 - 2635. [Abstract] [Full Text] [PDF]