Treatment of hypoxia-induced retinopathy with targeted proapoptotic peptidomimetic in a mouse model of disease.
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 alpha(v)beta3/alpha(v)beta5 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--alpha(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 alpha(v)beta3/alpha(v)beta5-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
Johanna
J
The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Sidman
Richard L
RL
Pasqualini
Renata
R
Arap
Wadih
W
D000818:Animals; D000831:Animals, Newborn; D001435:Bacteriophages / Q000235:genetics / Q000378:metabolism; D018826:CD13 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D043384:Glutamyl Aminopeptidase / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D019030:Receptors, Vitronectin / Q000378:metabolism; D012160:Retina / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D015861:Retinal Neovascularization; D014183:Transplantation, Heterologous
D039302:Integrin alphaVbeta3; D016023:Integrins; D008024:Ligands; D010455:Peptides; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase