Selective Targeting and Tissue Penetration to the Retina by a Systemically Administered Vascular Homing Peptide in Oxygen Induced Retinopathy (OIR).

Maria Vähätupa,Niklas Salonen,Hannele Uusitalo-Järvinen,Tero A H Järvinen

doi:10.3390/pharmaceutics13111932

Maria Vähätupa, Niklas Salonen + Show 2 more

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https://doi.org/10.3390/pharmaceutics13111932

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Journal: Pharmaceutics	Publication Date: Nov 15, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Tampere University, Tampere University Hospital

Abstract

Pathological angiogenesis is the hallmark of ischemic retinal diseases among them retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Oxygen-induced retinopathy (OIR) is a pure hypoxia-driven angiogenesis model and a widely used model for ischemic retinopathies. We explored whether the vascular homing peptide CAR (CARSKNKDC) which recognizes angiogenic blood vessels can be used to target the retina in OIR. We were able to demonstrate that the systemically administered CAR vascular homing peptide homed selectively to the preretinal neovessels in OIR. As a cell and tissue-penetrating peptide, CAR also penetrated into the retina. Hyperoxia used to induce OIR in the retina also causes bronchopulmonary dysplasia in the lungs. We showed that the CAR peptide is not targeted to the lungs in normal mice but is targeted to the lungs after hyperoxia-/hypoxia-treatment of the animals. The site-specific delivery of the CAR peptide to the pathologic retinal vasculature and the penetration of the retinal tissue may offer new opportunities for treating retinopathies more selectively and with less side effects.

Highlights

Accepted: 10 November 2021Hypoxia driven retinal neovascularization is a key feature in devastating ischemic retinal diseases such as proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) [1,2]
Using an anti-fluorescein antibody [25,26,29,34,35]), we detected a strong signal from preretinal tufts in animals injected with the CAR peptide and the retinal signal was substantially lower for mCAR (Figure 1)
Previous studies have demonstrated the homing potential of the CAR peptide to pulmonary diseases with a clear inflammatory component [29,34,38,39,40,41,42,43,44]. In line with these studies, we found that the CAR peptide homes to the bronchopulmonary dysplasia that is induced in the lungs of Oxygen-induced retinopathy (OIR) mice (Figure 3), whereas we could not demonstrate any peptide accumulation in the lungs of mice injected with the mCAR peptide injected mice

Summary

Introduction

Accepted: 10 November 2021Hypoxia driven retinal neovascularization is a key feature in devastating ischemic retinal diseases such as proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) [1,2]. When the cells of the retina experience hypoxia, the transcription factor hypoxia inducible factor-1α (HIF-1α) is stabilized [4,5,6,7,8]. The genes that the active HIF-1 signaling triggers in hypoxic cells include large number of angiogenic growth factors, of which VEGF is the most important one [4,5,7]. These growth factors direct the sprouting of the new blood vessel, i.e., angiogenesis, in attempt to deliver oxygen to and address the hypoxia in the tissue [8]. VEGF induces vascular permeability and leakage, which are evident in ocular

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