Abstract
Focussed radiosurgery may provide a means of inducing molecular changes on the luminal surface of diseased endothelium to allow targeted delivery of novel therapeutic compounds. We investigated the potential of ionizing radiation to induce surface expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells (EC) in vitro and in vivo, to assess their suitability as vascular targets in irradiated arteriovenous malformations (AVMs). Cultured brain microvascular EC were irradiated by linear accelerator at single doses of 0, 5, 15 or 25 Gy and expression of ICAM-1 and VCAM-1 measured by qRT-PCR, Western, ELISA and immunocytochemistry. In vivo, near-infrared (NIR) fluorescence optical imaging using Xenolight 750-conjugated ICAM-1 or VCAM-1 antibodies examined luminal biodistribution over 84 days in a rat AVM model after Gamma Knife surgery at a single 15 Gy dose. ICAM-1 and VCAM-1 were minimally expressed on untreated EC in vitro. Doses of 15 and 25 Gy stimulated expression equally; 5 Gy was not different from the unirradiated. In vivo, normal vessels did not bind or retain the fluorescent probes, however binding was significant in AVM vessels. No additive increases in probe binding were found in response to radiosurgery at a dose of 15 Gy. In summary, radiation induces adhesion molecule expression in vitro but elevated baseline levels in AVM vessels precludes further induction in vivo. These molecules may be suitable targets in irradiated vessels without hemodynamic derangement, but not AVMs. These findings demonstrate the importance of using flow-modulated, pre-clinical animal models for validating candidate proteins for vascular targeting in irradiated AVMs.
Highlights
Brain arteriovenous malformations (AVMs) are a leading cause of stroke in children and young adults, accounting for 4% of hemorrhagic strokes [1]
We examined the potential utility of using cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) as vascular targets in AVMs after radiation priming
Using in vivo NIR-fluorescence optical imaging, we found that normal vessels have low endogenous ICAM-1 and VCAM-1 expression, precluding binding of our targeted probes, but revealed that AVMs express high basal levels of these molecules, which was not further enhanced by a single focussed dose of radiation at 15 Gy
Summary
Brain arteriovenous malformations (AVMs) are a leading cause of stroke in children and young adults, accounting for 4% of hemorrhagic strokes [1]. A proposed method to achieve this goal is vascular targeting. This approach has been applied in cancer therapy where unique molecular markers expressed on the surface of tumor vessels are targeted by conjugated antibodies and prothrombotic factors to induce intravascular thrombosis [3]. Molecular differences that can discriminate diseased and normal endothelial cells (ECs) is the fundamental criterion for successful vascular targeting. Targeting moderately expressed proteins in AVMs may not provide sufficient discrimination from normal vessels, further, flow-regulated proteins may be expressed on AVM feeding arteries. While AVM vessels typically bypass the brain, forming arteriovenous shunts, branches deriving from the main feeding artery can supply blood to the brain, their inadvertent occlusion must be avoided
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