Assessing bladder hyper-permeability biomarkers in vivo using molecularly-targeted MRI

The objective was to investigate if some of the key molecular players associated with bladder hyper-permeability in interstitial cystitis/bladder pain syndrome (IC/BPS) could be visualized with molecularly-targeted magnetic resonance imaging (mt-MRI) in vivo. IC/BPS is a chronic, painful condition of the bladder that affects primarily women. It has been demonstrated over the past several decades that permeability plays a substantial role in IC/BPS. There are several key molecular markers that have been associated with permeability, including glycolsaminoglycan (GAG), biglycan, chondroitin sulfate, decorin, E-cadherin, keratin 20, uroplakin, vascular endothelial growth factor receptor 1 (VEGF-R1), claudin-2 and zonula occludens-1 (ZO-1). We used in vivo molecularly-targeted MRI (mt-MRI) to assess specific urothelial biomarkers (decorin, VEGF-R1, and claudin-2) associated with bladder hyper-permeability in a protamine sulfate (PS)-induced rat model. The mt-MRI probes consisted of an antibody against either VEGF-R1, decorin or claudin-2 conjugated to albumin that had also Gd-DTPA (gadolinium diethylene triamine penta acetic acid) and biotin attached. mt-MRI- and histologically-detectable levels of decorin and VEGF-R1 were both found to decrease following PS-induced bladder urothelial hyper-permeability, whereas claudin-2, was found to increase in the rat PS model. Verification of the presence of the mt-MRI probes were done by targeting the biotin moiety for each respective probe with streptavidin-hose radish peroxidase (HRP). Levels of protein expression for VEGF-R1, decorin and claudin-2 were confirmed with immunohistochemistry. In vivo molecularly-targeted MRI (mt-MRI) was found to successfully detect alterations in the expression of decorin, VEGFR1 and claudin-2 in a PS-induced rat bladder permeability model. This in vivo molecularly-targeted imaging approach has the potential to provide invaluable information to enhance our understanding of bladder urothelium hyper-permeability in IC/BPS patients, and perhaps be used to assist in developing novel therapeutic strategies.