Optical Imaging Biomarkers of Drug-Induced Vascular Injury

Abstract

Drug-induced vascular injury (DIVI), defined as arterial medial degeneration/necrosis usually associated with perivascular inflammation, is frequently observed in the mesenteric arteries of rats but the relevance to humans remains a hurdle for drug development. Here, we describe the evaluation of commercially available optical imaging biomarkers using a rat DIVI model. Male Sprague Dawley rats were administered 10 mg/kg/day of a proprietary soluble guanylate cyclase activator (sGCa). Optical agents, AngioSense for the detection of vessel permeability, MMPSense for the detection of activated matrix metalloproteinases (MMPs), and IntegriSense for the detection of αvβ3 integrin, were injected via tail vein 24 hours before fluorescence (FL) ex vivo imaging. Imaging found a statistically significant difference in FL from all optical agents between treated and vehicle groups (p < .05). Mesenteric arteries were further analyzed by histopathology, flow cytometry, and immunohistochemistry. Histopathology confirmed perivascular inflammation and/or arterial medial degeneration in the sGCa-treated animals. Flow cytometry of digested arteries revealed myeloid cells as a main source of MMPSense signal. Immunohistochemical analysis further identified elevated MMP-9 expression within arterial walls and surrounding tissue of treated animals. Together, these data demonstrate that MMPSense and AngioSense are sensitive optical imaging biomarkers for the quantification of DIVI in rat mesenteric arteries.

Vascular Imaging of Matrix Metalloproteinase Activity as an Informative Preclinical Biomarker of Drug-induced Vascular Injury

“…In this study, we investigated whether vascular remodelingassociated protease activity resulting from well-characterized models of hemodynamic and nonhemodynamic-mediated DIVI could be visualized ex vivo in affected vessels, thereby providing a novel tool for preclinical drug development and establishing proof of principle to stimulate further development of less invasive imaging capability. These investigations sought to further confirm and expand on previous observations using the same optical imaging biomarkers to detect soluble guanylate cyclase activator (sGCA)-induced vascular injury in rats (Lin et al 2015). Results were compared to circulating levels of TIMP-1 and neutrophil gelatinase-associated lipocalin (NGAL), both of which have been associated with vascular remodeling and inflammation preclinically and clinically (Cruz et al 2012;Fabunmi et al 1996;Galis, Muszynski, et al 1994;Monach et al 2011Monach et al , 2013Newby 2006;Yan et al 2001), to support their utility as complementary accessible biomarkers of DIVI.…”

Fluorescence imaging of bombesin and transferrin receptor expression is comparable to 18F-FDG PET in early detection of sorafenib-induced changes in tumor metabolism

“…This means that metabolic BRS-680 and TfV-750 tumor signal can both substitute for BLI in instances in which researchers cannot use luciferase-expressing tumor cell lines. A variety of other FLI probes can also show such utility in imaging late stage treatment outcomes [ 9 – 14 ].…”

“…As an alternative, there are many non-radioactive, FLI tools currently available for pre-clinical readouts, offering benefits of ready access, safety, probe stability, and the potential for multiplexing with more than one imaging probe. Indeed, many have shown that fluorescent imaging probes can be used to investigate a variety of important biological activities in tumor, such as vascular leak [ 9 ], hypoxia [ 10 , 11 ], integrin expression [ 12 ], cell death [ 13 ], and protease activity [ 14 ]. For metabolism imaging, some researchers have even explored the utility of near-infrared (NIR) fluorescent glucose probes for non-invasive imaging of glucose metabolism in tumors [ 15 , 16 ] as a potential optical equivalent of 18 F-FDG.…”

2-Photon Characterization of Optical Proteolytic Beacons for Imaging Changes in Matrix-Metalloprotease Activity in a Mouse Model of Aneurysm

“…Much of this prior work has been done using quenched agents that then generate high levels of fluorescence when the fluorophore is released by an enzyme-mediated reaction. Agents such as these have been put to commercial use such as EnzChek ® Gelatinase/Collagenase FRET based Assay Kit from (Molecular Probes ® , Invitrogen, Carlsbad, CA, USA) or MMPSense ® , MMPSense FAST ® , and ProSense ® (PerkinElmer, Inc., Waltham, MA, USA) in studies where MMPs play a central role in diseases such as cancer (invasion, progression, and metastasis), rheumatism, pulmonary disease, and cardiovascular disease (Leahy et al, 2015; Lin et al, 2015; Pivoraite et al, 2015). Each of these can have both advantages and disadvantages, such as EnzChek ® is specifically for in vitro assays.…”

“…(invasion, progression, and metastasis), rheumatism, pulmonary disease, and cardiovascular disease (Leahy et al, 2015;Lin et al, 2015;Pivoraite et al, 2015). Each of these can have both advantages and disadvantages, such as EnzChek ® is specifically for in vitro assays.…”