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Quantitative and functional assessment of treatment strategies for acute pancreatitis with optical fluorescence imaging in rats

Agarwal, Abhiruchi and Boettcher, Andreas and Kneuer, Rainer and Sari-Sarraf, Farid and Donovan, Adriana and Woelcke, Julian and Krucker, Thomas (2011) Quantitative and functional assessment of treatment strategies for acute pancreatitis with optical fluorescence imaging in rats. Plos, 8 (2). e55959. ISSN 1932-6203

Abstract

Background & Aims: Endoproteases or serine proteases activation is considered a key step in acute pancreatitis. Direct and early inhibition of such proteases may prevent further injury. Preclinical in vivo models are frequently used to evaluate both efficacy and potency of specific inhibitors of proteases. Such studies investigating potential therapies for pancreatitis require animal sacrifice at a pre-defined time point and hence, limit the assessment of dynamic processes resulting in pancreatitis. Use of non-invasive fluorescence imaging can help in real-time assessments of the effects of drug candidates on target inhibition, disease progression and severity. The aim of the study was to establish an imaging-based mode-of-action biomarker assay for protease activity in a preclinical model of experimental pancreatitis and to characterize protease inhibitors in this model.

Methods: An imaging model was established. Edema development and trypsin activation in pancreas were imaged with an experimental rat caerulein-injection model for pancreatitis. A fluorescence probe selectively activated by trypsin was synthetized and applied to observe the development of pancreatitisin real-time. Three trypsin inhibitors, including camostat and two experimental compounds, were used to evaluate the value of the fluorescent probe in assessing the change-of-state of pancreatitis in rat.

Results: a) Trypsin selectivity of the in-house fluorescent probe was established in vitro by a comprehensive protease panel. We showed dynamic edema development upon induction of pancreatitis with a blood pool fluorescent agent. The fluorescence probe selectively activated by trypsin enabled functional and dynamic imaging in vivo. We found dose dependent decrease of total fluorescence signal in pancreas upon inhibition with trypsin inhibitors, in contrast to untreated pancreatitis animals. Pancreatic to body weight ratio was not an accurate predictor of trypsin inhibition as determined by the trypsin activity-specific fluorescent probe.

Conclusions: Here we provide evidence that specific trypsin inhibition has the potential to prevent experimental pancreatitis in the rat caerulein injection model. We established that fluorescence imaging could be successfully used to access the mode-of-action of a trypsin inhibitor in real-time in vivo. In addition, we found that a dynamic assessment of trypsin activity by using a protease activated probe provides better understanding of progression of caerulein-induced experimental pancreatitis in contrast to classical tissue sample readouts when evaluating protease inhibitors. This model could be applied to preclinically optimize trypsin inhibitors towards intrapancreatic target inhibition.

Item Type: Article
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Keywords: activatable, fluorescence, in vivo, trypsin inhibitor, pharmacologic
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9305

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