Abstract
Molecular imaging could have great utility for detecting, classifying, and guiding treatment of brain disorders, but existing probes offer limited capability for assessing relevant physiological parameters. Here, we describe a potent approach for noninvasive mapping of cancer-associated enzyme activity using a molecular sensor that acts on the vasculature, providing a diagnostic readout via local changes in hemodynamic image contrast. The sensor is targeted at the fibroblast activation protein (FAP), an extracellular dipeptidase and clinically relevant biomarker of brain tumor biology. Optimal FAP sensor variants were identified by screening a series of prototypes for responsiveness in a cell-based bioassay. The best variant was then applied for quantitative neuroimaging of FAP activity in rats, where it reveals nanomolar-scale FAP expression by xenografted cells. The activated probe also induces robust hemodynamic contrast in nonhuman primate brain. This work thus demonstrates a potentially translatable strategy for ultrasensitive functional imaging of molecular targets in neuromedicine.
Highlights
Detection of molecular epitopes is vital to effective classification of cancers and determination of therapeutic strategies (Olar and Aldape, 2014; Reifenberger et al, 2016; Wen and Reardon, 2016)
To identify fibroblast activation protein (FAP)-sensitive vasoprobes, we began by creating a series of sterically inhibited calcitonin gene related peptide (CGRP) derivatives that we predicted could undergo FAP-dependent activation
We refer to this molecule as the FAP-sensitive vasoprobe (FAPVap)
Summary
Detection of molecular epitopes is vital to effective classification of cancers and determination of therapeutic strategies (Olar and Aldape, 2014; Reifenberger et al, 2016; Wen and Reardon, 2016). The development of sensitive in vivo assays for tumorassociated proteins is an important goal in brain cancer research and treatment. Several proteases are highly expressed on the surfaces of glioma cells and play key roles in infiltration of tumors into brain tissue (Mentlein et al, 2012). These enzymes are attractive both as diagnostic markers and as targets for therapy (Vandooren et al, 2016; Verdoes and Verhelst, 2016). Because the profiles of protease expression differ among disease subtypes, detecting proteases on cancer cells in situ could be of critical importance in classifying and subsequently treating brain tumors
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