Hemodynamic molecular imaging of tumor-associated enzyme activity in the living brain

eLife

Adrian L Slusarczyk¹  Robert Ohlendorf¹  Mitul Desai¹  Ashley A Chapin¹  Alan Jasanoff²  Jitendra Sharma³  Mriganka Sur³  Agata Wisniowska⁴ 

[1] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States;Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States;Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United States;Department of Nuclear Science & Engineering, Massachusetts Institute of Technology, Cambridge, United States;Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United States;Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, United States;

关键词: molecular imaging;    protease;    brain;    cancer;    MRI;    saimiri sciureus;    Rat;   

DOI  :  10.7554/eLife.70237

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY