The development of activity-based photoacoustic (PA) probes that can monitor disease biomarkers in deep tissue has the potential to replace invasive medical procedures such as biopsies, as well as aid in elucidating biological pathways. PA imaging is a powerful imaging modality that uses light (typically in the near-infrared range) to generate sound waves within tissue which can be detected as ultrasound to obtain high-resolution images in vivo. However, such probes must be highly optimized for in vivo performance and exhibit an exceptional safety profile. In this study, we have developed PACu-1, the first PA probe designed for biopsy-free assessment (BFA) of hepatic Cu via PA imaging. PACu-1 features a Cu(I)-responsive trigger appended to a PA compatible dye that has been optimized for ratiometric sensing. Due to the excellent performance of PACu-1, we were able to detect basal levels of Cu in healthy wildtype mice. To evaluate the performance of PACu-1 for the detection of elevated Cu, we utilized a Wilson's disease (WD) model and a liver metastasis model. Briefly, WD is a genetic disorder characterized by accumulation of Cu in the liver due to a genetic defect in the ATP7B Cu exporter. Additionally, hepatic Cu has been shown to be elevated in cancer metastasis. To further showcase the potential impact of PACu-1 for BFA, we designed and conducted two blind studies where in the first study we were able to successfully identify a WD animal from a group of healthy control mice and, in the second study, we were able to stratify a group of 12 animals (6 WD and 6 wildtype) with greater than 99.7% confidence. We envision that PACu-1 and future generations of PA Cu probes will allow us to perform and track Cu chelation therapy. In addition, future chemical tools will help to understand Cu as it relates to health.

Activity-based photoacoustic probe for biopsy-free assessment of copper status in murine models of Wilson’s disease and other in vivo applications

ACS Spring 2022

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