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Title: Multispectral photoacoustic imaging of tumor protease activity with a gold nanocage-based activatable probe
Authors: Liu, C 
Li, S 
Gu, Y 
Xiong, H
Wong, WK 
Sun, L 
Issue Date: Dec-2018
Source: Molecular imaging and biology, Dec. 2018, v. 20, no. 6, p. 919-929
Abstract: Purpose: Tumor proteases have been recognized as significant regulators in the tumor microenvironment, but the current strategies for in vivo protease imaging have tended to focus on the development of a probe design rather than the investigation of a novel imaging strategy by leveraging the imaging technique and probe. Herein, it is the first report to investigate the ability of multispectral photoacoustic imaging (PAI) to estimate the distribution of protease cleavage sites inside living tumor tissue by using an activatable photoacoustic (PA) probe.
Procedures: The protease MMP-2 is selected as the target. In this probe, gold nanocages (GNCs) with an absorption peak at ~ 800 nm and fluorescent dye molecules with an absorption peak at ~ 680 nm are conjugated via a specific enzymatic peptide substrate. Upon enzymatic activation by MMP-2, the peptide substrate is cleaved and the chromophores are released. Due to the different retention speeds of large GNCs and small dye molecules, the probe alters its intrinsic absorption profile and produces a distinct change in the PA signal. A multispectral PAI technique that can distinguish different chromophores based on intrinsic PA spectral signatures is applied to estimate the signal composition changes and indicate the cleavage interaction sites. Finally, the multispectral PAI technique with the activatable probe is tested in solution, cultured cells, and a subcutaneous tumor model in vivo.
Results: Our experiment in solution with enzyme ± inhibitor, cell culture ± inhibitor, and in vivo tumor model with administration of the developed probe ± inhibitor demonstrated the probe was cleaved by the targeted enzyme. Particularly, the in vivo estimation of the cleavage site distribution was validated with the result of ex vivo immunohistochemistry analysis.
Conclusions:This novel synergy of the multispectral PAI technique and the activatable probe is a potential strategy for the distribution estimation of tumor protease activity in vivo.
Keywords: Multispectral photoacoustic imaging
Activatable photoacoustic probe
Tumor protease activity
Gold nanocage
Molecular photoacoustic imaging
Publisher: Springer New York LLC
Journal: Molecular imaging and biology 
ISSN: 1536-1632
EISSN: 1860-2002
DOI: 10.1007/s11307-018-1203-1
Rights: © World Molecular Imaging Society, 2018
This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use (, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at:
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