Fluorescence Molecular Imaging and Tomography of Matrix Metalloproteinase-Activatable Near-Infrared Fluorescence Probe and Image-Guided Orthotopic Glioma Resection
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Malignant gliomas are major causes of cancer-related mortality and morbidity. Traditional surgery usually leads to incomplete resection of gliomas resulting in the high incidence of tumor recurrence. Advanced medical imaging technology, such as fluorescence imaging-guided surgery, combined with tumor-specific imaging probes allows the identification of tumor margins and improved surgery. However, there are two pressing issues that need to be addressed: first, few fluorescence imaging probes can specifically target gliomas; second, fluorescence molecular imaging (FMI) cannot get the in-depth information of deep-seated gliomas; both of which affect the complete removal of the gliomas.
In this study, the biodistribution of smart matrix metalloproteinase (MMP) targeting near-infrared (NIR) fluorescent probe MMPSense 750 FAST (MMP-750) was examined in both U87MG-GFP-fLuc glioma xenograft and orthotopic mouse models using FMI. Then, CT and FMI images of orthotopic gliomas were acquired for the reconstruction of fluorescence molecular tomography (FMT) using a randomly enhanced adaptive subspace pursuit (REASP) algorithm. Furthermore, the resection of orthotopic glioma was performed using the fluorescence surgical navigation system after the injection of the MMP-750 probe. After surgery, bioluminescence imaging (BLI) and hematoxylin and eosin staining were carried out to confirm the precision resection of the tumor.
FMI results showed that the MMP-750 probe can specifically target U87MG glioma in vivo. FMT presented the spatial information of the orthotopic glioma using the REASP reconstruction algorithm. Furthermore, MMP-750 could effectively delineate the tumor margin during glioma surgery leading to a complete resection of the tumors.
The smart MMP-750 specifically targets the glioma and FMT of MMP-750 provides 3D information for the spatial localization of the glioma. MMP-750 can work as an ideal fluorescence probe for guiding the intraoperative surgical resection of the glioma, possessing clinical translation.
Key wordsMatrix metalloproteinase Image-guided surgery Glioma Fluorescence molecular tomography
The authors thank Adjunct Assistant Professor Dr. Karen M. von Deneen from the University of Florida for her English editing of this paper.
This work was supported by the National Natural Science Foundation of China (81227901, 81470083, 81527805, and 61231004), the Research and Development Program of China (973) under Grant (2014CB748600, 2015CB755500), the Strategic Priority Research Program from the Chinese Academy of Sciences under Grant No. XDB02060010, the International Innovation Team of CAS under Grant No. 20140491524, Beijing Municipal Science & Technology Commission No. Z161100002616022, and Beijing Natural Science Foundation (Z16110200010000).
Compliance with Ethical Standards
All animal experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) at Peking University (Permit No.: 2011-0039).
Conflict of Interests
The authors declare that they have no conflict of interest.
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