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Development of PEGylated peptide probes conjugated with 18F-labeled BODIPY for PET/optical imaging of MT1-MMP activity

Kondo, Naoya, Temma, Takashi, Deguchi, Jun, Sano, Kohei, Ono, Masahiro, Saji, Hideo
Journal of Controlled Release 2015 v.220 pp. 476-483
apoptosis, clinical trials, fluorescence, image analysis, in vivo studies, intravenous injection, metalloproteinases, mice, monitoring, neoplasms, patients, peptides, polyethylene glycol, positron-emission tomography, surgery
Since the processing activity of the matrix metalloproteinase MT1-MMP regulates various cellular functions such as motility, invasion, growth, differentiation and apoptosis, precise in vivo evaluation of MT1-MMP activity in cancers can provide beneficial information for both basic and clinical studies. For this purpose, we designed a cleavable Positron Emission Tomography (PET)/optical imaging probe consisting of BODIPY650/665 and polyethylene glycol (PEG) conjugated to opposite ends of MT1-MMP substrate peptides. We used in vitro and in vivo fluorescence experiments to select suitable substrate peptide sequences and PEG sizes for the MT1-MMP probes and obtained an optimized structure referred to here as MBP-2k. Radiofluorinated MBP-2k ([18F]MBP-2k) was then successfully synthesized via an 18F–19F isotopic exchange reaction in BODIPY650/665. After intravenous injection into mice with xenografted tumors, [18F]MBP-2k showed significantly higher accumulation in HT1080 tumors with high MT1-MMP activity than in A549 tumors that have low MT1-MMP activity. Moreover, PET images showed better contrast in HT1080 tumors. These results show that [18F]MBP-2k can be used as a hybrid PET/optical imaging agent and is a promising probe for non-invasive monitoring of MT1-MMP activity in cancers. This probe may also efficiently combine targeted tumor imaging with image-guided surgery that could be beneficial for patients in the future.