量研学術機関リポジトリ「QST-Repository」は、国立研究開発法人 量子科学技術研究開発機構に所属する職員等が生み出した学術成果（学会誌発表論文、学会発表、研究開発報告書、特許等）を集積しインターネット上で広く公開するサービスです。 Welcome to QST-Repository where we accumulates and discloses the academic research results(Journal Publications, Conference presentation, Research and Development Report, Patent, etc.) of the members of National Institutes for Quantum Science and Technology.
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Rapid cellular proliferation and incomplete neovascularization in solid tumors leads to spatially heterogeneous regions with relatively low oxygen concentrations, called hypoxia. Hypoxia in tumors causes significant changes in various physiological processes such as DNA repair pathways, anaerobic respiration, metabolic reprograming, unregulated angiogenesis, and the spread of cancer stem cells [Chem. Soc. Rev. 2019, 48, 771–813]. Consequently, the plasticity of these processes results in the acquisition of the malignant phenotype in tumors. Therefore, effective imaging methods that allow for the detailed analysis of hypoxia are needed to elucidate tumor pathophysiology.
To date, a variety of imaging techniques for tumor hypoxia have been developed. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-based methods permit real-time monitoring and give three-dimensional (3D) information about tumor hypoxia without the limitation of imaging depth in vivo [Mol. Imaging Biol. 2010, 13, 399–410]. However, these imaging methods have poor resolution, restricting the detailed visualization of hypoxia-related biological events in cells or tissues. The imaging methods for tumor hypoxia with cellular resolution rely on tissue sectioning [Nat. Nanotechnol. 2016, 11, 724–730]. Although the reconstruction of serial sections theoretically enables 3D imaging of tumor hypoxia, it is impractical for multiple samples and difficult to obtain accurate data with the original tissue morphology.
Recently, optical tissue-clearing techniques have been developed for depth-independent visualization. These techniques enable 3D imaging with fluorescent probes including genetically encoded proteins and chemical dyes in entire tissues without the preparation of tissue sections [Cell 2014, 157, 726–739]. However, the application of these techniques with conventional hypoxia probes suffers from some challenges. For example, a well-known hypoxia probe (pimonidazole) and hypoxia makers (e.g. HIF1-) need specific antibodies to be visualized [Nat. Commun. 2012, 3, 710–783]. Due to the low tissue permeability of antibodies [Mol. Cancer Ther. 2019, 18, 213–226], the existence of these probes deep inside tumors cannot be detected. Additionally, hypoxia probes lacking the ability to covalently bind to cellular components can be washed from tumors during tissue-clearing treatments.
To achieve 3D and high-resolution imaging of tumor hypoxia throughout an entire tissue, we developed a fluorescent molecular probe for tumor hypoxia which is compatible with tissue-clearing. The fluorescent probe has low cytotoxicity, high fluorescence intensity in tissue-clearing solution, high tissue permeability, and the ability to covalently bind to cellular proteins only under hypoxic conditions. The designed probe was applied for the 3D imaging of spatially heterogeneous tumor hypoxia in combination with tissue-clearing.
Development of a fluorescent chemical probe for 3D and high-resolution imaging of tumor hypoxia
