A General Approach to Design Dual Ratiometric Fluorescent and Photoacoustic Probes for Quantitatively Visualizing Tumor Hypoxia Levels In Vivo

• Published in: Angewandte Chemie International Edition Vol. 61; no. 7; pp. e202107076 - n/a
• Main Authors: Zhang, Shuping, Chen, Hua, Wang, Liping, Qin, Xue, Jiang, Bang‐Ping, Ji, Shi‐Chen, Shen, Xing‐Can, Liang, Hong
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 07.02.2022; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Animals; Biomarkers; Breast cancer; Carbocyanines - chemical synthesis; Carbocyanines - chemistry; Cell Line, Tumor; Chemistry; Chemistry, Multidisciplinary; Drug Design; Dual ratiometric platform; Energy balance; Fluorescence; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - chemistry; Fluorescent indicators; Hypoxia; In vivo imaging; Mammary Neoplasms, Experimental - diagnostic imaging; Medical imaging; Mice; Mice, Nude; Molecular Structure; Nitrobenzene; Nitrogen dioxide; Nitroreductase; Optical Imaging; Photoacoustic effect; Photoacoustic Techniques; Physical Sciences; Quantitative detection; Scaffolds; Science & Technology; Solid tumors; Sulfur; Thioxanthene; Tumor Hypoxia; Tumors; Xenografts; Xenotransplantation; Dual ratiometric platform; NANOPARTICLES; Nitroreductase; Tumor hypoxia; AGENTS; MICROSCOPY; Quantitative detection; In vivo imaging; NEAR-INFRARED FLUORESCENCE
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202107076

Herein, we describe an energy balance strategy between fluorescence and photoacoustic effects by sulfur substitution to transform existing hemicyanine dyes (Cy) into optimized NIRF/PA dual ratiometric scaffolds. Based on this optimized scaffold, we reported the first dual‐ratio response of nitroreductase probe AS‐Cy‐NO2, which allows quantitative visualization of tumor hypoxia in vivo. AS‐Cy‐NO2, composed of a new NIRF/PA scaffold thioxanthene‐hemicyanine (AS‐Cy‐1) and a 4‐nitrobenzene moiety, showed a 10‐fold ratiometric NIRF enhancement (I773/I733) and 2.4‐fold ratiometric PA enhancement (PA730/PA670) upon activation by a biomarker (nitroreductase, NTR) associated with tumor hypoxia. Moreover, the dual ratiometric NIRF/PA imaging accurately quantified the hypoxia extent with high sensitivity and high imaging depth in xenograft breast cancer models. More importantly, the 3D maximal intensity projection (MIP) PA images of the probe can precisely differentiate the highly heterogeneous oxygen distribution in solid tumor. Thus, this study provides a promising NIRF/PA scaffold that may be generalized for the dual ratiometric imaging of other disease‐relevant biomarkers. We have described a general energy balance approach by sulfur substitution to transform existing hemicyanine dyes (Cy) into optimized NIRF/PA dual ratiometric scaffolds. Based on this optimized platform, the first dual‐ratio NIRF/PA response probe AS‐Cy‐NO2 was designed for quantitatively and precisely monitoring of tumor hypoxia levels in vivo.