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Theranostics 2024; 14(5):1860-1872. doi:10.7150/thno.88815 This issue Cite

Research Paper

Site-specific albumin tagging with NIR-II fluorogenic dye for high-performance and super-stable bioimaging

Ningning Zhu^1,2*, Jiajun Xu^1,2*, Qi Su^1,2, Tianyang Han^1,2, Ding Zhou^4✉, Yuewei Zhang^1,3✉, Shoujun Zhu^1,2✉

1. Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, First Hospital of Jilin University, Jilin University, Changchun 130021, P.R. China.
2. State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, P.R. China.
3. School of Chemistry and Pharmaceutical Engineering, Jilin Institute of Chemical Technology, Jilin 132022, P.R. China.
4. Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China.
* These authors contributed equally to this work.

✉ Corresponding authors: sjzhuedu.cn; zhangyueweichemcom; zhoudingedu.cn.

Abstract

Synthetic near-infrared-II (NIR-II) dyes are promising for deep tissue imaging, yet they are generally difficult to target a given biomolecule with high specificity. Furthermore, the interaction mechanism between albumin and cyanine molecules, which is usually regarded as uncertain "complexes" such as crosslinked nanoparticles, remains poorly understood.

Methods: Here, we propose a new class of NIR-II fluorogenic dyes capable of site-specific albumin tagging for in situ albumin seeking/targeting or constructing high-performance cyanine@albumin probes. We further investigate the interaction mechanism between NIR-II fluorogenic dyes and albumin.

Results: We identify CO-1080 as an optimal dye structure that produces a stable/bright NIR-II cyanine@albumin probe. CO-1080 exhibits maximum supramolecular binding affinity to albumin while catalyzing their covalent attachment. The probe shows exact binding sites located on Cys476 and Cys101, as identified by proteomic analysis and docking modeling.

Conclusion: Our cyanine@albumin probe substantially improves the pharmacokinetics of its free dye counterpart, enabling high-performance NIR-II angiography and lymphography. Importantly, the site-specific labeling tags between NIR-II fluorogenic dyes and albumin occur under mild conditions, offering a specific and straightforward synthesis strategy for NIR-II fluorophores in the fields of targeting bioimaging and imaging-guided surgery.

Keywords: NIR-II cyanine dye, cyanine@albumin, covalent binding site, site-specific labeling, NIR-II lymphography

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