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PET/NIR-II fluorescence imaging and image-guided surgery of glioblastoma using a folate receptor α-targeted dual-modal nanoprobe

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Abstract

Purpose

The surgery of glioblastoma (GBM) requires a maximal resection of the tumor when it is safe and feasible. The infiltrating growth property of the GBM makes it a challenge for neurosurgeons to identify the tumor tissue even with the assistance of the surgical microscope. This highlights the urgent requirement for imaging techniques that can differentiate tumor tissues during surgery in real time. Fluorescence image-guided surgery of GBM has been investigated using several non-specific fluorescent probes that emit light in the visible and the first near-infrared window (NIR-I, 700–900 nm), which limit the detection accuracy because of the non-specific targeting mechanism and spectral characteristics. Targeted NIR-II (1000–1700 nm) fluorescent probes for GBM are thus highly desired. The folate receptor (FR) has been reported to be upregulated in GBM, which renders it to be a promising target for specific tumor imaging.

Methods

In this study, the folic acid (FA) that can target the FR was conjugated with the clinically approved indocyanine green (ICG) dye and DOTA chelator for radiolabeling with 64Cu to achieve targeted positron emission tomography (PET) and fluorescence imaging of GBM.

Results

Surprisingly it was found that the resulted bioconjugate, DOTA-FA-ICG and non-radioactive natCu-DOTA-FA-ICG, were both self-assembled into nanoparticles with NIR-II emission signal. The radiolabeled DOTA-FA-ICG, 64Cu-DOTA-FA-ICG, was found to specifically accumulate in the orthotopic GBM models using in vivo PET, NIR-II, and NIR-I fluorescence imaging. The best time window of fluorescence imaging was demonstrated to be 24 h after DOTA-FA-ICG injection. NIR-II fluorescence image-guided surgery was successfully conducted in the orthotopic GBM models using DOTA-FA-ICG. All the fluorescent tissue was removed and proved to be GBM by the H&E examination.

Conclusion

Overall, our study demonstrates that the probes, 64Cu-DOTA-FA-ICG and DOTA-FA-ICG, hold promise for preoperative PET examination and intraoperative NIR-II fluorescence image-guided surgery of GBM, respectively.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The data generated or analyzed during this study are included in the manuscript and the supplementary information files.

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Acknowledgements

The authors would like to acknowledge the instrumental and technical support of the multi-modal biomedical imaging experimental platform, Institute of Automation, Chinese Academy of Sciences. The authors thank Prof. Hua Zhu from the Beijing Cancer Hospital for their efforts in the use of 64Cu and radiolabeling of the probe.

Funding

This study was supported by the National Key Research and Development Program of China (2017YFA0205200), National Natural Science Foundation of China (NSFC) (62027901, 81930053, 92059207, 81227901, 81701754), Beijing Natural Science Foundation (JQ19027), CAS Youth Interdisciplinary Team (JCTD-2021–08), the Strategic Priority Research Program (A) of Chinese Academy of Sciences (XDA16021200), and the Zhuhai High-level Health Personnel Team Project (Zhuhai HLHPTP201703).

Author information

Author notes

  1. Xiaojing Shi and Pengfei Xu contributed equally to this work.

Authors and Affiliations

  1. CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China

    Xiaojing Shi, Caiguang Cao, Jie Tian & Zhenhua Hu

  2. School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China

    Xiaojing Shi, Caiguang Cao, Jie Tian & Zhenhua Hu

  3. Institute of Clinical Pharmacy & Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, China

    Pengfei Xu

  4. State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Zhen Cheng

  5. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine, Beihang University, Beijing, China

    Jie Tian

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Contributions

Pengfei Xu synthesized the probe. Xiaojing Shi performed the experiments. Xiaojing Shi and Pengfei Xu analyzed the data and wrote the manuscript. Zhenhua Hu, Jie Tian, and Zhen Cheng supervised the designation of the experiments. Caiguang Cao assisted with data analysis.

Corresponding authors

Correspondence to Zhen Cheng, Jie Tian or Zhenhua Hu.

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This study only involved small animals. All the experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee of Institute of Automation, Chinese Academy of Sciences.

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Shi, X., Xu, P., Cao, C. et al. PET/NIR-II fluorescence imaging and image-guided surgery of glioblastoma using a folate receptor α-targeted dual-modal nanoprobe. Eur J Nucl Med Mol Imaging 49, 4325–4337 (2022). https://doi.org/10.1007/s00259-022-05890-x

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