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Magnetic-optical dual-modality imaging monitoring chemotherapy efficacy of pancreatic ductal adenocarcinoma with a low-dose fibronectin-targeting Gd-based contrast agent

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Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a lethal hypovascular tumor surrounded by dense fibrosis. Albumin-bound paclitaxel and gemcitabine (AG) chemotherapy is the mainstay of PDAC treatment through depleting peritumoral fibrosis and killing tumor cells; however, it remains challenging due to the lack of a noninvasive imaging method evaluating fibrotic changes during AG chemotherapy. In this study, we developed a dual-modality imaging platform that enables noninvasive, dynamic, and quantitative assessment of chemotherapy-induced fibrotic changes through near-infrared fluorescence molecular imaging (FMI) and magnetic resonance imaging (MRI) using an extradomain B fibronectin (EDB-FN)-targeted imaging probe (ZD2-Gd-DOTA-Cy7).

Methods

The ZD2-Gd-DOTA-Cy7 probe was constructed by conjugating a peptide (Cys-TVRTSAD) to Gd-DOTA and the near-infrared dye Cy7. PDAC murine xenograft models were intravenously injected with ZD2-Gd-DOTA-Cy7 at a Gd concentration of 0.05 mmol/kg or free Cy7 and Gd-DOTA as control. The normalized tumor background ratio (TBR) on FMI and the T1 reduction ratio on MRI were quantitatively analyzed. For models receiving AG chemotherapy or saline, MRI/FMI was performed before and after treatment. Histological analyses were performed for validation.

Results

The ZD2-Gd-DOTA-Cy7 concentration showed a linear correlation with the fluorescence intensity and T1 relaxation time in vitro. The optimal imaging time was 30 min after injection of the ZD2-Gd-DOTA-Cy7 (0.05 mmol/kg), only half of the clinic dosage of gadolinium. Additionally, ZD2-Gd-DOTA-Cy7 generated a 1.44-fold and 1.90-fold robust contrast enhancement compared with Cy7 (P < 0.05) and Gd-DOTA (P < 0.05), respectively. For AG chemotherapy monitoring, the T1 reduction ratio and normalized TBR in the fibrotic tumor areas were significantly increased by 1.99-fold (P < 0.05) and 1.78-fold (P < 0.05), respectively, in the control group compared with those in the AG group.

Conclusion

MRI/FMI with a low dose of ZD2-Gd-DOTA-Cy7 enables sensitive imaging of PDAC and the quantitative assessment of fibrotic changes during AG chemotherapy, which shows potential clinical applications for precise diagnosis, post-treatment monitoring, and disease management.

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Data availability

Data are available on request from the authors.

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (Grant Nos. 62027901, 82272111, 92159303, 82071896, 81871422, 81871514, and 81227901), Beijing Natural Science Foundation (Grant No. 7212207, 7244524), National High Level Hospital Clinical Research Funding (2022-PUMCH-D-001), and Peking University Third Hospital (BYSYZD2019018 and jyzc2018-02).

Funding

This study was funded by the National Natural Science Foundation of China (Grant Nos. 62027901, 82272111, 92159303, 82071896, 81871422, 81871514, and 81227901), Beijing Natural Science Foundation (Grant No. 7212207, 7244524), National High Level Hospital Clinical Research Funding (2022-PUMCH-D-001), and Peking University Third Hospital (BYSYZD2019018 and jyzc2018-02).

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Author notes

  1. Wenjia Zhang, Xiaolong Liang and Xinyu Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China

    Wenjia Zhang, Xinyu Zhang, Zhengyu Jin & Huadan Xue

  2. Department of Radiology, Peking University People’s Hospital, Beijing, 100032, China

    Wenjia Zhang

  3. CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, No. 95 Zhongguancun East Road, Beijing, 100190, China

    Wenjia Zhang, Wei Tong, Guangyuan Shi, Haozhuo Guo, Jie Tian & Yang Du

  4. Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China

    Xiaolong Liang

  5. Beijing Advanced Innovation Centre for Big Data-Based Precision Medicine, School of Medicine, Beihang University, Beijing, 100191, China

    Jie Tian

  6. The University of Chinese Academy of Sciences, Beijing, 100049, China

    Yang Du

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  1. Wenjia Zhang
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Contributions

Conception, design, and supervision were performed by Yang Du, Jie Tian, Zhengyu Jin, and Huadan Xue. Material preparation, data collection, and analyses were performed by Wenjia Zhang, Xiaolong Liang, Xinyu Zhang, Wei Tong, Guangyuan Shi, and Haozhuo Guo. The first draft of the manuscript was written by Wenjia Zhang, Xiaolong Liang, and Xinyu Zhang. The manuscript was edited by Yang Du, Jie Tian, Zhengyu Jin, and Huadan Xue. All authors commented on previous versions of the manuscript. All authors approved the final manuscript.

Corresponding authors

Correspondence to Zhengyu Jin, Jie Tian, Yang Du or Huadan Xue.

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All experimental studies were approved by the Ethics Committee of the Peking Union Medical College Hospital (XHDW-2022-016). The details of the experimental section are available in the supporting information.

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Zhang, W., Liang, X., Zhang, X. et al. Magnetic-optical dual-modality imaging monitoring chemotherapy efficacy of pancreatic ductal adenocarcinoma with a low-dose fibronectin-targeting Gd-based contrast agent. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06617-w

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