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Targeting Phosphatidylethanolamine with Fluorine-18 Labeled Small Molecule Probe for Apoptosis Imaging

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Abstract

Purpose

Externalization of phosphatidylethanolamine (PE) in dying cells makes the phospholipid an attractive target for apoptosis imaging. However, no ideal PE-targeted positron emission tomography (PET) radiotracer was developed. The goal of the study was to develop a novel PE-targeted radiopharmaceutical to imaging apoptosis.

Procedure

In this study, we have radiolabeled PE-binding polypeptide duramycin with fluorine-18 for PET imaging of apoptosis. Al[18F]F-NOTA-PEG3-duramycin was synthesized via chelation reaction of NOTA-PEG3-duramycin with Al[18F]F. PE-binding capacity of Al[18F]F-NOTA-PEG3-duramycin was determined in a competitive radiometric PE-binding assay. The pharmacokinetic profile was evaluated in Kunming mice. The apoptosis imaging capacity of Al[18F]F-NOTA-PEG3-duramycin was evaluated using in vitro cell uptake assay with camptothecin-treated Jurkat cells, along with in vivo PET imaging using erlotinib-treated nude mice.

Results

The total synthesis procedure lasted for 30 min, with a decay-uncorrected radiochemical yield of 21.3 ± 2.6 % (n = 10). Compared with the control cells, the binding of Al[18F]F-NOTA-PEG3-duramycin with camptothecin-induced apoptotic cells resulted in a tripling increase. A competitive radiometric PE-binding assay strongly confirmed the binding of Al[18F]F-NOTA-PEG3-duramycin to PE. The biodistribution study showed rapid blood clearance, prominent kidney retention, and low liver uptake. In the in vivo PET/CT imaging, Al[18F]F-NOTA-PEG3-duramycin demonstrated 2-fold increase in erlotinib-treated HCC827 tumors in nude mice.

Conclusion

Considering the facile preparation and improved biological properties, Al[18F]F-NOTA-PEG3-duramycin seems to be a promising PET tracer candidate for imaging apoptosis in the monitoring of cancer treatment.

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Funding

This work was funded by the National Natural Science Foundation (Nos. 81571704, 81671719, 81701723), the Science and Technology Foundation of Guangdong Province (Nos. 2016B090920087, 2018B030337001), and the Science and Technology Planning Project Foundation of Guangzhou (Nos. 201604020169, 201510010145).

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Authors and Affiliations

  1. Department of Nuclear Medicine and Medical Imaging, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

    Gongjun Yuan, Shaoyu Liu, Hui Ma, Shu Su, Fuhua Wen, Zhanwen Zhang, Jing Zhao, Liping Lin, Xianhong Xiang & Ganghua Tang

  2. Guangdong Engineering Research center for Translational Application of Medical Radiopharmaceuticals, Sun Yat-sen University, Guangzhou, 510080, China

    Gongjun Yuan, Shaoyu Liu, Hui Ma, Shu Su, Fuhua Wen, Xiaolan Tang, Zhanwen Zhang, Jing Zhao, Liping Lin, Xianhong Xiang, Dahong Nie & Ganghua Tang

  3. School of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China

    Xiaolan Tang

  4. Department of Radiation Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

    Dahong Nie

  5. Nanfang PET Center and Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Ganghua Tang

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  1. Gongjun Yuan
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  2. Shaoyu Liu
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  8. Jing Zhao
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  12. Ganghua Tang
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Corresponding authors

Correspondence to Dahong Nie or Ganghua Tang.

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The experiments were approved by the Institutional animal care and utilization committee (IACUU) of the first affiliated hospital, Sun Yat-sen University.

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Yuan, G., Liu, S., Ma, H. et al. Targeting Phosphatidylethanolamine with Fluorine-18 Labeled Small Molecule Probe for Apoptosis Imaging. Mol Imaging Biol 22, 914–923 (2020). https://doi.org/10.1007/s11307-019-01460-0

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