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PET imaging of EGFR expression using an 18F-labeled RNA aptamer

  • Siyuan Cheng
  • Orit Jacobson
  • Guizhi ZhuEmail author
  • Zhen Chen
  • Steve H. Liang
  • Rui Tian
  • Zhen Yang
  • Gang NiuEmail author
  • Xiaohua ZhuEmail author
  • Xiaoyuan ChenEmail author
Original Article

Abstract

Objective

Epidermal growth factor receptor (EGFR) is a theranostic biomarker for a variety of cancer types. The aim of the present study was to develop an 18F radiolabeled EGFR targeting RNA aptamer, and to investigate its ability to visualize and quantify EGFR in xenograft models.

Methods

Biolayer interferometry binding assay was used to detect the binding affinity of the alkyne-modified EGFR aptamer MinE07 (denoted as ME07) with recombinant human wild-type EGFR protein and the mutant EGFRvIII protein. Cy5-conjugated ME07 was used for flow cytometry and immunofluorescence staining, and an Alexa Fluor 488-labeled EGFR antibody (ab193244) was used as a control. 18F-Fluorobenzoyl (FB) azide was employed as a synthon to produce 18F-FB-ME07 via click chemistry, and the cellular uptake and internalization characteristics of 18F-FB-ME07 were investigated. Static PET scans, 60-min dynamic scans, and biodistribution study of 18F-FB-ME07 were performed in three types of tumor models.

Results

The Kd values of ME07 to wtEGFR and EGFRvIII proteins were 0.3 nM and 271 nM respectively. The A431, U87MG, and HCT-116 cells showed strong, weak, and negative binding with Cy5-ME07, which is consistent with EGFR expression level in these cells. Peak cell uptake values of 18F-FB-ME07 in A431, U87MG and HCT-116 cells were 2.86%, 2.19% and 0.88% of the added dose respectively. The mean internalization of 18F-FB-ME07 in these cells were 60.02%, 53.1%, and 52.8% of the total accumulated radioactivity. In static PET imaging, despite high uptake in the liver and kidneys, 18F-FB-ME07 showed reasonable accumulation in A431 tumors (1.02 ± 0.13 %ID/g at 30 min after injection). Of note, the uptake of 18F-FB-ME07 in A431 xenografts was significantly higher than that in U87MG and HCT-116 xenografts. In A431 xenografted mice, the tumor/blood ratio was 3.89 and the tumor/muscle ratio reached 8.65.

Conclusions

We for the first time generated an aptamer-derived EGFR targeting PET tracer 18F-FB-ME07, which showed highly selective targeting ability in mouse tumor models expressing different levels of EGFR. Our results suggest that 18F-FB-ME07 is a potential EGFR targeting molecular imaging probe for future clinical translation.

Keywords

EGFR RNA aptamer 18F-FB-ME07 PET 

Notes

Funding

This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), National Natural Science Foundation of China (81671718 and 81271600), and Natural Science Foundation of Hubei Province of China (2016CFB687).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

259_2018_4105_MOESM1_ESM.docx (370 kb)
ESM 1 (DOCX 370 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Nuclear Medicine and PET, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  2. 2.Laboratory of Molecular Imaging and NanomedicineNational Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH)BethesdaUSA
  3. 3.Department of Pharmaceutics, School of PharmacyVirginia Commonwealth UniversityRichmondUSA
  4. 4.Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of RadiologyHarvard Medical SchoolBostonUSA

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