Development of Netrin-1-targeted peptide probes derived from the Netrin-1/DCC complex for noninvasive imaging of tumors.

Authors

Shu Li, Shuang Wang, Xue Zhu, Zhihong Huang, Yang Jiao, Jiayuan Du, Jie Tang, Zhenfeng Liu, Ke Wang, Jing Fang

Published in

Bioorganic chemistry. Volume 182. Pages 110479. Sep 05, 2026. Epub Sep 05, 2026.

Abstract

Netrin-1 is a secreted glycoprotein that is overexpressed in non-small cell lung cancer (NSCLC) and breast cancer, making it an emerging biomarker for tumor diagnosis and targeted therapy. However, noninvasive imaging tools for quantitative assessment of Netrin-1 expression remain limited. In this study, leveraging the crystal structure of the Netrin-1/DCC complex, we rationally designed two Netrin-1-targeted peptides YP8 and LE7, through systematic in silico molecular docking, alanine scanning, and virtual amino acid mutation. Their corresponding ⁶⁸Ga-labeled PET tracers [⁶⁸Ga]Ga-NOTA-YP8 and [⁶⁸Ga]Ga-NOTA-LE7, were subsequently developed. Comparative evaluation revealed that [⁶⁸Ga]Ga-NOTA-LE7 exhibited superior Netrin-1 binding affinity, enhanced in vivo stability, and significantly improved tumor-to-background ratio. PET imaging demonstrated specific and robust uptake of [⁶⁸Ga]Ga-NOTA-LE7 in Netrin-1-positive A549 and 4T1 tumors, with minimal accumulation in Netrin-1-low MDA-MB-231 tumors. The NIRF probe ICG-LE7 further confirmed specific tumor targeting and enabled fluorescence-guided surgical resection. Collectively, these findings establish [⁶⁸Ga]Ga-NOTA-LE7 and ICG-LE7 as promising noninvasive diagnostic tools for Netrin-1 expression imaging.

PMID:
42702132
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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