Peptide-Conjugated MRI Probe Targeted to Netrin-1, a Novel Metastatic Breast Cancer Biomarker

Bioconjug Chem. 2024 Feb 21;35(2):265-275. doi: 10.1021/acs.bioconjchem.3c00558. Epub 2024 Feb 10.

Abstract

Despite significant progress in cancer imaging and treatment over the years, early diagnosis and metastasis detection remain a challenge. Molecular magnetic resonance imaging (MRI), with its high resolution, can be well adapted to fulfill this need, requiring the design of contrast agents which target specific tumor biomarkers. Netrin-1 is an extracellular protein overexpressed in metastatic breast cancer and implicated in tumor progression and the appearance of metastasis. This study focuses on the design and preclinical evaluation of a novel Netrin-1-specific peptide-based MRI probe, GdDOTA-KKTHDAVR (Gd-K), to visualize metastatic breast cancer. The targeting peptide sequence was identified based on the X-ray structure of the complex between Netrin-1 and its transmembrane receptor DCC. Molecular docking simulations support the probe design. In vitro studies evidenced submicromolar affinity of Gd-K for Netrin-1 (KD = 0.29 μM) and good MRI efficacy (proton relaxivity, r1 = 4.75 mM-1 s-1 at 9.4 T, 37 °C). In vivo MRI studies in a murine model of triple-negative metastatic breast cancer revealed successful tumor visualization at earlier stages of tumor development (smaller tumor volume). Excellent signal enhancement, 120% at 2 min and 70% up to 35 min post injection, was achieved (0.2 mmol/kg injected dose), representing a reasonable imaging time window and a superior contrast enhancement in the tumor as compared to Dotarem injection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor*
  • Contrast Media / chemistry
  • Humans
  • Magnetic Resonance Imaging / methods
  • Mice
  • Molecular Docking Simulation
  • Molecular Probes
  • Netrin-1
  • Peptides
  • Triple Negative Breast Neoplasms*

Substances

  • Biomarkers, Tumor
  • Molecular Probes
  • Netrin-1
  • Contrast Media
  • Peptides