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

• Published in: Bioconjugate chemistry Vol. 35; no. 2; pp. 265 - 275
• Main Authors: Moreau, Clémentine, Lukačević, Tea, Pallier, Agnès, Sobilo, Julien, Aci-Sèche, Samia, Garnier, Norbert, Même, Sandra, Tóth, Éva, Lacerda, Sara
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21-02-2024
• Subjects: Animal models; Animals; Biomarkers; Biomarkers, Tumor; Breast cancer; Cell surface receptors; Chemical Sciences; Contrast agents; Contrast media; Contrast Media - chemistry; DCC protein; Design; Gadolinium; Humans; In vivo methods and tests; Injection; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Medical imaging; Metastases; Metastasis; Mice; Molecular docking; Molecular Docking Simulation; Molecular Probes; Netrin-1; Peptides; Triple Negative Breast Neoplasms; Tumors
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.3c00558

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 (K D = 0.29 μM) and good MRI efficacy (proton relaxivity, r 1 = 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.