| Autor: |
Moreau, Cle´mentine, Lukac?evic´, Tea, Pallier, Agne`s, Sobilo, Julien, Aci-Se`che, Samia, Garnier, Norbert, Me^me, Sandra, To´th, E´va, Lacerda, Sara |
| Zdroj: |
Bioconjugate Chemistry; February 2024, Vol. 35 Issue: 2 p265-275, 11p |
| Abstrakt: |
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 vitrostudies evidenced submicromolar affinity of Gd–K for Netrin-1 (KD= 0.29 µM) and good MRI efficacy (proton relaxivity, r1= 4.75 mM–1s–1at 9.4 T, 37 °C). In vivoMRI 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. |
| Databáze: |
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