Peptide-conjugated MRI probe targeted to Netrin-1, a novel metastatic breast cancer biomarker - Aspects Moléculaires du Vivant
Article Dans Une Revue Bioconjugate Chemistry Année : 2024

Peptide-conjugated MRI probe targeted to Netrin-1, a novel metastatic breast cancer biomarker

Résumé

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.

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Chimie
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Dates et versions

hal-04630981 , version 1 (22-10-2024)

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Clémentine Moreau, Tea Lukačević, Agnès Pallier, Julien Sobilo, Samia Aci-Sèche, et al.. Peptide-conjugated MRI probe targeted to Netrin-1, a novel metastatic breast cancer biomarker. Bioconjugate Chemistry, 2024, 35 (2), pp.265-275. ⟨10.1021/acs.bioconjchem.3c00558⟩. ⟨hal-04630981⟩
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