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