MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent.
Metastasis is the primary cause of death in breast cancer patients. Early detection of high-risk breast cancer, including micrometastasis, is critical in tailoring appropriate and effective interventional therapies. Increased fibronectin expression, a hallmark of epithelial-to-mesenchymal transition, is associated with high-risk breast cancer and metastasis. We have previously developed a penta-peptide CREKA (Cys-Arg-Glu-Lys-Ala)-targeted gadolinium-based magnetic resonance imaging (MRI) contrast agent, CREKA-Tris(Gd-DOTA)3 (Gd-DOTA (4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl gadolinium), which binds to fibrin-fibronectin complexes that are abundant in the tumour microenvironment of fast-growing breast cancer. Here we assess the capability of CREKA-Tris(Gd-DOTA)3 to detect micrometastasis with MRI in co-registration with high-resolution fluorescence cryo-imaging in female mice bearing metastatic 4T1 breast tumours. We find that CREKA-Tris(Gd-DOTA)3 provides robust contrast enhancement in the metastatic tumours and enables the detection of micrometastases of size <0.5 mm, extending the detection limit of the current clinical imaging modalities. These results demonstrate that molecular MRI with CREKA-Tris(Gd-DOTA)3 may facilitate early detection of high-risk breast cancer and micrometastasis in the clinic.
1] Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA [2] Center for Bionanoengineering and State Key Laboratory of Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027 China.
Zhuxian
0000000271049915
Z
Zhou
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Mohammed
M
Qutaish
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Zheng
Z
Han
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Rebecca M
RM
Schur
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Yiqiao
Y
Liu
1] Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA [2] Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
David L
DL
Wilson
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Zheng-Rong
ZR
Lu
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000473:pathology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D014018:Tissue Distribution
C000607013:CREKA-Tris(Gd-DOTA)3; D003287:Contrast Media; D056831:Coordination Complexes; D005353:Fibronectins; D009842:Oligopeptides