By now most people know the immense value of magnetic resonance imaging (MRI) for determining an array of diseases or disorders of the body. Yet, for all its power, MRI is only as good as the physician reading the scans, and when used to determine cancer, the physicians are only as good as the chemicals employed to distinguish healthy tissue from cancerous tumors. Now, investigators at Case Western Reserve University (CWRU) have developed a new MRI contrasting agent that not only pinpoints breast cancers at early stages but differentiates between aggressive and slow-growing types.
“Doing both will help doctors find the right treatment,” noted senior study investigator Zheng-Rong Lu, Ph.D., professor of biomedical engineering at CWRU. “There's no such technology available now that we know of.” Findings from the new study were published by Dr. Lu and his colleagues today in Nature Communications in an article entitled “Targeted Gadofullerene for Sensitive Magnetic Resonance Imaging and Risk-Stratification of Breast Cancer.”
The gadolinium-based agent is also more efficient and safer than traditionally used compounds, requiring a gadolinium dose 20 times smaller—which is easily flushed from the body, leaving no accumulation in tissues—the researchers found in tests with mouse models. At the low dosage, the agent lights up cancer biomarkers during scans, overcoming the low sensitivity of MRI's for imaging the markers.
To make the agent, the CWRU team combined commercially available tri-gadolinium nitride metallofullerene (Gd3N@C80), a highly efficient contrast agent, with a peptide-labeled ZD2, which was developed in Dr. Lu's laboratory. “But the key technology for our targeted contrast agent is the peptide attached,” Dr. Lu stated.
“A peptide-targeted tri-gadolinium nitride metallofullerene, ZD2-Gd3N@C80, is synthesised for sensitive molecular magnetic resonance imaging of extradomain-B fibronectin in aggressive tumours,” the authors wrote. “ZD2-Gd3N@C80 has superior r1 and r2 relaxivities of 223.8 and 344.7 mM−1 s−1 (1.5 T), respectively. It generates prominent contrast enhancement in aggressive MDA-MB-231 triple negative breast cancer in mice at a low dose (1.7 µmol kg−1, 1 T), but not in oestrogen receptor-positive MCF-7 tumours. Strong tumour contrast enhancement is consistently observed in other triple negative breast cancer models, but not in low-risk slow-growing tumours. The dose of the contrast agent for effective molecular MRI is only slightly lower than that of ZD2-Cy5.5 (0.5 µmol kg−1) in fluorescence imaging.”
The peptide specifically targets the cancer protein extradomain-B fibronectin (EDB-FN). EDB-FN, which is associated with tumor invasion, metastasis, and drug resistance, is highly expressed in the matrix around cancerous cells in many aggressive forms of human cancers. In testing on six mouse models, MRIs detected breast cancers in all cases. But the signal created by the accumulation of contrast molecules on three aggressive triple-negative breast cancers (MDA-MB-231, Hs578T, and BT549) was significantly brighter. Because slow-moving ER-positive breast cancers (MCF-7, ZR-75-1, and T47D) produce less EDB-FN, fewer molecules attached. While detectable, the signal was muted.
“These results demonstrate that high-sensitivity molecular magnetic resonance imaging with ZD2-Gd3N@C80 may provide accurate detection and risk-stratification of high-risk tumours for the precision healthcare of breast cancer,” the authors concluded. Dr. Lu's lab is now investigating ways to reduce the cost of producing the agent to make it more attractive for clinical use.