A New OATP-Mediated Hepatobiliary-Specific Mn(II)-Based MRI Contrast Agent for Hepatocellular Carcinoma in Mice: A Comparison With Gd-EOB-DTPA.

Abstract

Growing concerns about the safety of gadolinium (Gd)-based contrast agents have reinforced the need for the development of Gd-free MRI contrast agents (CAs) that are effective in imaging liver tumors. To evaluate the ability of Mn-BnO-TyEDTA MRI CA to detect hepatocellular carcinoma in a mouse model of implanted liver tumor. Prospective. Thirteen orthotopically implanted liver tumor mice. 3.0 T/precontrast and postcontrast T1-weighted fast spoiled gradient recalled echo and T2-weighted fast recovery fast spin-echo imaging with fat suppression. The relative enhancement ratio was calculated and statistically compared. Lesion detection in postcontrast images was analyzed by calculations of area under the curve (AUC, the increases in liver-to-tumor contrast-to-noise ratio [∆CNR] vs. time curve). Mn or Gd levels were measured in the liver and tumoral tissues by inductively coupled plasma-mass spectrometry. Tumor specimens were stained with hematoxylin and eosin (H&E) and the expression of organic anion transfer peptide (OATP)1B1 was evaluated by immunofluorescence (IF) staining and mean fluorescence intensity (MFI) was calculated. Unpaired t-test and two-tailed paired t-test. P < 0.05 was considered statistical significance. Mn-BnO-TyEDTA and Gd-EOB-DTPA demonstrated nearly identical enhancement patterns in the liver, tumor, and psoas muscle and no difference in lesion detection (AUC10-30, Mn =851 ∆CR·min, AUC10-30, Gd =823 ∆CR·min). A Significant higher concentration of metal (Mn or Gd) was found in the liver compared to the tumor ([Mn]liver =0.88 ± 0.07 μmmol/g, [Mn]tumor =0.49 ± 0.05 μmmol/g, [Gd]liver =0.65 ± 0.07 μmmol/g, [Gd]tumor =0.27 ± 0.04 μmmol/g). IF staining showed significantly decreased expression of OATP1B1 in the tumor core compared to the liver (MFItumor =5.28 ± 1.54, MFIliver =25.49 ± 3.41). Mn-BnO-TyEDTA can provide comparable hepatobiliary tumor contrast enhancement to Gd-EOB-DTPA. 1 TECHNICAL EFFICACY: Stage 1.