Non-invasive quantitative imaging of hepatocellular carcinoma growth in mice by micro-CT using liver-targeted iodinated nano-emulsions

Nicolas Anton,Eric Robinet,Mohamed F Attia,Isabelle Goncalves,Marie Wattenhofer-Donzé,Tania Sorg,Hugues Jacobs,Alexandru Parlog,Ghina Bou About,Thierry F Vandamme

doi:10.1038/s41598-017-14270-7

Abstract

Hepatocellular carcinoma (HCC) is the only cancer for which non-invasive diagnosis is recognized by international guidelines. Contrast agent free ultrasound imaging, computed tomography (CT) and/or magnetic resonance imaging are techniques used for early detection and confirmation. Clinical evidence depicts that CT is 30% less precise as compared to MRI for detection of small tumors. In our work, we have reported some novel tools that can enhance the sensitivity and precision of CT applied to preclinical research (micro-CT). Our system, containing non-toxic nano-droplets loaded with iodine has high contrasting properties, liver and hepatocyte specificity and strong liver persistence. Micro-CT was performed on HCC model implanted in nude mice by intrahepatic injection. Contrast agent was administrated intravenously. This method allows an unprecedented high precision of detection, quantitative measurement of tumor volume and quantitative follow-up of the tumor development.

Highlights

Hepatocellular carcinoma (HCC) is the 5th most common cancer globally, representing 6% of all cancers, with a high mortality to incidence ratio and a unique geographic[1,2]
The pharmacokinetics of these nano-emulsions in healthy mice showed a total blood clearance and maximum hepatic accumulation after 24 h27. This is confirmed in orthotopic HCC tumor bearing mice, in which the vascular contrast is largely enhanced at D0 and the hepatic pattern very contrasted in the post-vascular phase
For each time-point, an inset is focused on the transverse section to emphasize the different morphological details with a color code: blood compartment, venae cava in red; the initial cavity in liver corresponding to the injection of Huh-7 cells in culture medium in blue; and the location of HCC tumor once formed in green

Summary

Introduction

Hepatocellular carcinoma (HCC) is the 5th most common cancer globally, representing 6% of all cancers, with a high mortality to incidence ratio and a unique geographic[1,2]. It is noteworthy that contrast enhanced ultrasound (CEUS) imaging is relegated at second/third-line diagnosis, and positron emission tomography (PET)-CT is not included in the guidelines for HCC diagnosis. MRI imaging stands out as the gold standard for early diagnosis, selective and functional imagining of HCC If this diagnosis approach is comparable with the one undertaken for the detection of liver metastasis[17], the strength of MRI lies in several physical techniques giving complementary information, like (i) fat-suppressed T2-weihted imaged for determining the tumor location, (ii) contrast-enhanced T1-weighted images that show a ring enhancement around the tumor, and (iii) confirmed by diffusion-weighted sequence. This reveals that the two key-points of the imaging efficiency of contrast agent depend on its (i) liver specificity and (ii) hepatocyte-specificity

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Conclusion