Study of the intra-arterial distribution of Fe₃O₄ nanoparticles in a model of colorectal neoplasm induced in rat liver by MRI and spectrometry

José J Echevarria-Uraga,¹ Ignacio García-Alonso,² Fernando Plazaola,³ Maite Insausti,³ Néstor Etxebarria,³ Alberto Saiz-López,⁴ Begoña Fernández-Ruanova<sup>5

1</sup>Radiology Department, Hospital de Galdakao-Usánsolo, Bizkaia, Spain; ²Experimental Surgery Laboratory, Medicine Faculty, University of the Basque Country, Bizkaia, Spain; ³Faculty of Science and Technology, University of the Basque Country, Bizkaia, Spain; ⁴Pathology Department, Hospital de Galdakao-Usánsolo, Bizkaia, Spain; ⁵Osatek SA Unidad del Hospital de Galdakao-Usánsolo, Bizkaia, Spain

Purpose: To evaluate, in an experimental model, the reliability of MRI for determining whether a higher iron concentration was obtained in tumor tissue than in normal liver parenchyma after intra-arterial administration of Fe₃O₄ lipophilic nanoparticles.
Materials and methods: WAG/RijCrl rats were inoculated in the left hepatic lobe with 25,000 syngeneic CC-531 colon adenocarcinoma cells, after which they were randomized into two groups: control (CG) and infused (IG). After confirming tumor induction, the IG rats received intra-arterial suspensions of Fe₃O₄ nanoparticles (2.6 mg) in Lipiodol^® (0.15 mL). To calculate the iron concentration, [Fe], in the tumor and liver tissues of both groups of rats, measurements of signal intensity from the tumors, healthy liver tissue, and paravertebral muscles were made on a 1.5T MRI system in gradient-echo DP* and T2*-weighted sequences. In addition, samples were collected to quantify the [Fe] by inductively coupled plasma-mass spectrometry (ICP-MS), as well as for histological analysis. Statistical analysis was performed with non-parametric tests, and Bland–Altman plots were produced; P values <0.05 were considered significant.
Results: In the CG rats (n = 23), the mean [Fe] values estimated by MRI and ICP-MS were 13.2 µmol • g^-1 and 5.9 µmol • g^-1, respectively, in the tumors, and 19.0 µmol • g^-1 and 11.7 µmol • g^-1, respectively, in the hepatic tissue. In the IG rats (n = 19), the values obtained by MRI and ICP-MS were 148.9 µmol • g^-1 and 9.4 µmol • g^-1, respectively, in the tumors, and 115.3 µmol • g^-1 and 11.6 µmol • g^-1, respectively, in the healthy liver tissue. The IG results revealed a clear disagreement between MRI and ICP-MS. In the comparative analysis between the groups regarding the [Fe] values obtained by ICP-MS, significant differences were found for the tumor samples (P < 0.001), but not for the hepatic tissue (P = 0.92). Under microscopy, scattered intravascular deposits of nanoparticles were observed, especially in the tumors.
Conclusion: ICP-MS demonstrated significant uptake of exogenous iron in tumor tissue. MRI was useful for quantifying the [Fe] in the different tissues in the CG animals, but not in the IG animals. Although the irregular distribution of nanoparticles caused an important bias in the measurements obtained by MRI, the relative increase in iron content inside the tumor was suggested.

Keywords: liver neoplasm, hepatic arterial infusion, ferromagnetic particle, iron concentration, MRI, spectrometry