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. 2024 Feb 22;25(5):2569.
doi: 10.3390/ijms25052569.

Monolacunary Wells-Dawson Polyoxometalate as a Novel Contrast Agent for Computed Tomography: A Comprehensive Study on In Vivo Toxicity and Biodistribution

Marko Stojanović  1 , Mirjana B Čolović  2 , Jovana Lalatović  3 , Aleksandra Milosavljević  4 , Nada D Savić  5 , Kilian Declerck  5 , Branimir Radosavljević  6 , Mila Ćetković  4 , Tamara Kravić-Stevović  4 , Tatjana N Parac-Vogt  5 , Danijela Krstić  6
Affiliations

Monolacunary Wells-Dawson Polyoxometalate as a Novel Contrast Agent for Computed Tomography: A Comprehensive Study on In Vivo Toxicity and Biodistribution

Marko Stojanović et al. Int J Mol Sci. .

Abstract

Polyoxotungstate nanoclusters have recently emerged as promising contrast agents for computed tomography (CT). In order to evaluate their clinical potential, in this study, we evaluated the in vitro CT imaging properties, potential toxic effects in vivo, and tissue distribution of monolacunary Wells-Dawson polyoxometalate, α2-K10P2W17O61.20H2O (mono-WD POM). Mono-WD POM showed superior X-ray attenuation compared to other tungsten-containing nanoclusters (its parent WD-POM and Keggin POM) and the standard iodine-based contrast agent (iohexol). The calculated X-ray attenuation linear slope for mono-WD POM was significantly higher compared to parent WD-POM, Keggin POM, and iohexol (5.97 ± 0.14 vs. 4.84 ± 0.05, 4.55 ± 0.16, and 4.30 ± 0.09, respectively). Acute oral (maximum-administered dose (MAD) = 960 mg/kg) and intravenous administration (1/10, 1/5, and 1/3 MAD) of mono-WD POM did not induce unexpected changes in rats' general habits or mortality. Results of blood gas analysis, CO-oximetry status, and the levels of electrolytes, glucose, lactate, creatinine, and BUN demonstrated a dose-dependent tendency 14 days after intravenous administration of mono-WD POM. The most significant differences compared to the control were observed for 1/3 MAD, being approximately seventy times higher than the typically used dose (0.015 mmol W/kg) of tungsten-based contrast agents. The highest tungsten deposition was found in the kidney (1/3 MAD-0.67 ± 0.12; 1/5 MAD-0.59 ± 0.07; 1/10 MAD-0.54 ± 0.05), which corresponded to detected morphological irregularities, electrolyte imbalance, and increased BUN levels.

Keywords: CO-oximetry status; X-ray attenuation; biochemical parameters; blood gas analysis; histological analysis; in vitro computed tomography imaging; in vivo toxicity; monolacunary Wells-Dawson polyoxotungstate; tissue distribution.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Scheme 1
Scheme 1
Structure of monolacunary Wells–Dawson polyoxotungstate (mono-WD POM), α2-K10P2W17O61.20H2O (red balls–oxygen).
Figure 1
Figure 1
(a) Images generated from a clinical CT scanner phantom scan of mono-WD POM and WSiA, ranging from 3.125 to 100 mM W; (b) the linear dependence of X-ray attenuation (expressed in Hounsfield units (HU)) on W/I concentration for the tungsten-containing compounds of various structures: Keggine structure POM (12-tungstosilicic acid, WSiA) (red circle), parent WD-POM (green triangle) [9] and its monolacunary derivative (mono-WD POM) (pink solid asterisk), and iodine-containing omnipaque (blue open asterisk) [9].
Figure 2
Figure 2
Arterial blood glucose levels in the control group and animals treated with 1/10 MAD, 1/5 MAD, and 1/3 MAD of mono-WD POM. The results are expressed as mean value ± SD. The significant values: ** p < 0.01.
Figure 3
Figure 3
Arterial blood lactate levels in the control group and animals treated with 1/10 MAD, 1/5 MAD, and 1/3 MAD of mono-WD POM. The results are expressed as mean value ± SD.
Figure 4
Figure 4
Arterial blood creatinine concentrations in the control group and animals treated with 1/10 MAD, 1/5 MAD, and 1/3 MAD of mono-WD POM. The results are expressed as mean value ± SD.
Figure 5
Figure 5
Arterial blood urea nitrogen (BUN) concentrations in the control group and animals treated with 1/10 MAD, 1/5 MAD, and 1/3 MAD of mono-WD POM. The results are expressed as mean value ± S.D. The significant values: *** p < 0.001, †† p < 0.01.
Figure 6
Figure 6
Histopathological evaluation of mono-WD POM-induced renal toxicity. Photographs of HE-stained rat kidney sections (a–h); image was captured under a light microscope with ×10 (a,c,e,g) and ×40 (b,d,f,h) magnifications. No differences were observed between the kidney tissues from the control group (a,b) and rats treated with 1/10 MAD (c,d) and 1/5 MAD (e,f), whereas tissue from rats treated with 1/3 MAD (g,h) showed necrosis of tubular cells (arrowhead) and glomerular sclerosis (arrows). TEM micrographs of kidney sections (1–4) show: (1) (×2800) control rat; (2) rat treated with 1/10 MAD showing (×4400) apoptosis of tubular cells (arrows); and (3) (×2800), (4) (×3500)) rats treated with 1/5 MAD and 1/3 MAD, respectively, showing necrosis of tubular cells (arrows).
Figure 7
Figure 7
Histopathological evaluation of mono-WD POM-induced hepatotoxicity. Photographs of HE-stained rat liver sections (a–h); image was captured under a light microscope with ×10 (a,c,e,g) and ×40 (b,d,f,h) magnifications. No differences were observed between the liver tissue from the control group (a,b) and rat treated with 1/10 MAD (c,d), whereas tissue from rats treated with 1/5 MAD (e,f) showed discrete necrosis (arrow), and 1/3 MAD (g,h) showed dilatation of sinusoidal spaces and discrete necrosis (arrow). TEM micrographs of liver sections (1–4) show: (1) (×2200) control rat; (2) (×2800) rat treated with 1/10 MAD showing apoptosis of endothelial cells (arrow); and (3) (×2200), (4) (×3500)) rats treated with 1/5 MAD and 1/3 MAD, respectively, showing necrosis of hepatocytes (arrows).
Figure 8
Figure 8
Histopathological evaluation of mono-WD POM-induced lung toxicity. Photographs of HE-stained rat lung sections (a–h); image was captured under a light microscope with ×10 (a,c,e,g), ×20 (f), and ×40 (b,d,h) magnifications. No differences were observed between the lung tissues from the control group (a,b) and rats treated with 1/10 MAD (c,d) and 1/5 MAD (e,f), whereas tissue from rats treated with 1/3 MAD (g, h) showed a thickening of interstitial spaces (arrows). TEM micrographs of lung sections (1–4) show: (1) (×2800) control rat; (2) (×3500) rat treated with 1/10 MAD showing normal lung tissue; and (3) (×8900), (4) (×4400)) rats treated with 1/5 MAD and 1/3 MAD, showing fibrosis and prominent fibrosis of lung interstitium (arrows), respectively.
Figure 9
Figure 9
Histopathological evaluation of mono-WD POM-induced cardiotoxicity. Photographs of HE-stained rat heart sections (a–h); image was captured under a light microscope with ×10 (a), ×20 (c,e,g), and ×40 (b,d,f,h) magnifications. No differences were observed between the heart tissues from the control group (a, b) and rats treated with 1/10 MAD (c,d), whereas tissues from rat treated with 1/5 MAD (e,f) and 1/3 MAD (g,h) showed a loss of striation in cardiac muscle cells (arrows). TEM micrographs of heart sections (1–4) show: (1) (×2800) control rat; (2) (×2800) rat treated with 1/10 MAD showing normal heart tissue; and (3) (×3300) rats treated with 1/5 MAD showing an interstitial bleeding (arrow); (4) (×2800) rats treated with 1/3 MAD showing necrosis of cardiac muscle cell (arrow) and necrosis of endothelial cell (arrowhead).
Figure 10
Figure 10
Tissue distribution of mono-WD POM in Wistar rats two weeks post-intravenously applied 1/10, 1/5, and 1/3 MAD, expressed as tungsten concentration (mean ± SD) in kidney, liver, lung, heart, and femur tissues. The difference between control and treated groups was presented as: * for 1/3 MAD group, † for 1/5 MAD group, and ‡ for 1/10 MAD group. The difference between 1/3 MAD and 1/5 MAD was presented as &, and between 1/3 MAD and 1/10 MAD as #. The significant values: *** p < 0.001, ** p < 0.01, ††† p < 0.001, ‡‡‡ p < 0.001, ‡‡ p < 0.01, &&& p < 0.001, ## p < 0.01, # p < 0.05.
Scheme 2
Scheme 2
Experimental design for in vivo acute toxicity evaluation of monolacunary Wells–Dawson polyoxotungstate (mono-WD POM).
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