Info
Background:
Spectral Photon Counting Computed Tomography (SPCCT) is an advanced CT imaging modality offering a very high spatial resolution and reduced radiation dose in comparison to conventional HR-CT [1]. It enables simultaneous detection and quantification of multiple contrast agents based on their specific K-edge energies. Current iodine-based CT contrast agents are suboptimal for SPCCT due to their low K-edge (33.2 keV) driving the need for agents with higher K edge energies [2]. Tungsten (W, K-edge = 69 keV) is promising yet understudied. In this study, tungsten containing polyoxometalates were investigated as candidates for stable and safe intravenous contrast agents. These metal-oxide clusters exhibit very high metal content (up to 76% W in Keggin type structures) and ultrasmall size (~1 nm), potentially enabling rapid renal clearance and limiting long term toxicity. However, their clinical translation remains challenging due to chemical stability issues at physiological pH, and the release of toxic inorganic by products [3].
Hypothesis/Objective:
This project focuses on formulating polyoxotungstates into effective ultrasmall SPCCT contrast agents, addressing current challenges in stability, toxicity, and biodistribution.
Methods:
Monolacunary polyoxotungstate with general formula [XW11O39]n-m- with X= P or Si (PW11 or SiW11) and their calcium complexes (PW11-Ca and SiW11-Ca) were synthesized and their identity and purity were characterized by 31P NMR, 29Si NMR, FTIR, Raman spectroscopy and MP-AES. Kinetic stability in fetal bovine serum at pH 7.4 was evaluated using 31P NMR and Raman Spectroscopy for up to 24 hours. In vitro safety evaluation was done by hemolysis assay in human red blood cells and cytotoxicity assays in RAW264.7, A549 and HEK293 cell lines. Contrast efficiency of SiW11-Ca was compared with Commercial agent Xenetix (Iodine) using in vitro SPCCT phantom studies. For in vivo biodistribution and pharmacokinetic studies, SiW11-Ca was intravenously administered to rats (100mgW/kg). Animals were imaged for up to 2 hours using SPCCT for quantitative biodistribution. W was also quantified in blood and organs using MP-AES and ICP up to 1 week. A proof of concept of pulmonary perfusion evaluation was performed in a Porcine model of pulmonary embolism (PE) with SiW11-Ca (27mgW/kg).
Results:
Ultrasmall W clusters (~1 nm) were successfully synthesized and characterization confirmed the identity and purity of all products. Calcium complexation improved structural stability. 31P NMR and raman spectra analysis showed that calcium complexation improved stability in serum. Raman spectra analysis showed 100% stability of SiW11-Ca in serum incubated for 24 hours in contrast to PW11-Ca (67%). All products showed less than 5% hemolysis up to 29 mgW/mL. Calcium complexation improved cytocompatibility for both PW11 and SiW11 with SiW11-Ca showing the highest biocompatibility across all tested cell lines. K-edge imaging of SiW11-Ca showed 21-fold increase in contrast-to-noise ratio over conventional CT imaging and a good quantitative correlation between prepared and measured W contents (R2 =0.99) demonstrating high performance of SPCCT. In vivo studies in rats showed low organ accumulation 2 hours post-injection as quantified by SPCCT based biodistribution analysis. SiW11-Ca showed a blood half-life of 1.3 h and was found to be rapidly excreted through urine within 6-15 min post-injection. K-edge imaging of SiW11-Ca in porcine PE model showed reduced perfusion in region of the lung with emboli allowing diagnosis.
Conclusion:
A novel ultrasmall tungsten based contrast agent, SiW11-Ca, was successfully synthesized and characterized. It exhibited superior kinetic stability, contrast to noise ratio, biocompatibility, and rapid clearance, supporting its translational potential for low dose pulmonary perfusion evaluation with spectral K edge imaging.
Image/Figure:
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Image/Figure Caption:
Diagnostic potential of tungsten K-edge imaging post-intravenous administration of a novel ultrasmall calcium complexed monolacunary polyoxotungstate (SiW11-Ca) in porcine pulmonary embolism model.
Author
Salim Aymeric Si-Mohamed, MD; PhD
Claude Bernard University Lyon 1