Evaluation of a Gadolinium-Based Nanoparticle (AGuIX) for Contrast-Enhanced MRI of the Liver in a Rat Model of Hepatic Colorectal Cancer Metastases at 9.4 Tesla

Abstract

Ziel: Vergleich eines Gd-basierten Nanopartikels (AGuIX) mit einem extrazellulären, niedermolekularen Kontrastmittel (Gd-DOTA) zur MRT der Leber bei 9,4 T in Ratten mit hepatischen Metastasen eines kolorektalen Karzinoms. Material und Methoden: 12 Ratten mit hepatischen Metastasen wurden mittels eines 9,4 T Tierscanners untersucht. Es wurden T1-gewichtete FLASH-Sequenzen (TR/TE = 45/2,5 ms, Flipwinkel = 45°, TA = 1: 23 min, FOV = 5,12 × 5,12 cm2, Matrix = 256 × 256) vor und an 10 Zeitpunkten nach KM-Gabe mittels Selbstgating akquiriert. Jedes Versuchstier erhielt 0,1 mmol/kg KG Gd-DOTA i. v. Zwei Tage später wurden die Untersuchungen nach Gabe von 0,01 mmol/kg KG AGuIX (entsprechend identischen Dosierungen an Gd) wiederholt. SNR von normalem Lebergewebe (SNRliver), stark und gering KM-affinen Anteilen der Tumoren (SNRtumor, hyperenh/SNRtumor, hypoenhanc), des Musculus erector spinae (SNRmuscle), CNR und Läsionsenhancement (LE) wurden basierend auf ROI-Messungen berechnet. Ergebnisse: Die Mittelwerte des SNRliver (Gd-DOTA: 14,6 +/-0,7; AGuIX: 28,2 +/-2,6; p < 0,001), SNRtumor, hyperenhanc (Gd-DOTA: 18,6 +/-1,2; AGuIX: 29,6 +/-2,8, p < 0,001), SNRtumor, hypoenhanc (Gd-DOTA: 12,0 +/-0,7; AGuIX: 15,4 +/-0,7, p < 0,001), SNRmuscle (Gd-DOTA: 12,3 +/-0,3; AGuIX: 14,0 +/-0,7, p < 0,001), des CNR (Gd-DOTA: -2,5 +/-0,2; AGuIX: -7,5 +/-1,0, p < 0,001) und des LE (Gd-DOTA: 3,8 +/-0,7; AGuIX: 14,9 +/-2,8/p = 0,001) waren nach Gabe von AGuIX signifikant höher. Trotz der höheren Molekülmasse zeigt AGuIX analog zum niedermolekularen Komplex Gd-DOTA eine maximale Signalanreicherung unmittelbar nach Injektion gefolgt von einem kontinuierlichen Auswaschen. Schlussfolgerungen: AGuIX zeigt ein besseres Enhancement als Gd-DOTA bei identischer Gd-Dosierungen. Dies basiert auf der Molekülstruktur Abstract ! Purpose: The aim of this study was to compare a Gd-based nanoparticle (AGuIX) with a standard extracellular Gd-based contrast agent (Gd-DOTA) for MRI at 9.4 T in rats with hepatic colorectal cancer metastases. Materials and Methods: 12 rats with hepatic metastases were subjected to MRI using a 9.4 T animal scanner. T1w self-gated FLASH sequences (TR/TE = 45/2.5 ms, alpha = 45°, TA = 1: 23 min, FOV = 5.12 × 5.12 cm 2 , matrix = 256 × 256) were acquired before and at 10 time points after contrast injection. Each animal received 0.1 mmol/kg BW Gd-DOTA i. v. 2 days later AGuIX was applied at 0.01 mmol/kg BW (representing equal Gd doses). The SNR of normal liver (SNRliver), hyper-and hypoenhancing parts of tumors (SNRtumor, hyperenh/SNRtumor, hypoenhanc), erector spinae muscle (SNRmuscle), CNR and lesion enhancement (LE) were calculated based on ROI measurements.

Key clinical beam parameters for nanoparticle-mediated radiation dose amplification

“…The need for increased efficacy of radiation therapy combined with more precise tumor localization suggests the implementation of a novel agent which can facilitate both radiation dose amplification and increased image contrast, simultanouesly. The nanoparticle tested in this study exhibits high MRI contrast 30 , low toxicity 31 , and high radiation dose amplification 15 17 32 . AGuIX (Active Guidance for Irradiation by X-rays) are ultrasmall (<5 nm) polysiloxane based nanoparticles with chelates of gadolinium entrapped in a DOTA structure 15 17 29 30 31 32 33 .…”

“…The nanoparticle tested in this study exhibits high MRI contrast 30 , low toxicity 31 , and high radiation dose amplification 15 17 32 . AGuIX (Active Guidance for Irradiation by X-rays) are ultrasmall (<5 nm) polysiloxane based nanoparticles with chelates of gadolinium entrapped in a DOTA structure 15 17 29 30 31 32 33 . AGuIX is curently approved for a Phase I clinical trial for magnetic resonance-guided radiation therapy 15 19 31 34 35 .…”

Safety Evaluation and Imaging Properties of Gadolinium-Based Nanoparticles in nonhuman primates

“…Commercially available gadolinium (Gd) chelates are molecular compounds containing one single Gd atom. Nevertheless, clustering several Gd chelates will enhance the relaxivity of the probe and thus, the related contrast imaging properties 11 12 . In this context, we used Gd-based nanoparticles for MRI purposes.…”

Magnetic Resonance Lymphography at 9.4 T Using a Gadolinium-Based Nanoparticle in Rats

“…For both contrast media employed in this experimental study, a negative correlation of r1 relaxivity with magnetic field strength has previously been reported. 20 Desirable gains in SNR due to the strong magnetic field employed may therefore be counteracted by impaired contrast media effectivity.…”

“…The molecule size and the rigid structure yield substantial MR contrast enhancement with higher r1 relaxivities than for free Gd-DOTA. 20 Solutions were prepared freshly for each animal from dry substance at a concentration of 3 mM AGuIX, 145 mM NaCl, 2 mM CaCl 2 •6 H 2 0, 5 mM HEPES, pH 7.4 from a sterile filtrated stock solution and sterile pure water (Aqua ad iniectabilia; B. Braun Melsungen AG, Melsungen, Germany). At a concentration of 3 mM, the nanoparticle solution contained 30 mM Gd-DOTA side residues.…”