Ferumoxytol is a licensed carbohydrate-coated, superparamagnetic iron oxide nanoparticle indicated in the treatment of anaemia. We show that, in contrast to other agents, it predominantly reduces T2, is confined to the blood pool for >1 hour post administration, and therefore could improve the efficiency of saturation pulses that aim to remove the 2,3-diphosphoglycerate signal from blood. This proof-of-principle study shows that Ferumoxytol could enable inorganic phosphate detection in vivo, and hence the determination of pH.
All experiments were performed with local ethical approval on a 7T Varian DDR system.
In vitro experiments: Fresh healthy human blood (3×2.7mL vials) was acquired via antecubital fossa venipuncture, and stored in sodium citrate buffer (Vactutainer, BD Healthcare). A cannulation tube was inserted to allow the in situ introduction of Ferumoxytol at the clinically indicated dose (4 mg/kg, or [Fe]=0.9mM in blood). 31P hard pulse spectra were acquired via a single loop surface coil (TR=512ms;10kHz bandwidth; 3840 averages; θErnst≈30∘ nominal flip angle) before and after addition of Ferumoxytol. Proton T2 was also measured by CPMG prior and post Ferumoxytol addition, and T1 by inversion recovery in both blood and serial dilutions of Feruomoxytol in saline.
In vivo demonstration: A healthy male Wistar rat (200g) was anaesthetised (isoflurane, 2% in 2L/min O2) and cannulated (tail vein). As an intermediate step to investiate the cardiac half-life of Ferumoxytol, short-axis proton CINE images of the heart were acquired (51.2×51.2mm2 FOV; 96×96 matrix; 1.2mm slice thickness; 20∘ FA; 4 averages; TR=4.16ms; TE=1.68mm2; 72mm volume coil) continuously prior to and up to one hour after the administration of Ferumoxytol. A short T1 phantom was included next to the animal as a signal reference.
Ferumoxytol is an efficient relaxation agent: As illustrated in Fig. 1, Ferumoxytol reduced saline T1 and T2 from 1183/362ms to 790/28ms at the physiological concentration of 0.5mM. In saline, this corresponds to a reduction in T1/T2 by a factor of 1.7/12.7. The observed behaviour was well described by a double exponential model, with short/long components of 1200/88mol−1 for T1 and 6600/310mol−1 for T2.
Reduction of blood pool signal: The T2 of fresh blood decreased by nearly an order of magnitude, from 65ms to 5.2ms following the addition of Ferumoxytol, whereas T1 reduced from approximately 800ms to 400ms. As a direct consequence, Ernst-angle hard pulse spectroscopy on whole human blood showed a reduction in all metabolites. The baseline-corrected integrated DPG peak amplitude reduced from 7×105 to 1×105. (Fig. 2)
Ferumoxytol is a blood-pool agent that is MR visible for >1 hour: Repeated CINE measurements show a uniform decrease in LV and RV signal compared to that of the phantom that is statistically significant, but no change in the myocardial signal (Fig. 3, p<10−7 by ANOVA). Given that the received signal under these conditions is proportional to T2 in the regime that T1≫TR this observed effect is consistent with a predominantly T2 mediated effect, as has been reported elsewhere.[7]
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