Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

Abstract

Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI).Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2 Ã signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m 2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI.Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman r ¼ 0.7824; P ¼ 0.0016).Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors.

Validation of MRI quantitative susceptibility mapping of superparamagnetic iron oxide nanoparticles for hyperthermia applications in live subjects

“…At 24 h post tail-vein injection of ferumoxytol, less than 0.1% of injected dose was found in tumor sites, while 11% of injected dose was accumulated in the liver ( Table 1). The uptake of ferumoxytol by the liver (~185 μg/ml) in mice was comparable to the levels reported for human subjects (~140 μg/ml) 38 . In comparison, the amount of ferumoxytol in our subcutaneous PC3 tumors (~10 μg/ml) was significantly lower than the levels in tumor lesion in the same study (median value ~ 34.5 μg/ ml) 38 .…”

“…The uptake of ferumoxytol by the liver (~185 μg/ml) in mice was comparable to the levels reported for human subjects (~140 μg/ml) 38 . In comparison, the amount of ferumoxytol in our subcutaneous PC3 tumors (~10 μg/ml) was significantly lower than the levels in tumor lesion in the same study (median value ~ 34.5 μg/ ml) 38 . Dominant liver uptake of ferumoxytol is consistent with the clinical use of ferumoxytol (that is digested by macrophages in the liver to release iron ions to the blood) to treat iron deficiency anemia in chronic kidney disease patients 39 .…”

Impact of Ferumoxytol Magnetic Resonance Imaging on the Rhesus Macaque Maternal-Fetal Interface

“…While there does appear to be a trend for slightly higher, though not statistically significant, iron content in fetal tissues, further studies will be needed to determine if this is a consistent result. There was a statistically significant increase in maternal liver iron content, which was expected since the liver is a main clearance organ for ferumoxytol, with resident hepatic macrophages (Kupffer cells) taking up ferumoxytol particles in studies in rabbit [46] and human subjects [47,48].…”

Translating nanomedicines: Thinking beyond materials? A young investigator's reply to ‘The Novelty Bubble’

“…Nevertheless, in order to drive nanomedicines' clinical translation, we should adopt a more critical and realistic view of what constitutes a novel nanomaterial in a proof-of-principle study versus what constitutes an actual nanomedicine that has the potential to benefit patients. In addition, adequate patient stratification is required to improve the outcomes of clinical trials and ultimately increase nanomedicines' clinical success [21][22][23].…”