MRI of Tumor-Associated Macrophages with Clinically Applicable Iron Oxide Nanoparticles

Abstract

Purpose The presence of tumor-associated macrophages (TAMs) in breast cancer correlates strongly with poor outcome. The purpose of this study was to develop a clinically applicable, non-invasive diagnostic assay for selective targeting and visualization of TAMs in breast cancer, based on magnetic resonance (MR) imaging and clinically applicable iron oxide nanoparticles. Experimental Design F4/80-negative mammary carcinoma cells and F4/80-positive TAMs were incubated with iron oxide nanoparticles and were compared regarding MR signal changes and iron uptake. MMTV-PyMT transgenic mice harboring mammary carcinomas underwent nanoparticle-enhanced MR up to 1 hour (h) and at 24 h post injection (p.i.). The tumor enhancement on MR images was correlated with the presence and location of TAMs and nanoparticles on confocal microscopy. Results In vitro studies revealed that iron oxide nanoparticles are preferentially phagocytosed by TAMs, but not by malignant tumor cells. In vivo, all tumors demonstrated an initial contrast agent perfusion on immediate postcontrast MR images with gradual transendothelial leakage into the tumor interstitium. At 24 h p.i., all tumors demonstrated a persistent signal decline on MR scans. TAM-depletion via αCSF1 mAb lead to significant inhibition of tumor nanoparticle enhancement. Detection of iron using DAB-enhanced Prussian Blue staining, and immunodetection of CD68 localized iron oxide nanoparticles to TAMs, indicating that the MR signal effects on delayed MR images were largely due to TAM-mediated uptake of contrast agent. Conclusion These data indicate that tumor-enhancement with clinically applicable iron oxide nanoparticles may serve as a new biomarker for long-term prognosis, related treatment decisions and the evaluation of new immune-targeted therapies.

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

“…FMX is composed of a nonstoichiometric magnetite core covered by a semisynthetic carbohydrate coating of polyglucose sorbitol carboxymethyl ether. FMX has slower clearance and delayed enhancement properties compared with gadolinium-based contrast agents and also allows after tissue deposition visualization of inflammatory cells in vessel walls and tissue because of uptake of the nanoparticles by macrophages (24,30). In preclinical studies, FMX did not interfere with the pharmacokinetics, biodistribution, or cellular distribution of liposomes within tumors (25).…”

Nanotoxicity of Inert Materials: The Case of Gold, Silver and Iron

“…MRI uses a combination of magnetic field radiofrequency pulse to image body organs containing IONP. They improve contrast of image and ensure imaging of target organs with particular safety for pediatrics and geriatrics patients (134)(135)(136)(137)(138).…”

Development of an antibody-based, modular biosensor for129Xe NMR molecular imaging of cells at nanomolar concentrations

“…CD14, in cooperation with Toll-like receptor 4, is a cell surface receptor for bacterial lipopolysaccharide (LPS) (27), meaning that stimulating macrophage cells with LPS in vitro (as we do in this study) and pairing them with unstimulated fibroblasts provides an ideal model system for comparing CD14 expression. As CD14 is a well-characterized macrophage marker, a xenon MRI CD14 biosensor could be used to image pathologies in which macrophage activation is important, as has been demonstrated by proton MRI for atherosclerosis (28) and tumor-associated macrophage populations (29), but with the added benefit of having switchable contrast and higher sensitivity.…”