New Strategies to Prolong the In Vivo Life Span of Iron-Based Contrast Agents for MRI

Abstract

Superparamagnetic iron oxide (SPIO) and ultra small superparamagnetic iron oxide (USPIO) nanoparticles have been developed as magnetic resonance imaging (MRI) contrast agents. Iron oxide nanoparticles, that become superparamagnetic if the core particle diameter is ~ 30nm or less, present R1 and R2 relaxivities which are much higher than those of conventional paramagnetic gadolinium chelates. Generally, these magnetic particles are coated with biocompatible polymers that prevent the agglomeration of the colloidal suspension and improve their blood distribution profile. In spite of their potential as MRI blood contrast agents, the biomedical application of iron oxide nanoparticles is still limited because of their intravascular half-life of only few hours; such nanoparticles are rapidly cleared from the bloodstream by macrophages of the reticulo-endothelial system (RES). To increase the life span of these MRI contrast agents in the bloodstream we proposed the encapsulation of SPIO nanoparticles in red blood cells (RBCs) through the transient opening of cell membrane pores. We have recently reported results obtained by applying our loading procedure to several SPIO nanoparticles with different chemical physical characteristics such as size and coating agent. In the current investigation we showed that the life span of iron-based contrast agents in the mice bloodstream was prolonged to 12 days after the intravenous injection of murine SPIO-loaded RBCs. Furthermore, we developed an animal model that implicates the pretreatment of animals with clodronate to induce a transient suppression of tissue macrophages, followed by the injection of human SPIO-loaded RBCs which make it possible to encapsulate nanoparticle concentrations (5.3-16.7mM Fe) higher than murine SPIO-loaded RBCs (1.4-3.55mM Fe). The data showed that, when human RBCs are used as more capable SPIO nanoparticle containers combined with a depletion of tissue macrophages, Fe concentration in animal blood is 2-3 times higher than iron concentration obtained by the use of murine SPIO-loaded RBCs.

Tracking short-term biodistribution and long-term clearance of SPIO tracers in magnetic particle imaging

“…For example the approach taken by Antonelli et al (Antonelli, Sfara, Battistelli, et al 2013; Antonelli, Sfara, Weber, et al 2016) of loading SPIO nanoparticles in red blood cells (RBCs). Antonelli et al were able to achieve a blood circulation half-life of 48 hours for Resovist loaded RBCs.…”

Red Blood Cells as Carriers of Iron Oxide-Based Contrast Agents for Diagnostic Applications

“…The authors have suggested this method for the prolongation of SPIOs contrast agents life span in the blood circulation; optimally, this extends the blood retention time toward the half-life of RBCs, which is around 11 days in mice 128 and 30 days in humans. 129 Interestingly, in order to increase SPIO concentrations in animal blood circulation Antonelli et al 126 have developed a new procedure that involves the infusion of human SPIO-loaded RBCs in animal models, mice and rats. Before the infusion, the animals were treated with clodronate, a potent bisphosphonate (BP) generally used to inhibit osteoclastic bone resorption which is able to induce a reversible depletion of tissue macrophages.…”

“…The results showed how higher iron concentrations in animal bloodstream can be obtained using larger SPIO nanoparticle containers, such as human red blood cells, combined with a transient depletion of tissue macrophages induced by clodronate. 126 The improved in vivo SPIO life span could significantly aid MRI diagnosis in a clinical setting where delays can occur and also allows the RBCs to enter deep into body tissues. Indeed, the increased stability and viability of the SPIOloaded RBCs would allow the same patient to be imaged 134 have applied the loading procedure to a new contrast agent, the P904 ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles coated by hydrophilic derivatives of glucose, [135][136][137][138] developed by Guerbet Laboratories.…”

Magnetic Particle Imaging: A Novel in Vivo Imaging Platform for Cancer Detection

“…For these applications, nanoparticles can be encapsulated in PEGylated PRINT nanoparticles with circulation half-life of 19.5 hours 34 or in red blood cells with tracer life span in the mice bloodstream prolonged to 12 days. 35 …”