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

Antonella Antonelli,Elisabetta Manuali,Stefano Papa,Serafina Battistelli,Sonia Salamida,Carla Sfara,Marcella Arcangeletti,Barbara Canonico,Mauro Magnani,Angelique Louie

doi:10.1371/journal.pone.0078542

Antonella Antonelli, Elisabetta Manuali + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0078542

Copy DOI

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.

Highlights

Superparamagnetic iron oxide (SPIO) particles are iron oxide nanocrystals with different core materials, magnetite (Fe3O4) or maghemite (γ-Fe2O3), different hydrodynamic diameters and different coatings such as polyethylene glycol (PEG), dextran, chitosan, silica, phospholipids, generally used as biocompatible materials to improve in vivo stability [1,2,3].For the past two decades, dextran coated SPIO particles such as AMI-227 (Sinerem®), AMI-25 (Endorem®) or carboxydextran coated particles such as SHU 555A (Resovist®)have served as contrast-enhancing probes for magnetic resonance imaging (MRI), today they are no longer commercially available [4,5]
Since the macrophage cells of the liver, spleen and lymph tissues play a critical role in the removal of opsonized particles, the SPIO nanoparticles are commonly used for MRI analysis of these organs [8]
The total preparation procedure resulted in a cell recovery of human Resovist®, Endorem® or Sinerem®-loaded red blood cells (RBCs) ranging from 60 to 70%, which was similar to the recovery rate for unloaded cells

Summary

Introduction

Superparamagnetic iron oxide (SPIO) particles are iron oxide nanocrystals with different core materials, magnetite (Fe3O4) or maghemite (γ-Fe2O3), different hydrodynamic diameters and different coatings such as polyethylene glycol (PEG), dextran, chitosan, silica, phospholipids, generally used as biocompatible materials to improve in vivo stability [1,2,3].For the past two decades, dextran coated SPIO particles such as AMI-227 (Sinerem®), AMI-25 (Endorem®) or carboxydextran coated particles such as SHU 555A (Resovist®)have served as contrast-enhancing probes for MRI, today they are no longer commercially available [4,5]. Following intravenous administration, SPIOs are rapidly coated by serum proteins [6,7]. This opsonization process renders the particles recognizable by the body’s major defence system, the RES. Since the macrophage cells of the liver, spleen and lymph tissues play a critical role in the removal of opsonized particles, the SPIO nanoparticles are commonly used for MRI analysis of these organs [8]. Advances in nanotechnology and molecular cell biology have led to improved stability and biocompatibility of iron oxidebased nanoparticles, but SPIO survival in the bloodstream is still limited. We propose the use of red blood cells (RBCs) as carriers of SPIO nanoparticles to obtain a blood pool tracer with longer blood retention time [15]. RBCs, thanks to their unique properties which allow them to be reversibly opened under hypotonic conditions without losing their natural features and functionalities, can be used as intravascular carriers for different bioactive substances including drugs, therapeutic proteins, nucleotide analogues, cancer chemotherapeutics and nucleic acids [16]

Methods

Results

Conclusion