Nanomagnetic Sensing of Blood Plasma Protein Interactions with Iron Oxide Nanoparticles: Impact on Macrophage Uptake

One of the first biointeractions of magnetic nanoparticles with living systems is characterized by nanoparticle–protein complex formation. The proteins dynamically encompass the particles in the protein corona. Here we propose a method based on nanomagnetism that allows a specific <i>in situ</i> monitoring of interactions between iron oxide nanoparticles and blood plasma. Tracking the nanoparticle orientation through their optical birefringence signal induced by an external magnetic field provides a quantitative real-time detection of protein corona at the surface of nanoparticles and assesses eventual onset of particle aggregation. Since some of the plasma proteins may cause particle aggregation, we use magnetic fractionation to separate the nanoparticle clusters (induced by “destabilizing proteins”) from well-dispersed nanoparticles, which remain isolated due to a stabilizing corona involving other different types of proteins. Our study shows that the “biological identity” (obtained after the particles have interacted with proteins) and aggregation state (clustered <i>versus</i> isolated) of nanoparticles depend not only on their initial surface coating, but also on the concentration of plasma in the suspension. Low plasma concentrations (which are generally used <i>in vitro</i>) lead to different protein/nanoparticle complexes than pure plasma, which reflects the <i>in vivo</i> conditions. As a consequence, by mimicking <i>in vivo</i> conditions, we show that macrophages can perceive several different populations of nanoparticle/protein complexes (differing in physical state and in nature of associated proteins) and uptake them to a different extent. When extrapolated to what would happen <i>in vivo</i>, our results suggest a range of cell responses to a variety of nanoparticle/protein complexes which circulate in the body, thereby impacting their tissue distribution and their efficiency and safety for diagnostic and therapeutic use

Cooperative Organization in Iron Oxide Multi-Core Nanoparticles Potentiates Their Efficiency as Heating Mediators and MRI Contrast Agents

In the pursuit of optimized magnetic nanostructures for diagnostic and therapeutic applications, the role of nanoparticle architecture has been poorly investigated. In this study, we demonstrate that the internal collective organization of multi-core iron oxide nanoparticles can modulate their magnetic properties in such a way as to critically enhance their hyperthermic efficiency and their MRI <i>T</i>₁ and <i>T</i>₂ contrast effect. Multi-core nanoparticles composed of maghemite cores were synthesized through a polyol approach, and subsequent electrostatic colloidal sorting was used to fractionate the suspensions by size and hence magnetic properties. We obtained stable suspensions of citrate-stabilized nanostructures ranging from single-core 10 nm nanoparticles to multi-core magnetically cooperative 30 nm nanoparticles. Three-dimensional oriented attachment of primary cores results in enhanced magnetic susceptibility and decreased surface disorder compared to individual cores, while preserving a superparamagnetic-like behavior of the multi-core structures and potentiating thermal losses. Exchange coupling in the multi-core nanoparticles modifies the dynamics of the magnetic moment in such a way that <i>both</i> the longitudinal and transverse NMR relaxivities are also enhanced. Long-term MRI detection of tumor cells and their efficient destruction by magnetic hyperthermia can be achieved thanks to a facile and nontoxic cell uptake of these iron oxide nanostructures. This study proves for the first time that cooperative magnetic behavior within highly crystalline iron oxide superparamagnetic multi-core nanoparticles can improve simultaneously therapeutic and diagnosis effectiveness over existing nanostructures, while preserving biocompatibility

Heat-Generating Iron Oxide Nanocubes: Subtle “Destructurators” of the Tumoral Microenvironment

Several studies propose nanoparticles for tumor treatment, yet little is known about the fate of nanoparticles and intimate interactions with the heterogeneous and ever-evolving tumor environment. The latter, rich in extracellular matrix, is responsible for poor penetration of therapeutics and represents a paramount issue in cancer therapy. Hence new strategies start aiming to modulate the neoplastic stroma. From this perspective, we assessed the efficacy of 19 nm PEG-coated iron oxide nanocubes with optimized magnetic properties to mediate mild tumor magnetic hyperthermia treatment. After injection of a low dose of nanocubes (700 μg of iron) into epidermoid carcinoma xenografts in mice, we monitored the effect of heating nanocubes on tumor environment. In comparison with the long-term fate after intravenous administration, we investigated spatiotemporal patterns of nanocube distribution, evaluated the evolution of cubes magnetic properties, and examined nanoparticle clearance and degradation processes. While inside tumors nanocubes retained their magnetic properties and heating capacity throughout the treatment due to a mainly interstitial extracellular location, the particles became inefficient heaters after cell internalization and transfer to spleen and liver. Our multiscale analysis reveals that collagen-rich tumor extracellular matrix confines the majority of nanocubes. However, nanocube-mediated hyperthermia has the potential to “destructure” this matrix and improve nanoparticle and drug penetration into neoplastic tissue. This study provides insight into dynamic interactions between nanoparticles and tumor components under physical stimulation and suggests that nanoparticle-mediated hyperthermia could be used to locally modify tumor stroma and thus improve drug penetration