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Abstract
Iron oxide nanoparticles (IONPs) have been increasingly used in biomedical applications, but the comprehensive understanding of their interactions with biological systems is relatively limited. In this study, we systematically investigated the in vitro cell uptake, cytotoxicity, in vivo distribution, clearance and toxicity of commercially available and well-characterized IONPs with different sizes and coatings. Polyethylenimine (PEI)-coated IONPs exhibited significantly higher uptake than PEGylated ones in both macrophages and cancer cells, and caused severe cytotoxicity through multiple mechanisms such as ROS production and apoptosis. 10 nm PEGylated IONPs showed higher cellular uptake than 30 nm ones, and were slightly cytotoxic only at high concentrations. Interestingly, PEGylated IONPs but not PEI-coated IONPs were able to induce autophagy, which may play a protective role against the cytotoxicity of IONPs. Biodistribution studies demonstrated that all the IONPs tended to distribute in the liver and spleen, and the biodegradation and clearance of PEGylated IONPs in these tissues were relatively slow (>2 weeks). Among them, 10 nm PEGylated IONPs achieved the highest tumor uptake. No obvious toxicity was found for PEGylated IONPs in BALB/c mice, whereas PEI-coated IONPs exhibited dose-dependent lethal toxicity. Therefore, it is crucial to consider the size and coating properties of IONPs in their applications.
Highlights
Magnetic iron oxide nanoparticles (IONPs) have been used for a wide range of biomedical applications such as drug delivery, magnetic resonance imaging (MRI), thermal ablation therapy, in vivo cell tracking, and magnetic separation of cells or molecules[1]
It has been reported that Iron oxide nanoparticles (IONPs) larger than 100 nm in diameter are rapidly trapped in the liver and spleen through macrophage phagocytosis, whereas IONPs smaller than 10 nm in diameter are likely to be eliminated through renal clearance[6]
It is generally believed that the size of nanoparticles for cancer therapy should be in the range of 5–100 nm, in which the blood circulation time and enhanced permeability and retention (EPR) effect are maximized[13,14,15,16]
Summary
Magnetic iron oxide nanoparticles (IONPs) have been used for a wide range of biomedical applications such as drug delivery, magnetic resonance imaging (MRI), thermal ablation therapy, in vivo cell tracking, and magnetic separation of cells or molecules[1]. The size uniformity of IONPs will affect their in vivo pharmacokinetics and biodistribution results, and a low polydispersity index (PDI) might be more desirable for uniform and repeatable performance Surface coating is another important factor affecting the destiny and biological effects of IONPs. Due to the colloidal instability of bare IONPs, different types of natural and synthetic coating materials such as dextran, Pluronic, and polyethylene glycol (PEG) were used to improve the stability and blood circulation of IONPs. Among them, PEG is the most popular coating polymer, which has excellent anti-fouling property (preventing opsonization) and high steric hindrance to stabilize IONPs8. The in vivo biodistribution, tumor uptake, clearance, and toxicity of these IONPs were investigated in both SKOV-3 tumor bearing nude mice and BALB/c mice, respectively
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