Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings

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.

Biodistribution and toxicity of epitope‐functionalized dextran iron oxide nanoparticles in a pregnant murine model

“…However, given on previous results on surface makers, there is enough evidence that the SNAREs are not immunogenic. This characteristic is likely due to the dextran and PEG coating, as previously suggested by others (Feng et al, ; Unterweger et al, ).…”

“…Upon evading immune activation and potential for phagocytic uptake, nanoparticles are prone to clearance by the liver and the reticuloendothelial system (RES). Ultra‐small IONPs (<50 nm in diameter) have been shown to benefit from slower opsonization and clearance while dextran and PEG surface coating of IONPs result in improved stability and blood circulation times (Feng et al, ; Singh et al, ). Investigating the clearance rate of IONPs, we reported serum total iron concentration similar to saline‐treated controls at 24 h postinjection, suggesting clearance of SNAREs.…”

“…Investigating the clearance rate of IONPs, we reported serum total iron concentration similar to saline‐treated controls at 24 h postinjection, suggesting clearance of SNAREs. Several other groups have also demonstrated serum iron concentration as an effective measurement of IONPs in the blood and blood clearance at 24 hr (Feng et al, ; Sharma et al, ). To Elucidate the effect of PEG on NP clearance, we compared the clearance rates by determining the AUC for DIONP‐ and SNARE‐treated dams.…”

“…Only a handful of studies have investigated the biological effects and toxicity of IONP (Feng et al, ; Singh et al, ; Unterweger et al, ) and a few publications probed the effects of IONP in the fetal compartment (Ali Noori, Modaresi, Messripour, Yousefi, & Amiri, ; Di Bona, Xu, Gray, et al, ). Seemingly, the results on biodistribution, toxicity, and clearance of IONPs reported in literature are divergent, due to the variations in size, surface‐coating (e.g., dextran, polyethylene glycol (PEG), citric acid), surface‐charge, and experimental conditions (e.g., route of administration, cell types, incubation time points; Feng et al, ). Amid such concerns, the next major step is to establish the safety of our SNARE formulation in pregnant mice, which will serve as the test bed for future efficacy studies should safety worries be set aside.…”

Preparation of Scalable Silica‐Coated Iron Oxide Nanoparticles for Nanowarming

“…Cancer treatment requires a nanoparticle which is stable in biological fluids (i.e., blood, interstitial, or intracellular), has heating properties tuned to cell destruction, and a low collateral toxicity profile. In some cases, the nanoparticle is even designed for cancer cell uptake . However, IONPs used for nanowarming need to have different properties than those optimized for cancer treatment.…”