Table 3 Summary of representative studies evaluating the biocompatibility and toxicity of SPIONs
From: Nanotoxicological profiles of clinically approved nanoplatforms
Formulation composition | Preparation method | Dose (administration route) | Animal/cell type | Cell/tissue target | Biocompatibility-/toxicity-related outcomes | References |
|---|---|---|---|---|---|---|
In vitro studies | ||||||
SPIONs decorated with hyaluronic acid and transferrin | Chemical coprecipitation | 25–250 μg/mL | HeLa cells | Adenocarcinoma cells | No significant difference in cell viability between SPIONs and PBS control following 24-h incubation | Pan et al. [103] |
SPIONs capped with PEG or triethylene glycol | One-pot decomposition of iron(III) acetylacetonate in triethylene glycol | 1–160 μg/mL | Mouse fibroblast cells | Normal mouse fibroblasts | Except some morphological changes, all the SPIONs showed no significant decrease in cell viability when compared to the controls after 72-h incubation | Arteaga-Cardona et al. [10] |
SPIONs coated with sodium oleate (SO-IONPs), or with SO + PEG (SO-PEG-IONPs), or with SO + PEG + PLGA (SO-PEG-PLGA-IONPs) | Chemical coprecipitation | 0.1–100 µM | Mouse L5178Y lymphoma and Bhas 42 cells | Cancerous cells | SO-IONPs and SO-PEG-PLGA-IONPs showed no mutagenicity, while the effect of SO-PEG-IONPs was ambiguous. SO-PEG-PLGA-IONPs were carcinogenic in a concentration-dependent manner | Gábelová et al. [39] |
SPIONs solubilized with PEG | Chemical coprecipitation | 1–150 μM | MCF-7 cells | Breast cancer cell | No remarkable decrease in cell viability or change in cell cycle progression after 24-h incubation | Kansara et al. [67] |
SPIONs solubilized with tetramethylammonium11-aminoundecanoate | One-pot decomposition of iron(III) acetylacetonate in 1,2-hexadecanediol | 0.1–100 μg/mL | G9T, SF126, U87, MB157, SKBR3, WI-38, SVGp12 | Human normal, glia and breast cancer cells | No cytotoxicity up to 10 μg/m, but overt decrease in cell viability at 100 μg/mL following 72 h of incubation | Ankamwar et al. [6] |
Core–shell Fe3O4–Au composite magnetic NPs | Chemical coprecipitation | 25–100 mg/mL | Mouse fibroblast cell line (L-929) | Murine fibroblasts | No significant difference in cell viability between the experimental group and the control following 48-h incubation | Li et al. [82] |
Ag-, Au-, Cs- or Pt-coated Fe3O4 microparticles | Chemical coprecipitation | 2.5–40 mg/mL | Mouse fibrosarcoma cell line (L-929) | Murine fibroblasts | Naked particles showed no cytotoxicity below 5 mg/mL, while modified ones were not cytotoxic up to 20 mg/mL after 24 h of incubation | Xia et al. [150] |
Fe3O4 nanocrystals coated with PEGylated phospholipid | Thermal decomposition of iron pentacarbonyl | 0.003–0.2 mg Fe/mL | HeLa cells | Adenocarcinoma cells | NPs exhibited dose-dependent changes in cell viabilities | Gu et al. [48] |
SiO2-coated SPIONs modified with DMSA | Chemical coprecipitation | 1–3 mg/mL | Human blood and Wuzhishan mini-pigs blood | Blood cells | No remarkable coagulation-fibrinolysis or haemolysis over 120 min of exposure | Xiang et al. [151] |
Polyethylenimine (PEI)-coated SPIONs modified with PEG | Chemical coprecipitation | 6.25–100 µg/mL | SH-SY5Y, U937 and MCF-7 cell lines | Human neuroblastoma, lymphoma and breast cancer cells | Non-PEGylated PEI-particles increased cytotoxicity and ROS production due to high surface charge. Both PEGylated and non-PEGylated cationic IONPs caused cell morphology changes | Hoskins et al. [57] |
Polyethylenimine (PEI)-coated and PEG-coated SPIONs | Not reported | 3.125–100 µg/mL | RAW264.7 and SKOV-3 cells | Macrophages and ovarian cancer cells | PEI-coated SPIONs caused higher ROS generation, apoptosis than PEG-SPIONs | Feng et al. [37] |
Rod and spherical Fe3O4 NPs versus Fe3O4 microparticles | Not reported | 10–200 µg/mL | RAW 264.7 cells | Mouse macrophage | Rod SPIONs showed higher cytotoxicity due to greater membrane damage and ROS production than other particles | Lee et al. [77] |
SPIONs decorated with tetraethyl orthosilicate (TEOS), (3-aminopropyl) trimethoxysilane (APTMS), TEOS-APTMS or citrate | Chemical coprecipitation | 100–1000 ppm | Mouse fibroblast cell line (L-929) | Murine fibroblasts | SPIONs at higher doses showed variable cytotoxicity and genotoxicity profiles depending on functional groups and particle sizes, while lower doses (below 500 ppm) were safe for all NPs batches | Hong et al. [56] |
In vivo studies | ||||||
SPIONs decorated with hyaluronic acid and transferrin | Chemical coprecipitation | 24Â mg Fe/kg (IV) | Female Balb/c nude mice | Blood, heart, liver, spleen, lung and kidney | No obvious changes in organ functional biomarkers investigated. Body weights were maintained over time 30Â days | Pan et al. [103] |
SPIONs capped with PEG or triethylene glycol | One-pot decomposition of iron (III) acetylacetonate in triethylene glycol | 50 mg of Fe per mouse (IV) | New Zealand rabbit | Brain, meninges, liver, kidneys, intestines, lungs and spleen | Histopathological analyses revealed no overt structural changes or tissue damage, despite the hepatic and splenic accumulation over 3 days | Arteaga-Cardona et al. [10] |
Doxorubicin-loaded SPIONs decorated with folic acid | Chemical coprecipitation | 70.75–1132 µg/mL (IV) | Zebrafish embryo and larvae | Heart, nervous system | Unlike plain drug, SPIONs showed no larvae death and morphological changes. Drug cardiotoxicity was overtly reduced | Igartúa et al. [60] |
Core–shell Fe3O4–Au composite magnetic NPs | Chemical coprecipitation | 1.77–19.89 g/kg (IP) | KunMing albino mice, New Zealand rabbits and beagle dog | Murine blood, heart, spleen, lung, kidney and brain | No obvious histopathological changes (after 2 weeks) or haemolysis. No increase in micronucleus formation. Dogs liver injection (0.1 g/kg) exhibited no acute tissue toxicity after 4 weeks) | Li et al. [82] |
Ag-, Au-, Cs- or Pt-coated Fe3O4 microparticles | Chemical coprecipitation | 5000Â mg/kg (oral) | Spleen-deficient rats | Blood cells, bone marrow, liver | Cs-coated and naked Fe3O4 particles showed DNA/chromosome damage and haemolysis. Au, Ag and Pt coating improved biosafety profile of Fe3O4 | Xia et al. [150] |
Dextran-coated SPIONs decorated with goat anti-mouse IgG and Fe3O4 polystyrene-coated microparticles | Not reported | 1.65–1.69 mg/eye (intravitreal injection) | Sprague–Dawley rats | Eye | Injected and noninjected eyes showed no significant differences in intraocular pressure, corneal endothelial cell count, retinal morphology and photoreceptor function over 5 months after injection | Raju et al. [116] |
Fe3O4 nanocrystals coated with PEGylated phospholipid | Thermal decomposition of iron pentacarbonyl | 5Â mg Fe/kg (IV) | Wild-type BALB/c mice | Liver, spleen and blood | No histopathological or biochemical changes, except an increase in hepatic aspartate transaminase and alanine transaminase. No change in blood counts and body weights over 1Â month | Gu et al. [48] |
SiO2-coated SPIONs modified with DMSA | Chemical coprecipitation | 0.5–1.0 mg/kg (IV) | New Zealand rabbits and Wuzhishan mini pigs | Liver, kidney, heart, blood | No histopathological, inflammatory or immunostimulatory perturbations over 12 days | Xiang et al. [151] |
SPIONs | Not reported | 10–200 µg/mL (0.3 mL/egg) | White leghorn (Gallus gallus domesticus) | Fertilized eggs | 100% mortality at 200 µg/mL. At lower doses (< 100 µg/mL), neuronal loss and body weight decrease were observed after 17–19 days of incubation | Patel et al. [107] |
Polyethylenimine (PEI)-coated SPIONs and PEG-coated SPIONs | Not reported | 1–5 mg/kg | SKOV-3 tumour-bearing nude mice and BALB/c mice | Spleen, liver, blood | PEI-coated SPIONs showed marked dose-dependent lethal toxicity, while PEG-SPIONs caused no death but rather acceptable tissue toxicity up to 5 mg/kg | Feng et al. [37] |