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Small versus Large Iron Oxide Magnetic Nanoparticles: Hyperthermia and Cell Uptake Properties

Iacovita, Cristian, Florea, Adrian, Dudric, Roxana, Pall, Emoke, Moldovan, Alin, Tetean, Romulus, Stiufiuc, Rares, Lucaciu, Constantin·2016·Molecules
DOI 10.3390/molecules21101357PMC PMC6274490
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Abstract

Efficient use of magnetic hyperthermia in clinical cancer treatment requires biocompatible magnetic nanoparticles (MNPs), with improved heating capabilities. Small (~34 nm) and large (~270 nm) Fe3O4-MNPs were synthesized by means of a polyol method in polyethylene-glycol (PEG) and ethylene-glycol (EG), respectively. They were systematically investigated by means of X-ray diffraction, transmission electron microscopy and vibration sample magnetometry. Hyperthermia measurements showed that Specific Absorption Rate (SAR) dependence on the external alternating magnetic field amplitude (up to 65 kA/m, 355 kHz) presented a sigmoidal shape, with remarkable SAR saturation values of ~1400 W/gMNP for the small monocrystalline MNPs and only 400 W/gMNP for the large polycrystalline MNPs, in water. SAR values were slightly reduced in cell culture media, but decreased one order of magnitude in highly viscous PEG1000. Toxicity assays performed on four cell lines revealed almost no toxicity for the small MNPs and a very small level of toxicity for the large MNPs, up to a concentration of 0.2 mg/mL. Cellular uptake experiments revealed that both MNPs penetrated the cells through endocytosis, in a time dependent manner and escaped the endosomes with a faster kinetics for large MNPs. Biodegradation of large MNPs inside cells involved an all-or-nothing mechanism.

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Figure 1 TEM images of Fe3O4 MNPs synthesized in (a) PEG 200; and (b) EG and their corresponding size distribution histograms (c,d) fitted to a log-normal distribution (black lines) and XRD diffractions patterns (e,f).
Figure 1 TEM images of Fe3O4 MNPs synthesized in (a) PEG 200; and (b) EG and their corresponding size distribution histograms (c,d) fitted to a log-normal distribution (black lines) and XRD diffractions patterns (e,f).CC BY · PubMed Central
Figure 2 Magnetic hysteresis loops of Fe3O4 MNPs synthesized in (a) PEG 200; and (b) EG. The insets are a zoom-in the hysteresis loops.
Figure 2 Magnetic hysteresis loops of Fe3O4 MNPs synthesized in (a) PEG 200; and (b) EG. The insets are a zoom-in the hysteresis loops.CC BY · PubMed Central
Figure 3 SAR values of Fe3O4 MNPs synthesized in PEG 200 starting at 25 °C (a) and at 37 °C (b); and EG starting at 25 °C (c) and at 37 °C (d) as a function of applied AC magnetic field amplitude and at a frequency of 355 kHz. The data were fitted with a sigmoidal function (Equation (3)) (red and pink lines).
Figure 3 SAR values of Fe3O4 MNPs synthesized in PEG 200 starting at 25 °C (a) and at 37 °C (b); and EG starting at 25 °C (c) and at 37 °C (d) as a function of applied AC magnetic field amplitude and at a frequency of 355 kHz. The data were fitted with a sigmoidal function (Equation (3)) (red and pink lines).CC BY · PubMed Central
Figure 4 TEM images of D407 cells containing small Fe3O4 MNPs after 4 h (a,b) and 24 h (c,d) incubation time. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (a, left) formation of an endosome with small Fe3O4 MNPs; (a, right) detailed view of a Fe3O4 MNPs containing endosome; (b,d) detailed views of Fe3O4 MNPs in direct contact with the cytosol.
Figure 4 TEM images of D407 cells containing small Fe3O4 MNPs after 4 h (a,b) and 24 h (c,d) incubation time. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (a, left) formation of an endosome with small Fe3O4 MNPs; (a, right) detailed view of a Fe3O4 MNPs containing endosome; (b,d) detailed views of Fe3O4 MNPs in direct contact with the cytosol.CC BY · PubMed Central
Figure 5 TEM images of A549 cells containing small Fe3O4 MNPs after 4 h (a,b) and 24 h (c,d) incubation. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (a, left) small Fe3O4 MNPs attached to plasma membrane prior to formation of endosomes; (a, right) formation of an endosome with small Fe3O4 MNPs; (b) detailed views of small Fe3O4 MNPs in direct contact with the cytosol; (c) detailed view of an endosome containing small Fe3O4 MNPs.
Figure 5 TEM images of A549 cells containing small Fe3O4 MNPs after 4 h (a,b) and 24 h (c,d) incubation. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (a, left) small Fe3O4 MNPs attached to plasma membrane prior to formation of endosomes; (a, right) formation of an endosome with small Fe3O4 MNPs; (b) detailed views of small Fe3O4 MNPs in direct contact with the cytosol; (c) detailed view of an endosome containing small Fe3O4 MNPs.CC BY · PubMed Central
Figure 6 TEM images of D407 cells containing large Fe3O4 MNPs after 4 h (a,b) and 24 h of incubations (c,d). Many of the large Fe3O4 MNPs fragment into small Fe3O4 MNPs. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (b) detailed views of large Fe3O4 MNPs in direct contact with the cytosol; (c) formation of two endosomes with large Fe3O4 MNPs, and a cluster of MNPs in contact with the cytosol.
Figure 6 TEM images of D407 cells containing large Fe3O4 MNPs after 4 h (a,b) and 24 h of incubations (c,d). Many of the large Fe3O4 MNPs fragment into small Fe3O4 MNPs. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (b) detailed views of large Fe3O4 MNPs in direct contact with the cytosol; (c) formation of two endosomes with large Fe3O4 MNPs, and a cluster of MNPs in contact with the cytosol.CC BY · PubMed Central
Figure 7 TEM images of A549 cells containing large Fe3O4 MNPs after incubations of 4 h (a,b) and 24 h (c,d). Many of the large Fe3O4 MNPs fragment into small Fe3O4 MNPs. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (a) a large Fe3O4 MNPs containing endosome; (b,d) detailed views of large Fe3O4 MNPs in direct contact with the cytosol; (c) a large Fe3O4 MNPs containing endosome, in the proximity of the plasma membrane, and next to two clusters of MNPs in contact with the cytosol.
Figure 7 TEM images of A549 cells containing large Fe3O4 MNPs after incubations of 4 h (a,b) and 24 h (c,d). Many of the large Fe3O4 MNPs fragment into small Fe3O4 MNPs. The letters N denote the nucleus, whereas the letters E indicate the endosomes. Insets show: (a) a large Fe3O4 MNPs containing endosome; (b,d) detailed views of large Fe3O4 MNPs in direct contact with the cytosol; (c) a large Fe3O4 MNPs containing endosome, in the proximity of the plasma membrane, and next to two clusters of MNPs in contact with the cytosol.CC BY · PubMed Central

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Metadata

Authors
Iacovita, C., Florea, A., Dudric, R., Pall, E., Moldovan, A., Tetean, R., Stiufiuc, R., & Lucaciu, C.
Venue
Molecules
Publisher
MDPI AG
Published
2016-10-13
Volume
21
Issue
10
Pages
1357
ISSN
1420-3049
DOI
10.3390/molecules21101357
PMC
PMC6274490
Cited by
57
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Romanian National Authority for Scientific Research, CNCSIS-UEFISCDI (PN-II-ID-PCE-2012-4-0531, PN-II-RU-TE-2014-4-1770)

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