Magnetic hyperthermia (MHT) exploits magnetic nanoparticles (MNPs) to burn solid tumors. Here, we overview promising MNPs and magnetic assemblies used in MHT alone or in combination with chemotherapy, radiotherapy, immunotherapy or phototherapy.
Magnetic hyperthermia (MH) based on magnetic nanoparticles (MNPs) is a promising
adjuvant therapy for cancer treatment. Particle clustering leading to complex magnetic
interactions affects the heat generated by MNPs during MH. The heat efficiencies,
theoretically predicted, are still poorly understood because of a lack of control of the
fabrication of such clusters with defined geometries and thus their functionality. This
study aims to correlate the heating efficiency under MH of individually coated iron
oxide nanocubes (IONCs) versus soft colloidal nanoclusters made of
small groupings of nanocubes arranged in different geometries. The controlled clustering
of alkyl-stabilized IONCs is achieved here during the water transfer procedure by tuning
the fraction of the amphiphilic copolymer, poly(styrene-co-maleic
anhydride) cumene-terminated, to the nanoparticle surface. It is found that increasing
the polymer-to-nanoparticle surface ratio leads to the formation of increasingly large
nanoclusters with defined geometries. When compared to the individual nanocubes, we show
here that controlled grouping of nanoparticles—so-called “dimers”
and “trimers” composed of two and three nanocubes,
respectively—increases specific absorption rate (SAR) values, while conversely,
forming centrosymmetric clusters having more than four nanocubes leads to lower SAR
values. Magnetization measurements and Monte Carlo-based simulations support the
observed SAR trend and reveal the importance of the dipolar interaction effect and its
dependence on the details of the particle arrangements within the different
clusters.
Herein, by studying a stepwise phase transformation of 23 nm FeO-Fe3O4 core-shell nanocubes into Fe3O4, we identify a composition at which the magnetic heating performance of the nanocubes is not affected by the medium viscosity and aggregation. Structural and magnetic characterizations reveal the transformation of the FeO-Fe3O4 nanocubes from having stoichiometric phase compositions into Fe 2+ deficient Fe3O4 phases. The resultant nanocubes contain tiny compressed and randomly distributed FeO sub-domains as well as structural defects. This phase transformation causes a tenfold increase in the magnetic losses of the nanocubes, which remains exceptionally insensitive to the medium viscosity as well as aggregation unlike similarly sized single-phase magnetite nanocubes. We observe that the dominant relaxation mechanism switches from Néel in fresh core-shell nanocubes to Brownian in partially oxidized nanocubes and once again to Néel in completely treated nanocubes. The Fe 2+ deficiencies and structural defects appear to reduce the magnetic energy barrier and anisotropy field, thereby driving the overall relaxation into Néel process. The magnetic losses of the particles remain unchanged through a progressive internalization/association to ovarian cancer cells. Moreover, the particles induce a significant cell death after being exposed to hyperthermia treatment. Here, we present the largest heating performance that has been reported to date for 23 nm iron oxide nanoparticles under cellular and intracellular conditions. Our findings clearly demonstrate the positive impacts of the Fe 2+ deficiencies and structural defects in the Fe3O4 structure on the heating performance under cellular and intracellular conditions.
Here, we propose the use of magnetic hyperthermia as a means to trigger the oxidation of Fe1−xO/Fe3−δO4 core-shell nanocubes to Fe3−δO4 phase. As a first relevant consequence, the specific absorption rate (SAR) of the initial core-shell nanocubes doubles after exposure to 25 cycles of alternating magnetic field stimulation. The improved SAR value was attributed to a gradual transformation of the Fe1−xO core to Fe3−δO4, as evidenced by structural analysis including high resolution electron microscopy and Rietveld analysis of X-ray diffraction patterns. The magnetically oxidized nanocubes, having large and coherent Fe3−δO4 domains, reveal high saturation magnetization and behave superparamagnetically at room temperature. In comparison, the treatment of the same starting core-shell nanocubes by commonly used thermal annealing process renders a transformation to γ-Fe2O3. In contrast to other thermal annealing processes, the method here presented has the advantage of promoting the oxidation at a macroscopic temperature below 37 °C. Using this soft oxidation process, we demonstrate that biotin-functionalized core-shell nanocubes can undergo a mild self-oxidation transformation without losing their functional molecular binding activity.
The design of magnetic nanostructures whose magnetic heating efficiency remains unaffected at the tumor site is a fundamental requirement to further advance magnetic hyperthermia in clinic. This work demonstrates that the confinement of magnetic nanoparticles (NPs) into a submicrometric cavity is a key strategy to enable a certain degree of nanoparticle motion and minimize aggregation effects, consequently preserving the magnetic heat loss of iron oxide nanocubes (IONCs) under different conditions, including intracellular environments. We fabricated magnetic Layer-by-Layer (LbL) self-assembled polyelectrolyte submicrometric capsules using three different approaches, and we studied their heating efficiency as obtained in aqueous dispersions and once internalized by tumor cells. First, IONCs were added to the hollow cavities of LbL submicrocapsules, allowing the IONCs to move to a certain extent in the capsule cavities.Second, IONCs were co-encapsulated into solid calcium carbonate cores coated with LbL polymer shells.Third, IONCs were incorporated within the polymer layers of the LbL capsule walls. In aqueous solution, the higher specific absorption rate (SAR) values were related to the ones of free IONCs, while lower SAR values were recorded for capsule/core assemblies. However, after uptake by cancer cell lines (SKOV-3 cells), the SAR values of the free IONCs were significantly lower than those observed for capsule/core assemblies, especially after prolonged incubation periods (24 and 48 hours). These results show that IONCs packed into submicrocavities preserve the magnetic losses, as SAR values remained almost invariable. Conversely, free IONCs without the protective capsule shell agglomerated and their magnetic losses are strongly reduced. Indeed, IONC loaded capsules and free IONCs reside inside endosomal and lysosomal compartments after cellular uptake, show magnetic losses strongly reduced due to the immobilization and aggregation in centrosymmetrical structures in the intracellular vesicles. The confinement of IONCs into submicrometric cavities is a key strategy to provide a sustained and predictable heating dose inside biological matrices.
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