Regular Article
The influence of cation incorporation and leaching in the properties of Mn-doped nanoparticles for biomedical applications

https://doi.org/10.1016/j.jcis.2020.06.011Get rights and content

Abstract

Hypothesis

Superparamagnetic MnxFe3-xO4 nanoparticles are promising materials for applications in biomedicine and other fields. Small variations in the Mn/Fe ratio have a strong impact on the properties of the nanoparticles. Those variations may be caused by the synthesis itself and by common post-synthesis manipulations like surface modification.

Experiments

Mn-ferrite nanoparticles have been prepared changing systematically the Mn/Fe ratio of the metal precursors and repeating each reaction three times. Nanoparticles were subjected to surface modification with two different and typical molecules to stabilize them in aqueous media. The discrepancy in the Mn/Fe ratios of the precursors with the ones measured after the synthesis and the surface modification have been studied, as well as its impact on the saturation magnetization, blocking temperature, contrast enhancement for magnetic resonance imaging, magnetic heating, and on the cytotoxicity.

Findings

Mn is incorporated in the nanoparticles in a relatively lower amount than Fe and, as this report shows for the first time, both Mn and Fe ions leach out from the nanoparticles during the surface modification step. The blocking temperature decreases exponentially as the Mn/Fe ratio increases. The transverse and longitudinal relaxation times and the magnetic heating ability change appreciably even with small variations in the composition.

Introduction

Magnetic nanoparticles are the subject of research of many groups across many disciplines because their current and potential applications fields as diverse as energy storage and conversion, environmental remediation, the oil & gas industry, inkjet printing, microrobotics, rheology and biomedicine [1], [2], [3], [4], [5], [6], [7], [8], [9]. Among other materials, iron oxide superparamagnetic nanoparticles (IONPs), mainly maghemite (γ-Fe2O3) and magnetite (Fe3O4) nanoparticles and related ferrites, are especially well suited for biomedical applications due to their low biotoxicity and the emergence of superparamagnetism at the nanoscale [10]. In biomedicine, they are mostly used as contrast agents in magnetic resonance imaging (MRI), for medical imaging and diagnosis purposes, and as localized heat nanosources when an alternating magnetic field (HAC) is applied, a feature that can be exploited to heat up tumor cells and eventually kill them (magnetic hyperthermia) [9]. A common way to engineer IONPs is to dope them with divalent metal cations other than iron to prepare ferrites of the type MxFe3-xO4 (being M typically Mn2+, Co2+, Zn2+). In this regard, it has been shown that the inclusion of these secondary cations can have a strong influence on their magnetic properties. Thus, the incorporation of Zn2+ cations in the nanostructure has been shown to increase the saturation magnetization (MS) values of the nanoparticles, up to a value of x = 0.5 in ZnxFe3-xO4 [11], [12], while the incorporation of Co2+ cations enhances the magnetocrystalline anisotropy which may result in an increase of the blocking temperature (TB, the temperature below which the material changes from a superparamagnetic state to a thermally stable or blocked one) [13] and a higher coercivity [11], [14]. On the other hand, when Mn2+ is the doping cation, its weak spin–orbit coupling causes a decrease in the magnetocrystalline anisotropy as the Mn2+ ratio in the ferrite increases [14], [15]. As a consequence, the ferrimagnetic IONPs doped with Mn2+ present a smaller anisotropy energy barrier and change from a superparamagnetic state to a blocked one at lower temperatures. Non-stoichiometric manganese ferrite nanoparticles of the type MnxFe3-xO4 have been reported to enhance T2 contrast in MRI, compared to non-doped magnetite or maghemite, due to an increase of the MS values that takes place up to certain doping level [16]. It has been also shown that the heating ability of Mn ferrite exposed to HAC has a strong dependence on the doping level [17]. Therefore a precise control of the composition is crucial to tune the properties of the nanoparticles.

Among the different synthetic routes that can be used to prepare nanoferrites, the thermal decomposition of metal precursors (most often acetylacetonate coordination complexes) in organic solvents with high boiling points is the method that provides the best results in terms of size control and magnetic properties [9], [18]. Non-stoichiometric MxFe3-xO4 can be prepared through this route by adjusting the ratio of the metal precursors, although it is important to realize that differences in the thermodynamics and kinetics of the metal precursors’ decomposition may lead to M/Fe ratios different than the expected ones and, therefore, to different properties [14], [17], [19], [20], [21]. Nanoparticles obtained through the thermal decomposition route are hydrophobic and, for biomedical applications, it is most often necessary to transfer them to aqueous dispersion. This step is usually accomplished through surface modification via ligand substitution. An important and hardly investigated issue that should be considered is cation leaching from the nanostructure to the surrounding medium. It can take place during or after the surface modification step, modifying the composition and the magnetic properties of the nanoparticles. Thus, cobalt leaching during dialysis has been reported with Co ferrite nanoparticles coated with silica or with organic ligands, affecting their performance as MRI contrast agents [22], [23]. Other works have shown how the release of metal cations can cause cytotoxicity due, for example, to the generation of radical oxygen species [24], [25]. In this work, we have synthesized MnxFe3-xO4 nanoparticles by thermal decomposition of the corresponding Mn and Fe acetylacetonates. The Mn/Fe ratio has been systematically varied and each synthesis has been repeated three times to study the reproducibility. The obtained nanoparticles have very similar core sizes, independently of the actual Mn/Fe ratio and without applying any size-sorting procedure. Transfer to water has been performed through ligand substitution with meso-2,3-dimercaptosuccinic acid (DMSA) and dopamine (DOPA), two organic molecules extensively studied with nanoparticles for biomedical applications [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. The variation of the Mn/Fe ratios after surface modification, during dialysis and at different pHs has been studied, as well as its impact on the magnetic properties of the nanoparticles. AC susceptibility measurements show that the blocking temperatures decrease with increasing amounts of Mn2+ in the nanostructure, and allow determining the change in the anisotropy energy barrier induced by the Mn/Fe variation. The influence of the composition on the contrast enhancement for MRI and the heating abilities under AC magnetic fields have been also studied, as well as the cell viabilities with breast cancer (MCF-7) and pancreatic cancer (PANC-1) cell lines.

Section snippets

Materials

Commercial products iron(III) acetylacetonate ([Fe(acac)3], 97%), manganese(II) acetylacetonate ([Mn(acac)2], 98%), oleic acid (90%), 1,2-dodecanediol (97%), oleylamine (70%), 1-octadecene (90%), toluene (99.8%), dimethyl sulfoxide (>99.5%), dopamine hydrochloride (DOPA, 98%) and meso-2,3-dimercaptosuccinic acid (DMSA, 98%) were purchased from Aldrich and used without further purification. Tetrahydrofuran (THF, 99.8%), n-hexane (99%) and ethanol (EtOH, 96%) were purchased from Scharlab.

Synthesis of Mn ferrite nanoparticles

A series of ferrite nanoparticles of the type MnxFe3-xO4 (0 ≤ x ≤ 1) has been prepared by thermal decomposition of the corresponding acetylacetonate (acac) complexes, [Fe(acac)3] and [Mn(acac)2], with 1-octadecene as solvent and in the presence of oleic acid, oleylamine and 1,2-dodecanediol. Molar ratios [Mn(acac)2]/[Fe(acac)3] = 0, 0.09, 0.20, 0.33 and 0.50 (for MnxFe3-xO4 with x = 0, 0.25, 0.5, 0.75, 1) have been employed in the synthesis to study the degree of incorporation of the cation Mn2+

Conclusions

Non-stoichiometric manganese-doped ferrites have been synthesized by thermal decomposition changing systematically the ratio of manganese and iron precursors. The incorporation of the secondary cation Mn2+ and the reproducibility of the synthesis have been studied finding that similar core sizes are obtained in all cases and that there is a small, but not negligible, variability in the Mn/Fe molar ratio for the same syntheses. In addition, the Mn/Fe ratio in the synthesized nanoparticles is

CRediT authorship contribution statement

DG-S: experimental synthesis and characterization of nanoparticles: work. RA provided support in synthesis and characterization. NL-G, PM-R and AS: evaluation in cell lines, with the support of DG-S. CN: XPS characterization. FH and DG-S: relaxometry data acquisition and analysis. LG and DG-S: AC magnetic characterization and magnetic heating experiments. Gorka Salas: methodology design and supervision. DG-S and GS wrote the manuscript and all authors contributed to it. All authors commented

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the Spanish Ministry of Economy and Competitiveness (project MAT2015-71806-R, SAF2017-87305-R, PGC2018-096016-B-I00), Comunidad de Madrid (projects P2018/NMT-4321, NANOMAGCOST-CM, and B2017/BMD-3867, RENIM-CM), and European Commission H2020 programme (project NOCANTHER, grant agreement no. 685795). IMDEA Nanociencia acknowledges support from the 'Severo Ochoa' Programme for Centres of Excellence in R&D (grant SEV-2016-0686). DG-S gratefully acknowledges Consejería de

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