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Review

Magnetic Iron Nanoparticles: Synthesis, Surface Enhancements, and Biological Challenges

by
Jesús Roberto Vargas-Ortiz
1,
Carmen Gonzalez
2,* and
Karen Esquivel
1,*
1
División de Investigación y Posgrado, Facultad de Ingeniería, Universidad Autónoma de Querétaro, Cerro de las Campanas, Santiago de Queretaro 76010, Mexico
2
Facultad de Ciencias Quimicas, Universidad Autonoma de San Luis Potosi, Av. Dr. Manuel Nava Num. 6, Zona Universitaria, San Luis Potosi 78210, Mexico
*
Authors to whom correspondence should be addressed.
Processes 2022, 10(11), 2282; https://doi.org/10.3390/pr10112282
Submission received: 4 October 2022 / Revised: 28 October 2022 / Accepted: 2 November 2022 / Published: 4 November 2022
(This article belongs to the Special Issue Magnetic Materials for Environmental and Biomedical Applications)

Abstract

:
This review focuses on the role of magnetic nanoparticles (MNPs), their physicochemical properties, their potential applications, and their association with the consequent toxicological effects in complex biologic systems. These MNPs have generated an accelerated development and research movement in the last two decades. They are solving a large portion of problems in several industries, including cosmetics, pharmaceuticals, diagnostics, water remediation, photoelectronics, and information storage, to name a few. As a result, more MNPs are put into contact with biological organisms, including humans, via interacting with their cellular structures. This situation will require a deeper understanding of these particles’ full impact in interacting with complex biological systems, and even though extensive studies have been carried out on different biological systems discussing toxicology aspects of MNP systems used in biomedical applications, they give mixed and inconclusive results. Chemical agencies, such as the Registration, Evaluation, Authorization, and Restriction of Chemical substances (REACH) legislation for registration, evaluation, and authorization of substances and materials from the European Chemical Agency (ECHA), have held meetings to discuss the issue. However, nanomaterials (NMs) are being categorized by composition alone, ignoring the physicochemical properties and possible risks that their size, stability, crystallinity, and morphology could bring to health. Although several initiatives are being discussed around the world for the correct management and disposal of these materials, thanks to the extensive work of researchers everywhere addressing the issue of related biological impacts and concerns, and a new nanoethics and nanosafety branch to help clarify and bring together information about the impact of nanoparticles, more questions than answers have arisen regarding the behavior of MNPs with a wide range of effects in the same tissue. The generation of a consolidative framework of these biological behaviors is necessary to allow future applications to be manageable.

Graphical Abstract

1. Introduction

Nanoparticles (NPs) and nanostructured materials have innovative properties due to their small size, large surface area, crystalline arrangement, composition, and reactivity [1,2]. These properties confer unique and specific effects, such as superparamagnetism, surface area and charge, and optic and magnetic properties different from their bulk presentation [3,4,5,6,7]. The design of these materials influences the final properties they present. Due to the different crystalline planes exposed on the surface of the said particles, they could externalize other atoms of the structure, which interact differently with the environment where they are found [8,9].
A well-known example is magnetic materials; when found on the nanoscale, iron oxide nanoparticles (IONPs) obtain a single-domain phenomenon known as superparamagnetism [10,11] that can shorten the relaxation times as contrast agents in magnetic resonance imaging (MRI) [12,13] travel to target locations with magnetic fields [11] and simultaneously play a role in both diagnostics and treatment, known as theranostics, by vibrating and heating. Recent design strategies of IONP-based nanoplatforms describe the rationale for the combination of other functional materials with IONPs and test their possible applications in smart nanomedicine theranostics [14]. However, dispersed NPs tend to form unstable suspensions in culture media, and modifying their surface chemistry, for example, with rhodium citrate, can increase their adverse effects, cytotoxicity, and uptake in breast cancer cell cultures [15]. Whether particles can become toxic by increasing their size (agglomerates) or by maintaining their nanometric size in dispersions is debated. Nevertheless, the increasing size implies a reduction in the number of atoms on the surface; thus, they become bulk materials and have reduced harmful effects [16,17,18,19,20,21,22].
Size is crucial when designing structures that interact at some point with the human body [23,24,25]. The range of cell sizes in the human body is wide, from the granules of the cerebellum in the brain (5 µm) up to the ovule (0.1 mm). Between these cells, a great variety of sizes are among the different systems responsible for maintaining homeostasis within the body. All these cells are three orders of magnitude larger than an NP [26]. Considering that one main application of magnetic nanoparticles is in diagnostics and treatment, such as imaging, the importance of these interactions becomes paramount to consent.
Imaging plays a crucial role in diagnosis because of the importance of the swiftness, efficiency, and accuracy of reliable early detection of diseases within the human body, such as cancer and inflammation [27]. Various contrast agents have been used to better visualize resolution by increasing the contrast between healthy and abnormal tissue that occurs within the human body, such as gadolinium, manganese, and barium [28]. Contrast agents for MRI are classified according to their specific characteristics, including: (i) chemical composition, (ii) route of administration, (iii) magnetic properties, (iv) effect on the magnetic resonance imaging, (v) biodistribution, and (vi) imaging applications (target/organ-specific agents) [29]. MNPs provide a potential promising alternative due to their improved magnetic characteristics (superparamagnetism) in terms of specificity, ease of functionalization, and biocompatibility.
Most of these agents are complexes of lanthanide elements such as Gd3+ or transition-metal manganese (Mn2+) with superparamagnetic magnetite particles [30]. These factors are used to shorten T1 or T2 relaxation times; the signal intensity on T1-weighted images is enhanced, or the signal intensity on T2-weighted images is decreased [31]. T1 and T2 are two different relaxation durations used to describe abnormalities in tissue. Most paramagnetic contrast agents are positive agents, which shorten the T1 relaxation time so that enhancements appear bright on T1-weighted images. However, these agents are used in an average of one-third of the analyses, given their low precision, problems brought on by the release of free gadolinium (Gd3+) [29], and the risk of presenting severe adverse effects in pediatric patients [32]. Dysprosium, superparamagnetic agents, and ferromagnetic agents are negative contrast agents [33,34], while enhancing parts appear darker on T2-weighted images [31]. MRI contrast agents incorporate chelating agents to reduce storage in the human body, improve excretion, and reduce adverse effects [35]. However, they must be used immediately due to their short shelf life [36].
Magnetite and maghemite are nowadays regarded as safe. They are now in clinical usage as MRI contrast agents [37,38,39], pharmaceutical agents [40,41], and a combination of both treatment and diagnostics, also known as theranostics [42,43,44], due to their significant superparamagnetic characteristics (around 40 to 90 Am2/kg) achievable because of their nanometric size (10nm) (Figure 1).
Magnetite and maghemite are the most suitable MNPs, but their iron oxidation states and structures differ, affecting their final physicochemical characteristics [45]. Other types of magnetic nanoparticles exist with similar promising properties, including titanomagnetite cobalt and nickel-based magnetic materials [46,47]. Nevertheless, the full impact of the nanoparticles in general and in the case of magnetic materials is still under study to correlate MNPs’ size, morphology, concentration, and crystallinity with different biological specimens. A collection of research from different cell lines and tissues has shown inconsistent results from cell–MNP interactions [48], such as uptake by mononuclear cell infiltration in mice liver [49,50,51,52], leaching of different ions such as Fe2+ [53,54,55], apoptosis via over-endocytosis, [56,57,58], oxidative stress by passive diffusion, receptor-mediated endocytosis unchaining mitochondrial stress [59,60], and DNA damage leaching Fe2+ into the cell’s core, increasing temperature while vibrating [61,62,63].
This array of properties that NMs possess have made it possible to generate significant advances in different areas, specifically biomedicine. For example, in the treatment and diagnosis of diseases, the role of MNPs has become increasingly important in the last two decades, but the short-, medium-, and long-term toxicological implications are set aside. This review focuses on the collection of various studies on assessment and challenges with regard to synthesis routes, biological evaluation, and the impact of iron MNPs to gather their different characteristics and properties, and studies presenting the possible effects in various biological assays and assessments to raise awareness of the correct use and disposal of MNPs to generate an integrative background of knowledge enabling improved visualization of the context behind the biological behavior of the iron MNPs.

2. Magnetic Nanoparticle Synthesis Methods

For manufacturing quality control and achieving the required outcomes for different applications, defined parameters for NPs’ diverse characteristics are essential. These NPs, composed of magnetic iron oxide, Fe3O4 (magnetite), and γ-Fe2O3 (maghemite), among other common structures with modified surface chemistry, are considered promising materials for widespread industrial applications in computer and sensing materials [64,65,66], the textile industry [67,68], ferrofluids [69,70], the remediation industry for the degradation of herbicides and emergent contaminants [71,72,73] and intrinsic magnetic properties [74,75], the biomedical area for iron deficiency anemia [76,77], imaging and diagnostics [78,79,80,81], heat cauterization treatments [82,83,84], and drug delivery [81,85,86,87,88] due to their chemical nature and biocompatibility. The unique characteristics that MNPs possess depend on the synthesis conditions.
Therefore, it is crucial to examine nanomaterials based on the physicochemical characteristics they acquired from the synthesis route used to obtain them (Figure 2).
Like most nanoparticles, MNPs have a high surface-area-to-volume ratio, implying they have qualities that are different from those of bulk material, such as a lower melting point, a lower sintering temperature, and distinct magnetic properties [35,89,90,91].
Different MNPs can be obtained by acquiring unique morphologies depending on the synthesis route and their conditions, such as temperature, pressure, reaction time, reagent casting, etc. (Figure 3), that could modify the MNPs’ physicochemical properties, surface functionalization, and magnetic properties. A ferromagnetic nanoparticle’s behavior is highly influenced by its size. When the size is reduced, it transforms from a multidomain particle to a single-magnetic-domain nanoparticle and finally to a superparamagnetic nanoparticle [81]. All the latter properties are achievable through different methods of synthesis to control the shape and coating in the case of functionalized materials.
Several synthesis routes have been created to obtain different morphologies, crystal growth, sizes, magnetic saturation, and surface charges of MNPs using parameters such as temperature, pressure, sonochemistry, and biological assistance with equipment, which can be simple to acquire, such as those obtained via an ultrasonic bath, to relatively complex microwave devices. These routes can provide specific MNP properties for different applications (Table 1).

2.1. Wet-Chemical Methods

2.1.1. Coprecipitation Synthesis

Coprecipitation is the ideal method for synthesis simplicity. This synthesis is a straightforward, well-known, cheap, and effortless process for obtaining MNPs (Fe3O4 and γ-Fe2O3) from a usual 1:2 molar ratio of ferric/ferrous salt solution by adding basic-pH solutions at standard temperature or increased temperature [117,118]. Most of the reactions could be helped with an inert gas atmosphere to prevent additional oxidation and to maintain their magnetic properties [119,120]. The ferric/ferrous ratio, the salt utilized, such as chlorides, sulfates, or nitrates, the reaction temperature, the pH value, and the ionic strength of the medium all influence the size, morphology, and composition of the magnetic particles [117], making the quality of magnetic particles entirely repeatable if the synthesis conditions are controlled. On the other hand, control over particle size attributes is reduced due to the rapid creation of particles. Overall, the coprecipitation methodology creates abundant MNPs, with strong magnetic properties (50 to 90 Am2kg−1) but poor control over shape and size compared to other synthesis methods.

2.1.2. Thermal Decomposition

Thermal decomposition of organo-metallic precursor compounds in different solvents (organic and water) with high boiling points and stabilizing surfactants is a potential strategy for producing monodispersed magnetite nanoparticles without particle aggregation [83,121,122].
Thanks to the nucleation process, several synthesis variants have been developed for synthesizing MNPs with controllable size and morphology thanks to the nucleation process. Additionally, by promoting the adsorption of additives, e.g., the oleic acid–oleylamine ligand pair, the growth of nanocrystals can be achieved, inspired by the synthesis of high-quality semiconductor nanocrystals and oxides in a wet-chemical medium through thermal decomposition [95,97,121,123]. As a result, smaller superparamagnetic nanoparticles can be obtained. The nucleation condition of this method provides the possibility of the particles being separated from growth, unlike coprecipitation, preventing a more complex reaction process that can lead to oxidation [121]. In broad terms, the thermal decomposition synthesis process is one of the most appraised in terms of adequate size and morphological control. Thermal decomposition allows control over particle size, strong magnetic properties (40 to 90 Am2kg−1), and high yield with easy access to precursors, with oxygen concentration being the crucial factor in producing the desired iron oxide structure.

2.1.3. Hydrothermal Synthesis

One of the most frequent ways of preparing NMs is hydrothermal synthesis. Straightforwardly, hydrothermal synthesis synthesizes single-crystal nanoparticles relying on the solubility of an aqueous solution (water) in the traditional crystal-making synthesis involving high temperatures and pressures [124]. It is essentially a solution-reaction-based synthesis method. The creation of NMs in hydrothermal synthesis can occur over a wide range of temperatures, from ambient temperature to extremely high temperatures (130–250 °C). The different vapor pressures in the reaction, in either low-pressure or high-pressure conditions (0 and 3–4 MPa), can be utilized to control the morphology of the materials to be synthesized, crystallizing the material in a sealed container [125,126] and highly improving the preferential growth of different planes of the MNPs [127]. Nevertheless, the high pressure and temperatures sacrifice the magnetic properties of the MNPs compared to other, cheaper, and simpler synthesis routes.

2.1.4. Sol–Gel Synthesis

In the materials science and engineering field, sol–gel synthesis is a traditional and commonly used technique in the wet-chemical approach, mainly used for NM fabrication (typically metal oxides) [101,102]. It usually begins with a colloidal solution that serves as a precursor for an integrated network of isolated particles. The system is shaped by a sol phase, a stable dispersion of colloidal particles in a solvent, and a gel, a continuous three-dimensional network that encloses the colloidal liquid phase. The aggregation of colloidal particles forms the network in a colloidal gel. The particles in a polymer gel have a polymeric sub-structure formed by the accumulation of sub-colloidal aggregates [116]. There are definite advantages of the sol–gel reaction over the previous wet-chemical or aqueous synthesis method, such as the simple dispersion in solvents, due to hydrophilic ligands on the surface of MNPs, which are used in the surface coating and for high control over size and shape; however, the high costs of the reagent precursors (i.e., alkoxides), the low yield compared to other techniques, such as coprecipitation, and poor obtention of magnetite structure limit the access of the sol–gel synthesis.

2.1.5. Microemulsion Synthesis

The self-assembly synthesis methodology of micro- and NMs has piqued interest in recent decades because of its unique features compared to bulk material analogs due to the mechanical and physicochemical property changes at the micro- and nanoscale. A surfactant stabilizes micro-domains in a thermodynamically stable and isotropic dispersion of two immiscible liquids (usually water and an oil-based compound) (Figure 4). It includes various structures and combinations that correlate to various self-assembled colloidal system performances [128]. The vital interaction to consider is the surfactant stabilizing the formed domains, which should be carefully chosen for the desired material. Iron oxide nanoparticles have been synthesized through this method. Iron ionic precursors, such as chlorides, in a basic-pH medium, such as ammonium, can be dissolved in water to create a reaction-ready space capable of producing the desired particle condensation [104,129,130]. This method offers control of the size of the nanoparticle through the solution of precursors and the available space provided in these solutions by adjusting the water-to-surfactant ratio, which entails a chemical reaction that converts soluble precursors to an insoluble in the aqueous phase, thus altering nanoparticle size [128,130]. Although monodispersed nanoparticles can be synthesized through microemulsion with reasonable control over size and shape, this technique has the lowest efficiency output, poor magnetite presence, and, consequently, low magnetic properties (20 to 60 Am2kg−1).

2.2. Assisted Methods

2.2.1. Sonochemically Assisted

Acoustic cavitation is defined as the creation, expansion, and implosive collapse of bubbles in liquids bombarded with high-intensity sound, resulting in a transitory and localized temperature of 5000 K and a pressure of 1000 bar [85,131]. This collapse results in intense localized heat and pressures with minimal periods [132], commonly known as hotspots. This technology produces structures using the chemical effect of ultrasound. It provides a novel route without the use of high temperatures, high pressures, or extended reaction periods, ideal for the formation of materials with complex structures sensitive to extreme heat conditions (magnetic materials) [133,134]. The ultrasonic methodology route depends strongly on the cavitation and amplitude parameters applied to the particles. It can be observed sometimes as a complementary step in other synthesis routes to improve specific properties, such as coprecipitation, and to provide rapid reaction times or control of emulsion factors [132,133,135], producing the medium output of strong magnetic nanoparticles without the shape and size control of other techniques.

2.2.2. Microwave-Assisted

The orientation of molecules that occur when irradiated with any source of electromagnetic waves, aligning their dipoles within the external field, creates a strong internal heat resulting from the excitation with electromagnetic radiation [136,137]. The shape and size of the obtained nanoparticles, as well as their magnetic characteristics, may vary slightly depending on the experimental parameters, such as the precursor material or reaction temperature [109,136,138,139,140,141]. Microwave heating of a solution of iron oxide nanostructures such as magnetite and hematite has been used to improve their magnetic properties, sacrificing crystal structure [138,142]. This process has a variety of advantages over conventional heating-based procedures, such as high reaction rates and excellent product yields, due to the rapid localized heating provided by microwaves [143,144], reducing process time and energy costs compared to the conventional thermal methods, making microwave-assisted synthesis methods more appealing for iron oxide nanoparticles.
Both approaches are relatively simple processes in time and reaction times, obtaining specific control over the nanoparticles.

2.3. Biological Synthesis Routes

Several researchers are now looking at creating dependable, clean, and environmentally acceptable experimental procedures for NP synthesis. The biosynthesis of NPs utilizing various biological components, such as plant derivatives, is a strategy with a lot of promise.
Oxidation and other thermic methods tend to sacrifice structure to gain control over the synthesis, size, magnetic properties, morphology, etc. [18,88,141,145]. Several types of magnetotactic bacteria can create biologically manufactured domain-specific iron oxide nanoparticles called magnetosomes via biomineralization, which can be caused by Fe(III)-reducing bacteria such Thermoanaerobacter, Bdellovibrionota, Proteobacteria (alpha, eta, zeta, gamma), SAR324, and Phoenix dactylifera species [146,147,148,149], typically grown from a ferric oxyhydroxide precursor at 65 °C. The resulting magnetite crystals, 5–140 nm in size, are confined in a biological membrane regulating the magnetosome’s size and form [148,150,151]. Magnetosomes in bacteria are grouped in chains with the [111] crystal plane with narrow down-size distribution [152].
Green synthesis of NMs can result from, for instance, bacteria-driven synthesis of living organisms’ capacity to reduce metal and oxides into defined structures within their metabolism. Additionally, different plant species have biological extracts or the capability to hyper-accumulate metal ions in tissues to form nanoparticles or decrease them in various organs to generate metal oxide structures, as shown through different phytoremediation studies [153]. As a result, many extracts from other plant parts, such as the leaves, stem, root, fruit, and seed, have been employed to synthesize nanoparticles. Using natural extracts of plant parts is a very cost-effective and environmentally friendly approach. It does not require the use of any intermediate base groups such as silane (Si-H), mercaptoundecanoic acid (MUA), oleic acid, cetyltrimethylammonium bromide (CTAB), polyvinylpyrrolidone (PVP) [154], or sodium cholate, among others [155]. Likewise, expensive equipment and precursors are not required. Because of the variety of metabolites in the plant extracts, such as phenolic compounds that have ion-reducing capabilities, most of the efforts associated with obtaining MNPs using plant extracts have been through the implementation of the leaves as the source of these extracts [156,157,158,159]. Several aspects must be considered when producing NMs through leaf extractions: the solvent, the plant origin, extraction methods, reaction time, and external industrial chemical reagents [155,160].
MNPs are typically functionalized with various substances (such as citrate, phosphate, chitosan, polyethylene glycol, albumin, silica, iron oxides, and metals) to increase colloidal stability and biocompatibility since uncoated MNPs have the propensity to flocculate when exposed to physiological fluids [161] and tend to present unfavorable effects [162]. The assessment of the size and zeta potential as a function of time in various media (culture medium, phosphate buffer, in the absence or presence of fetal bovine serum (FBS)) will help us to understand how MNPs behave when they are in contact with bio-relevant culture media. Although it is a novel approach to NP production, excessive energy consumption, long reaction times, and the difficulty of obtaining precise chemical reactions to describe the mechanisms underlying the biosynthesis process are the primary issues with the synthesis process [163,164].

2.4. Surface Coating

Just like bulk materials, iron materials are prone to rust and corrosion. Iron oxide nanoparticles cannot be used as a core material to produce treatments or pharmacological agents per se without the addition of functional [82,165], biocompatible [166], inert, or target coatings [167,168]. MNP design is essential in biomedical applications. The features of the MNP core are determined by form and size, but the choice of added ligands and coatings significantly impacts the colloidal stability and functions [169], further specifying their properties for later applications.
It is a known fact that MNPs have an inherent instability when preserved over long periods due to their magnetism [170,171,172], which leads to a loss in dispersibility because of the aggregation and formation of large particles and reduces the surface energy, generating a loss of magnetism. Non-coated iron nanoparticles easily oxidize when are exposed to air due to their high chemical activity and unstable spinel structure, especially magnetite and maghemite nanoparticles. They have a maximum shelf life of about 8 to 12 months [116,173]. As a result, chemically stabilizing simple iron oxide nanoparticles to prevent damage during or after their subsequent exposition and/or application becomes an essential factor to consider because most biological organisms and applications require aqueous solutions to be administered [44,174]. Generally speaking, polymers, SiO2, carbon-derived structures, and metal material coats of a nanoscale substance constitute a family of composite nanoparticles [175] to reduce their negative impacts on living organisms and serve as ligands for functionalization [167].

2.4.1. Silica Coating

Due to its chemical stability, diversity in surface alterations, and limited loss of initial magnetism, silica (SiO2) has been regarded as the best material to safeguard MNPs. Silica is beneficial in attaching different biological ligands to the iron oxide surface. Silica coatings, metal, or metal oxide coatings help stabilize the nanoparticles in the solution. Silica coating is the preferred material when applying layers to MNPs due to its increased biocompatibility, ability to bond with organic linkers, and simple synthesis methodology [176,177]. Different methodologies for coating MNPs and nanoparticles are based on the desired properties, thickness, silica percentage, and later functionalization [100]. The Stöber methodology is the most used and straightforward because of its simple application. It requires a sol–gel precursor, which is hydrolyzed and condensed to obtain SiO2 sheets that will cover the desired material [178]. A modified microemulsion method using a multilayer silica coating applied to nanoparticles with relative simplicity, assisted by microwave radiation, has proven very effective at controlling single layers of a few atoms [179].

2.4.2. Carbon-Based Coatings

By adding functional groups to the iron oxide surface, such as hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), or silane (-SH), various bioactive compounds can be bonded. Due to the benefits of linking several kinds of molecules to the coating [174,180], carbon coatings are popular. These provide a magnetic core material with strong chemical and thermal stability, high intrinsic electric conductivity, and an efficient oxidation barrier. Hydrophilic carbon coatings also provide enhanced stability and dispersibility. With the co-precipitation and surface oxidation of CNTs, nanoparticles have been effectively created, resulting in hybrid materials with improved conductive properties from 16 meV at 20 °C to a maximum of 67 meV at 120 °C [181]. Different synthesis methods can be used to produce core–shell nanostructures. The three-step process uses MNPs as precursors, applying any synthesis route previously mentioned, e.g., heating or applying plasma, to prepare the surface (which may cause oxidation), coat it with polymers, and finally, carbonate it with an annealing treatment [182,183,184].

2.4.3. Metallic Coatings

One of the disadvantages, if not the most important, of MNPs is the tendency to change the crystal structure of the magnetite via oxidation [185]. The idea of linking a nanoscale oxide phase with a metal surface to create a metal–oxide hybrid material with unique features is appealing. Monodispersed iron oxide–metal nanostructures with binary characteristics, such as core–shell, core–satellites, or dumbbell structures, achieve enhanced stability and biocompatibility through the change in charge [186]. Noble metals in bulk appear to have inert behavior, biocompatibility, and no significant interactions with other elements, which could make them ideal in biomedical applications [187]. Due to their interaction with external fields and the ease with which they are recovered, reused, or altered with magnetic manipulation, MNPs, namely magnetite and maghemite, are particularly appealing as components of multifunctional NMs, and the general biocompatibility of noble metal nanoparticles makes these materials the ideal combination for biomedical applications [186,188].
Conventionally, forming an amorphous or oxidate phase in nanostructured magnetic materials has been a drawback of the synthesis process. Given its often negligible contribution to effective saturation magnetization, the amorphous fraction is frequently portrayed as a “dead” magnetic component and a material waste [189]. The core–shell morphology with an ordered core and a shell with structural/magnetic disorder often describes this scenario as the simplest example of MNPs.

2.4.4. Polymer Coatings

Microemulsion polymerization and the sol–gel technique are frequently used in situ synthesis methods that traditionally produce a core–shell or matrix-dispersed structure [49]. It is still difficult to regulate the colloidal stability and thickness of the created structures. Post-synthesis methods such as the one-pot approach, self-assembly, or heterogeneous polymerization are commonly chosen for the polymeric coating of MNPs to avoid excess particle oxidation [190,191].
Utilizing polymer coatings has allowed for increased MNP stability and an expansion of the application space by altering different functional groups [192] to provide properties such as the connection with optoelectronic segments, imaging, diagnosis, and treatment, enabling conjugated polymers with a delocalized electrical structure [193].
These are brief applications of covers and functionalization coatings that can be applied to MNPs, known as multicoated or multicore. However, more properties can be attached to these materials, combining coating types [194,195] to solve deficiencies of the iron NP core, such as biocompatibility or recovery of the material. A typical method for creating multicore nanoparticles is to trap many magnetic cores inside a polymeric matrix [195]. Three main approaches to the synthesis of polymer/SPION hybrid multicore particles have been reported in the literature: (i) polymerization in the presence of the nanoparticles [196]; (ii) SPION formation from iron salts along an existing polymer particle; and (iii) in the emulsification process (ESE) within a precipitating polymer [197].

2.5. Nanocomposites

Nanocomposites are materials with more than two phases, which have units with at least one dimension within the nanoscale present in the matrix material to produce integrated functional systems with additional properties [198]. Nanosized particles of various magnetic materials have been inserted into extended matrix materials (i.e., organic or inorganic polymers). Additionally, the future importance of magnetic nanocomposite materials made from renewable resources will undoubtedly rise to safely recover the material, making it a reusable source [199,200,201]. They blend the characteristics of the filler with the matrix material to create innovative functional materials that are tailored to the requirements of a specific application, such as when magnetite nanoparticles are enclosed in a short-chain amphiphilic block copolymer combined with an organic pigment during the self-assembly of higher-order polymer structures to create biosynthetic, bifunctional, and magnetically active materials with poly(ethylene oxide)-block-poly(butadiene) (PEO-b-PBD) [202].
In general, a wide variety of host materials, such as organic polymers, silica, or even liquid media, are used in nanocomposites [203,204,205].

3. Biological Challenges

Nanotechnology, NMs, and nanostructures have been around humans since the early days at the beginning of the industry and early metallurgy [206,207,208]. We can state that the human–nanostructures interaction is not contemporary. Although the appropriate determination of “nano” was given centuries later by Richard Zsigmondy, the Nobel Laureate in Chemistry (1925), he was the first to suggest the term “nanometer” [209] to the scientific world. He was the first to measure the size of particles such as gold colloids [210,211,212], and he developed the term nanometer to describe particle size using a microscope. However, only about 30 years ago, the significance of these nanostructured materials was apparent to researchers of disciplines as diverse as medicine and photoelectronics due to the different and novel characteristics conferred by their size. Researchers have discovered that size affects materials’ physicochemical characteristics, such as their magnetic properties [119,213,214].
MNPs can intervene in different steps and applications in both medical and industrial sectors. Because these particles are composed of iron and oxygen, they have been targeted as the standard material for medical applications because of their magnetic properties. They can act as a carrier for drug and heat delivery [81,86,215,216], a potential treatment when undergoing vibrating or carrier structure breaking processes [82,217,218,219,220], and even a contrast and targeting agent [80,213,219,220,221], shortening periods between the diagnosis and treatment, which is a crucial factor in medical processes and biocompatible needs. At least, that was the original thought. Over the past two decades, research has shown mixed results from the same tissue in different assays assessing the toxicity of MNPs (Table 2). However, the concentration range is extensive. Most research focuses on the spherical shape of the nanoparticle, giving controversial results depending on the study. Spherical particles produce no effect when analyzed through ROS and TB in lung cells, but a comet assay reveals oxidative DNA damage, as shown in Table 2.
Although many studies have assessed the biological effects of MNPs, a consensus has not been achieved on safety parameters.
Biological processes imply a series of pathways, reactions, and signaling at a molecular level, all taking place around 1 to 100 nm, which is, coincidently, the action size range of nanostructured materials. It is unsurprising then that, as such, nanotechnology and nanostructure materials require special attention and safety parameters to function and not interfere with any other healthy cells and systems when applied to biological systems (Figure 5).
Like any type of active drug substance and new material, nanostructured materials must be subjected to different test methods to determine their effects and their impact on health, regardless of whether they will be used in the medical sector or not [17,247,248,249]. Among the most used biological assays are the in vivo, in vitro, and the so-called ex vivo tests. For the ex vivo tests, a target organ (heart, lungs, kidney, liver) is kept in a controlled system outside the body to observe its interactions with an active ingredient (such as nanoparticles or any vasoactive controls, acetylcholine, phenylephrine) in real time [250,251,252,253]. Ex vivo tests have obvious advantages over other methods, including rapid results, a relatively low cost, and reduced use of live animal exposure [254,255].
In the case of heavy metals, such as bulk iron, adverse effects at concentrations around 350 µgdL−1 are observed [256]. Additionally, the leaching of different ionic species can occur in the ferrous state (Fe2+), which is insoluble, or in the ferric state (Fe3+), which can directly interfere with agents related to oxidation [54,55,257]. Hemoglobin as molecular oxygen (O2) and nitric oxide (NO2, NO3), a representative mediator in cardiac muscle [258], is a free radical synthesized enzymatically by endothelial NO synthase (eNOS), neuronal synthases (nNOS), and inducible (iNOS) [258,259,260,261].
Detection of the non-favorable response of different substances in biological systems can be classified into three main categories, depending on the biological section (cell, tissue, organ, and system) that has been tested. In vitro is specifically for single cells and tissue sections in controlled conditions in culture. In in vivo tests, the complex interactions between systems (cardiovascular, respiratory, endocrine, digestive, renal, and nervous) are tested. Moreover, a relatively new biological evaluation test has been raised, ex vivo, which maintains isolated organs or segments in an external, controlled environment to detect changes in physiology in real time (Figure 6).
In vivo studies can evaluate the primary stages of the adverse effects due to their availability and relative ease of use compared to other studies. Ex vivo tests are a relatively new approach to toxicology, bringing advantages over in vitro studies because of their capacity to assess real-time effects on specific organs or tissue sections (heart, lungs, kidneys, liver), isolating the tissue from the general bloodstream. Ex vivo analysis tends to isolate specific organs from the animal and maintain them in a controlled environment. Complex organs such as the heart require a more delicate approach in retrieval from the bloodstream, necessitating a constant flow rate or pressure modes [262]; however, isolation from blocking of the aorta and immediate recovery and attachment to the external parameters can preserve the organ long enough to study it [250,253,263,264]. Lastly, in vivo assays are the last evaluation before human trials and determine the complex response of different biological system interactions and the impact of active substances.

3.1. In Vitro Toxicology

Different in vitro tests are available to verify toxicity; the lactate dehydrogenases test (LDH), sulforhodamine B (SRB) assay, protein assay, neutral red assay, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay are a few of the often-used assays [59].
Tetrazolium salt, derived from MTT, is transformed into a purple, insoluble formazan complex by a mitochondrial dehydrogenase enzyme. These enzymes are only found in active mitochondria; hence, the process only occurs in healthy cells [265]. The LDH leakage test, commonly used due to its dependability, speed, and ease of assessment, determines lactate dehydrogenase leakage to the extracellular medium in damaged cells [266]. Trypan blue is the test most often employed for viability studies. The test provides an uncomplicated way to assess cellular viability by fixing the cells in a solution of trypan blue and paraformaldehyde after being deposited onto slides. Nonviable cells have a heavy blue stain, but viable cells do not [266]. However, this method does not distinguish between apoptotic cells.
The safety assessment of MNPs on cell lines (in vitro) is uncomplicated, straightforward, and affordable since the experiment can be reliably controlled. Toxicity in MNPs has been associated with dosage dependence, time, and surface modification [267].
Since in vitro testing is the first approach to understanding the impact of material in a living organism, it is not unusual that the information collected from in vitro and in vivo tests happens to be controversial. This results from the complex bodily interactions and different systems coexisting in an in vivo test [268]. However, these tests unify the results of the full impact of the materials or pharmaceutical agents.

3.2. Ex Vivo Toxicity

Physiological models have been used for a long time as a valuable tool for the study of endogenous molecules such as hormones, neurotransmitters, and other mediators under normal or pathophysiological conditions, such as cardiovascular, respiratory, and digestive disorders, to name a few [250,252].
Physiological ex vivo models of isolated tissues and organs allow the evaluation of the particular functioning of a tissue or organ in NPs’ presence, for example, ducts related to the cardiovascular system (aorta, arterioles, mesenteric, etc.), respiratory system (trachea, bronchi, bronchioles), and digestive system (small or large intestine); or in the study of organs such as the heart, kidney, lung, and liver; and the biochemical communications between the organs and tissues [269]. By separating the organ from the general circulation, identifying metabolites generated from the interaction with MNPs becomes easier [270].
This is a novel approach to assessing the toxicology of MNPs, but the road ahead is still long and full of opportunity. These assays produce exciting results in cardiovascular heart contractility and NO production.

3.3. In Vivo Toxicity

Although in vivo toxicity investigations take longer, cost more, entail ethical considerations, and have more complicated techniques (such as toxicokinetic processes) [271], they offer a clear benefit over in vitro experiments. Even though there is not enough in vivo research on the toxic effects of MNPs, those studies that do exist provide valuable information on possible toxicity, such as alternating current biosusceptometry (ACB) [272]. The ACB system is a biomagnetic approach previously described and used in pharmacological and gastrointestinal research in animals and people [273], as well as recently for detecting MNPs [274].
For the best results in the therapeutic or diagnostic application, the MNPs are aggregated in a specific tissue using a magnet, which might result in high concentrations in that location [275]. This may result in large amounts of free Fe ions in the exposed tissue, resulting in cellular damage and/or significantly influencing subsequent cell generations [276].
When MNPs enter the body, they interact with the bodily fluids and then bind to the proteins to form a protein corona, a nanoparticle–protein complex. The MNPs–corona complex is essential for the particles to perform as intended because MNPs interact with one another in vivo through the formation of this structure, which serves as the biological identity of the MNPs [277]. As a result, understanding the surrounding protein composition, particularly the individual proteins present in the MNPs–corona complex and their affinities, is crucial for understanding how the MNPs will act in vivo.
These toxicological assays and approaches provide a different view of a material’s effect on other parts of complex systems, increasing the understanding of its full impact on nature and living organisms. All these efforts have expanded the body of knowledge on nanotoxicology and help in regulating the novel properties that nanoscale materials bring to different fields (Table 3).

4. Regulation and Control

Even though research and toxicity approaches have been made to identify the potential toxicity of MNPs, there are no clear regulatory parameters to control these materials’ production, interaction, and disposal. Different organizations have made several proposals since 2011 around the world (Table 4).
The idea of safe-by-design is becoming an increasingly significant approach to nanosafety. Nanotechnology-based products must be safe to use throughout their lifespan, from manufacture to disposal, recycling, and reuse. A well-established general idea in industrial innovation, safe-by-design was first developed for nanomaterials in the European Union’s (EU) flagship project NANoREG [281].
The legislation on Registration, Evaluation, Authorization, and Restriction of Chemicals, or REACH, in the European Union is responsible for regulating chemical agents [288]. REACH defines any NMs as “nanoforms,” creating a new guideline with which to contemplate these new materials and their properties. It has a section establishing that a material composed of less than 50% nanostructures is classified as a bulk material without considering its dissemination to the environment or biological organisms. However, these guidelines were defined in 2013, and just recently, the term nanoform was implemented [286].
Another administration agency, the U.S. Food and Drug Administration (FDA), which is in charge of the regulation of product safety, has provided a guideline to specify if a manufactured good possesses nanotechnology or nanoscale properties with two criteria: (i) whether a substance or finished product is designed to have at least one exterior dimension, an interior structure, or a surface structure in the nanoscale range (approximately 1 nm to 100 nm) and (ii) whether a substance or finished product is developed to show characteristics or phenomena, such as physical or chemical characteristics or biological consequences, even if these dimensions fall beyond the nanoscale range, up to one micrometer (1000 nm) [285]. The FDA guideline, however, was released in 2014 and concluded that nanomaterials are not subject to premarket review but urged the industry to consult with the agency early in the product development process, leaving nanomaterials stranded with no regulations.
Canada’s regulations on environmental and health hazards are controlled by the Canadian Environmental Protection Act (CEPA), which put out regulatory parameters in 2013 on how to modify current risk assessment procedures considering the unique features shown by chemicals at the nanoscale in line with the Organization for Economic Co-operation and Development (OECD) proposal [287]. In the latest draft of June 2022, the CEPA proposed mediating NM risk in three appraisals: (i) substance identity, taking into account composition, shape, agglomeration, surface chemistry, dissolution in biological media, and any other specification that the material may possess according to the manufacturer; (ii) exposure assessment, be it direct contact or indirect contact (water, air, soil), and release potential or fragmentation; (iii) hazard assessment, considering toxicological endpoints such as acute toxicity, repeated-dose toxicity, genetic toxicity, reproductive or developmental toxicity, carcinogenicity, toxicokinetics, etc. The final step is the risk characterization, as determined by the points established in part 5, Section 64 of CEPA: (a) the material has or may have an immediate or long-term harmful effect on the environment or its biological diversity; (b) the material constitutes or may constitute a danger to the environment on which life depends; and (c) the material constitutes or may constitute a danger in Canada to human life or health.
It is well-known that MNPs have different properties than their counterparts on a macroscopic scale. Studies have been conducted to determine their toxicity in various body organs with multiple materials [289,290,291]. However, reported viability results on the same material in different tissues within the body have presented contradictory results depending on the type of tissue to which these materials were administrated [1,51,59,219,248,292,293,294], so their regulation must be specialized. Furthermore, it is marked correctly to prevent a significant effect on society and the environment [295].

5. Conclusions and Perspective

MNPs exhibit interesting novel properties due to their superparamagnetism, reduced size (10 nm), and versatility in forming functionalized composites that increase their applications as theranostics. However, these same problem-solving qualities can be responsible for causing possible adverse biological impacts in the future if they result in excessive and unregulated use. Different global initiatives have been launched to address this new branch called nanotoxicology and nanoethics. This must be considered when applying any NMs in any sector, not just MNPs, whether it is industry or medicine, to ensure the correct handling of the material and prevent other environmental and health problems due to the improper use of new versatile materials. However, the vast properties of NPs, even with the same composition, be it size, morphology, surface charge, magnetism, or general reactivity, present a problematic task ahead in mitigating NPs’ effects. Slowly but steadily, though, the regulations for MNPs are taking shape. Still, the interaction and pathways of NPs are yet to be uncovered. There is no comprehensive image of the toxicological impact of magnetic nanoparticles on biological cells. Even though the literature is full of extensive analyses of different biological systems discussing the toxicology aspects of MNPs used in biomedical applications, they give mixed and inconclusive results depending on the assay implemented to determine their biological effects with an exhaustive list of parameters. Narrowing this down to a consensus list would help to generate a consolidative framework for these biological behaviors to allow manageable future applications. Finally, using only one nanomaterial parameter in the same tissue to make a consensus on the adverse effects and impact of MNPs leads to unreliable results.

Author Contributions

Conceptualization, J.R.V.-O., C.G. and K.E.; investigation, J.R.V.-O.; resources, C.G. and K.E.; writing—original draft preparation, J.R.V.-O.; writing—review and editing, C.G. and K.E.; visualization, C.G. and K.E.; supervision, K.E.; project administration, C.G. and K.E.; funding acquisition, K.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Universidad Autónoma de Querétaro (FIN202116; FIN202106).

Data Availability Statement

Not applicable.

Acknowledgments

JRVO thanks CONACyT for the scholarship granted. KE thanks the engineering faculty at UAQ for the financial support given through the Attention to National Problems fund FI-UAQ FIN202116 and the Universidad Autónoma de Querétaro through the fund FONDEC-UAQ 2021FIN202106. All the images were created with BioRender.com (PG24DGDY7O; RY24DGDYA6; EC24DGDYC5; PU24DGDYEK).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Khan, I.; Saeed, K.; Khan, I. Nanoparticles: Properties, applications and toxicities. Arab. J. Chem. 2019, 12, 908–931. [Google Scholar] [CrossRef]
  2. Missaoui, W.N.; Arnold, R.D.; Cummings, B.S. Toxicological status of nanoparticles: What we know and what we don’t know. Chem. Biol. Interact. 2018, 295, 1–12. [Google Scholar] [CrossRef] [PubMed]
  3. Scarpelli, F.; Mastropietro, T.F.; Poerio, T.; Godbert, N. Mesoporous TiO2 Thin Films: State of the Art. Titan. Dioxide-Mater. A Sustain. Environ. 2018, 508, 135–142. [Google Scholar]
  4. Madkour, L.H. Environmental Impact of Nanotechnology and Novel Applications of Nano Materials and Nano Devices; Springer: Cham, Germany, 2019; Volume 116. [Google Scholar]
  5. Prabha, S.; Arya, G.; Chandra, R.; Ahmed, B.; Nimesh, S. Effect of size on biological properties of nanoparticles employed in gene delivery. Artif. Cells Nanomed. Biotechnol. 2016, 44, 83–91. [Google Scholar] [CrossRef]
  6. Gong, S.; Cheng, W. One-Dimensional Nanomaterials for Soft Electronics. Adv. Electron. Mater. 2017, 3, 1600314. [Google Scholar] [CrossRef]
  7. Navalón, S.; García, H. Nanoparticles for catalysis. Nanomaterials 2016, 6, 123. [Google Scholar] [CrossRef] [Green Version]
  8. Turci, F.; Pavan, C.; Leinardi, R.; Tomatis, M.; Pastero, L.; Garry, D.; Anguissola, S.; Lison, D.; Fubini, B. Revisiting the paradigm of silica pathogenicity with synthetic quartz crystals: The role of crystallinity and surface disorder. Part. Fibre Toxicol. 2016, 13, 1–12. [Google Scholar] [CrossRef] [Green Version]
  9. Selim, A.A.; Al-Sunaidi, A.; Tabet, N. Effect of the surface texture and crystallinity of ZnO nanoparticles on their toxicity. Mater. Sci. Eng. C 2012, 32, 2356–2360. [Google Scholar] [CrossRef]
  10. Usov, N.A.; Rytov, R.A.; Bautin, V.A. Properties of assembly of superparamagnetic nanoparticles in viscous liquid. Sci. Rep. 2021, 11, 1–11. [Google Scholar]
  11. Hu, M.; Butt, H.-J.; Landfester, K.; Bannwarth, M.B.; Wooh, S.; Thérien-Aubin, H. Shaping the Assembly of Superparamagnetic Nanoparticles. ACS Nano 2019, 13, 3015–3022. [Google Scholar] [CrossRef] [Green Version]
  12. Yin, X.; Russek, S.E.; Zabow, G.; Sun, F.; Mohapatra, J.; Keenan, K.E.; Boss, M.A.; Zeng, H.; Liu, J.P.; Viert, A.; et al. Large T 1 contrast enhancement using superparamagnetic nanoparticles in ultra-low field MRI. Sci. Rep. 2018, 8, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Szpak, A.; Fiejdasz, S.; Prendota, W.; Strączek, T.; Kapusta, C.; Szmyd, J.; Nowakowska, M.; Zapotoczny, S. T1–T2 Dual-modal MRI contrast agents based on superparamagnetic iron oxide nanoparticles with surface attached gadolinium complexes. J. Nanoparticle Res. 2014, 16, 1–11. [Google Scholar] [CrossRef] [PubMed]
  14. Gao, Y.; Shi, X.; Shen, M. Intelligent Design of Ultrasmall Iron Oxide Nanoparticle-Based Theranostics. ACS Appl. Mater. Interfaces 2021, 13, 45119–45129. [Google Scholar] [CrossRef] [PubMed]
  15. Chaves, N.L.; Estrela-Lopis, I.; Böttner, J.; Lopes, C.A.P.; Guido, B.C.; de Souza, A.R.; Báo, S.N. Exploring cellular uptake of iron oxide nanoparticles associated with rhodium citrate in breast cancer cells. Int. J. Nanomed. 2017, 12, 5511–5523. [Google Scholar] [CrossRef] [Green Version]
  16. Shrestha, S.; Wang, B.; Dutta, P. Nanoparticle processing: Understanding and controlling aggregation. Adv. Colloid Interface Sci. 2020, 279, 102162. [Google Scholar] [CrossRef]
  17. Kendall, M.; Ding, P.; Kendall, K. Particle and nanoparticle interactions with fibrinogen: The importance of aggregation in nanotoxicology. Nanotoxicology 2010, 5, 55–65. [Google Scholar] [CrossRef]
  18. Babakhani, P. The impact of nanoparticle aggregation on their size exclusion during transport in porous media: One- and three-dimensional modelling investigations. Sci. Rep. 2019, 9, 1–12. [Google Scholar] [CrossRef] [Green Version]
  19. Ashraf, M.A.; Peng, W.; Zare, Y.; Rhee, K.Y. Effects of Size and Aggregation/Agglomeration of Nanoparticles on the Interfacial/Interphase Properties and Tensile Strength of Polymer Nanocomposites. Nanoscale Res. Lett. 2018, 13, 1–7. [Google Scholar] [CrossRef]
  20. Bahadar, H.; Maqbool, F.; Niaz, K.; Abdollahi, M. Toxicity of Nanoparticles and an Overview of Current Experimental Models. Iran. Biomed. J. 2016, 20, 1–11. [Google Scholar]
  21. Magdolenova, Z.; Collins, A.; Kumar, A.; Dhawan, A.; Stone, V.; Dusinska, M. Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles. Nanotoxicology 2014, 8, 233–278. [Google Scholar] [CrossRef]
  22. Sun, D.; Gong, L.; Xie, J.; Gu, X.; Li, Y.; Cao, Q.; Li, Q.; Luodan, A.; Gu, Z.; Xu, H. Toxicity of silicon dioxide nanoparticles with varying sizes on the cornea and protein corona as a strategy for therapy. Sci. Bull. 2018, 63, 907–916. [Google Scholar] [CrossRef] [Green Version]
  23. Pope, C.A.; Cohen, A.J.; Burnett, R.T. Cardiovascular disease and fine particulate matter lessons and limitations of an integrated exposure-response approach. Circ. Res. 2018, 122, 1645–1647. [Google Scholar] [CrossRef] [PubMed]
  24. United States Environmental Protection Agency. Particle Pollution and Cardiovascular Effects. 2021. Available online: https://www.epa.gov/pmcourse/particle-pollution-and-cardiovascular-effects (accessed on 24 February 2022).
  25. Schulz, H.; Harder, V.; Ibald-Mulli, A.; Khandoga, A.; Koenig, W.; Krombach, F.; Radykewicz, R.; Stampfl, A.; Thorand, B.; Peters, A. Cardiovascular Effects of Fine and Ultrafine Particles. J. Aerosol Med. 2005, 18, 1–22. [Google Scholar] [CrossRef] [PubMed]
  26. Hoshyar, N.; Gray, S.; Han, H.; Bao, G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine 2016, 11, 673–692. [Google Scholar] [CrossRef] [Green Version]
  27. Savliwala, S.; Chiu-Lam, A.; Unni, M.; Rivera-Rodriguez, A.; Fuller, E.; Sen, K.; Threadcraft, M.; Rinaldi, C. Magnetic Nanoparticles; Elsevier Inc.: Amsterdam, The Netherlands, 2019. [Google Scholar]
  28. FDA. Information on Gadolinium-Based Contrast Agents Regulatory History and Labeling from Drugs @ FDA; FDA: Silver Spring, MD, USA, 2017. [Google Scholar]
  29. Xiao, Y.-D.; Paudel, R.; Liu, J.; Ma, C.; Zhang, Z.-S.; Zhou, S.-K. MRI contrast agents: Classification and application (Review). Int. J. Mol. Med. 2016, 38, 1319–1326. [Google Scholar] [CrossRef] [Green Version]
  30. Zhen, Z.; Xie, J. Development of Manganese-Based Nanoparticles as Contrast Probes for Magnetic Resonance Imaging. Theranostics 2012, 2, 45–54. [Google Scholar] [CrossRef]
  31. De León-Rodríguez, L.M.; Martins, A.F.; Pinho, M.C.; Rofsky, N.M.; Sherry, A.D. Basic MR relaxation mechanisms and contrast agent design. J. Magn. Reson. Imaging 2015, 42, 545–565. [Google Scholar] [CrossRef] [Green Version]
  32. Neeley, C.; Moritz, M.; Brown, J.J.; Zhou, Y. Acute side effects of three commonly used gadolinium contrast agents in the paediatric population. Br. J. Radiol. 2016, 89, 20160027. [Google Scholar] [CrossRef] [Green Version]
  33. Watson, A.D. The use of gadolinium and dysprosium chelate complexes as contrast agents for magnetic resonance imaging This substituent group is believed to provide the required. J. Alloy. Compd. 1994, 207, 14–19. [Google Scholar] [CrossRef]
  34. Norek, M.; Peters, J.A. MRI contrast agents based on dysprosium or holmium. Prog. Nucl. Magn. Reson. Spectrosc. 2011, 59, 64–82. [Google Scholar] [CrossRef]
  35. Urian, Y.; Atoche-Medrano, J.; Quispe, L.T.; Félix, L.L.; Coaquira, J. Study of the surface properties and particle-particle interactions in oleic acid-coated Fe3O4 nanoparticles. J. Magn. Magn. Mater. 2021, 525, 167686. [Google Scholar] [CrossRef]
  36. Kaur, I.P.; Kakkar, V.; Deol, P.K.; Yadav, M.; Singh, M.; Sharma, I. Issues and concerns in nanotech product development and its commercialization. J. Control Release 2014, 193, 51–62. [Google Scholar] [CrossRef] [PubMed]
  37. Deng, L.; Liu, Z.; Li, L. Hybrid nanocomposites for imaging-guided synergistic theranostics. In Nanomaterials for Drug Delivery and Therapy; Elsevier Inc.: Amsterdam, The Netherlands, 2019; pp. 117–147. [Google Scholar]
  38. Oliveira, E.; Rocha, M.; Froner, A.P.; Basso, N.; Zanini, M.; Papaléo, R. Synthesis and nuclear magnetic relaxation properties of composite iron oxide nanoparticles. Quim. Nova 2018, 42, 57–64. [Google Scholar] [CrossRef]
  39. Williams, H.M. The application of magnetic nanoparticles in the treatment and monitoring of cancer and infectious diseases. Biosci. Horizons 2017, 10, 1–10. [Google Scholar] [CrossRef] [Green Version]
  40. Lamon, L.; Asturiol, D.; Richarz, A.; Joossens, E.; Graepel, R.; Aschberger, K.; Worth, A. Grouping of nanomaterials to read-across hazard endpoints: From data collection to assessment of the grouping hypothesis by application of chemoinformatic techniques. Part. Fibre Toxicol. 2018, 15, 1–17. [Google Scholar] [CrossRef]
  41. Hensley, D.; Tay, Z.W.; Dhavalikar, R.; Zheng, B.; Goodwill, P.; Rinaldi, C.; Conolly, S. Combining magnetic particle imaging and magnetic fluid hyperthermia in a theranostic platform. Phys. Med. Biol. 2017, 62, 3483–3500. [Google Scholar] [CrossRef] [Green Version]
  42. Hapuarachchige, S.; Artemov, D. Theranostic Pretargeting Drug Delivery and Imaging Platforms in Cancer Precision Medicine. Front. Oncol. 2020, 10, 1131. [Google Scholar] [CrossRef]
  43. Thorat, N.D.; Lemine, O.M.; Bohara, R.A.; Omri, K.; El Mir, L.; Tofail, S.A.M. Superparamagnetic iron oxide nanocargoes for combined cancer thermotherapy and MRI applications. Phys. Chem. Chem. Phys. 2016, 18, 21331–21339. [Google Scholar] [CrossRef]
  44. Siddhardha, B.; Parasuraman, P. Theranostics application of nanomedicine in cancer detection and treatment. In Nanomaterials for Drug Delivery and Therapy; Elsevier Inc.: Amsterdam, The Netherlands, 2019; pp. 59–89. [Google Scholar]
  45. Kosuda, K.M.; Bingham, J.M.; Wustholz, K.L.; Van Duyne, R.P. Nanostructures and Surface-Enhanced Raman Spectroscopy. In Handbook of Nanoscale Optics and Electronicsvol; Elsevier Ltd.: Amsterdam, The Netherlands, 2010; Volume 1–5. [Google Scholar]
  46. Morcos, B.; Lecante, P.; Morel, R.; Haumesser, P.H.; Santini, C.C. Magnetic, structural and chemical properties of cobalt nanoparticles synthesized in ionic liquids Bishoy. Langmuir 2018, 34, 7086–7095. [Google Scholar] [CrossRef]
  47. Ahghari, M.R.; Soltaninejad, V.; Maleki, A. Synthesis of nickel nanoparticles by a green and convenient method as a magnetic mirror with antibacterial activities. Sci. Rep. 2020, 10, 1–10. [Google Scholar] [CrossRef]
  48. Malhotra, N.; Lee, J.-S.; Liman, R.A.D.; Ruallo, J.M.S.; Villaflores, O.B.; Ger, T.-R.; Hsiao, C.-D. Potential Toxicity of Iron Oxide Magnetic Nanoparticles: A Review. Molecules 2020, 25, 3159. [Google Scholar] [CrossRef] [PubMed]
  49. Patsula, V.; Tulinska, J.; Trachtová, Š.; Kuricova, M.; Liskova, A.; Španová, A.; Ciampor, F.; Vavra, I.; Rittich, B.; Ursinyova, M. Toxicity evaluation of monodisperse PEGylated magnetic nanoparticles for nanomedicine. Nanotoxicology 2019, 13, 510–526. [Google Scholar] [CrossRef] [PubMed]
  50. Genevière, A.-M.; Derelle, E.; Escande, M.-L.; Grimsley, N.; Klopp, C.; Ménager, C.; Michel, A.; Moreau, H. Responses to iron oxide and zinc oxide nanoparticles in echinoderm embryos and microalgae: Uptake, growth, morphology, and transcriptomic analysis. Nanotoxicology 2020, 14, 1342–1361. [Google Scholar] [CrossRef]
  51. Guggenheim, E.J.; Rappoport, J.Z.; Lynch, I. Mechanisms for cellular uptake of nanosized clinical MRI contrast agents. Nanotoxicology 2020, 14, 504–532. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Feng, Q.; Liu, Y.; Huang, J.; Chen, K.; Huang, J.; Xiao, K. Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings. Sci. Rep. 2018, 8, 1–13. [Google Scholar] [CrossRef] [Green Version]
  53. Zhao, J.; Brugger, J.; Pring, A. Mechanism and kinetics of hydrothermal replacement of magnetite by hematite. Geosci. Front. 2019, 10, 29–41. [Google Scholar] [CrossRef]
  54. Qiu, T.-S.; Fang, X.-H.; Wu, H.-Q.; Zeng, Q.-H.; Zhu, D.-M. Leaching behaviors of iron and aluminum elements of ion-absorbed-rare-earth ore with a new impurity depressant. Trans. Nonferrous Met. Soc. China 2014, 24, 2986–2990. [Google Scholar] [CrossRef]
  55. Strasser, H.; Brunner, H.; Schinner, F. Leaching of iron and toxic heavy metals from anaerobically-digested sewage sludge. J. Ind. Microbiol. Biotechnol. 1995, 14, 281–287. [Google Scholar] [CrossRef]
  56. Polasky, C.; Studt, T.; Steuer, A.-K.; Loyal, K.; Lüdtke-Buzug, K.; Bruchhage, K.-L.; Pries, R. Impact of Superparamagnetic Iron Oxide Nanoparticles on THP-1 Monocytes and Monocyte-Derived Macrophages. Front. Mol. Biosci. 2022, 9. [Google Scholar] [CrossRef]
  57. Singh, N.; Jenkins, G.J.; Asadi, R.; Doak, S.H. Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev. 2010, 1, 5358. [Google Scholar] [CrossRef] [Green Version]
  58. Du, S.; Li, J.; Du, C.; Huang, Z.; Chen, G.; Yan, W. Overendocytosis of superparamagnetic iron oxide particles increases apoptosis and triggers autophagic cell death in human osteosarcoma cell under a spinning magnetic field. Oncotarget 2016, 8, 9410–9424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Patil, R.M.; Thorat, N.D.; Shete, P.B.; Bedge, P.A.; Gavde, S.; Joshi, M.G.; Tofail, S.A.; Bohara, R.A. Comprehensive cytotoxicity studies of superparamagnetic iron oxide nanoparticles. Biochem. Biophys. Rep. 2018, 13, 63–72. [Google Scholar] [CrossRef] [PubMed]
  60. Jiang, P.; Gan, M.; Yen, S.-H.; Dickson, D.W. Nanoparticles With Affinity for α-Synuclein Sequester α-Synuclein to Form Toxic Aggregates in Neurons With Endolysosomal Impairment. Front. Mol. Neurosci. 2021, 14, 1–14. [Google Scholar] [CrossRef]
  61. Shukla, R.K.; Badiye, A.; Vajpayee, K.; Kapoor, N. Genotoxic Potential of Nanoparticles: Structural and Functional Modifications in DNA. Front. Genet. 2021, 12, 1–16. [Google Scholar] [CrossRef] [PubMed]
  62. Russell, E.; Dunne, V.; Russell, B.; Mohamud, H.; Ghita, M.; McMahon, S.J.; Butterworth, K.T.; Schettino, G.; McGrry, C.K.; Prise, K.M. Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells. Radiat. Oncol. 2021, 16, 1–16. [Google Scholar] [CrossRef] [PubMed]
  63. Cellai, F.; Munnia, A.; Viti, J.; Doumett, S.; Ravagli, C.; Ceni, E.; Mello, T.; Polvani, S.; Giese, R.W.; Baldi, G.; et al. Magnetic Hyperthermia and Oxidative Damage to DNA of Human Hepatocarcinoma Cells. Int. J. Mol. Sci. 2017, 18, 939. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Döpke, C.; Grothe, T.; Steblinski, P.; Klöcker, M.; Sabantina, L.; Kosmalska, D.; Blachowicz, T.; Ehrmann, A. Magnetic Nanofiber Mats for Data Storage and Transfer. Nanomaterials 2019, 9, 92. [Google Scholar] [CrossRef] [Green Version]
  65. Grothe, T.; Sabantina, L.; Klöcker, M.; Junger, I.J.; Döpke, C.; Ehrmann, A. Wet Relaxation of Electrospun Nanofiber Mats. Technologies 2019, 7, 23. [Google Scholar] [CrossRef] [Green Version]
  66. Papavasileiou, A.; Panagiotopoulos, I.; Prodromidis, M.I. All-screen-printed graphite sensors integrating permanent bonded magnets. Fabrication, characterization and analytical utility. Electrochimica Acta 2020, 360, 136981. [Google Scholar] [CrossRef]
  67. Verma, S.; Kumar, V.; Gupta, K.D. Performance analysis of flexible multirecess hydrostatic journal bearing operating with micropolar lubricant. Lubr. Sci. 2012, 24, 273–292. [Google Scholar] [CrossRef]
  68. Shahidi, S. Magnetic nanoparticles application in the textile industry—A review. J. Ind. Text. 2019, 50, 970–989. [Google Scholar] [CrossRef]
  69. Bustamante-Torres, M.; Romero-Fierro, D.; Arcentales-Vera, B.; Pardo, S.; Bucio, E. Interaction between Filler and Polymeric Matrix in Nanocomposites: Magnetic Approach and Applications. Polymers 2021, 13, 2998. [Google Scholar] [CrossRef] [PubMed]
  70. Coutinho, M.; Miranda, J.A. Peak instability in an elastic interface ferrofluid. Phys. Fluids 2020, 32, 5. [Google Scholar] [CrossRef]
  71. Peyghami, A.; Moharrami, A.; Rashtbari, Y.; Afshin, S.; Vosuoghi, M.; Dargahi, A. Evaluation of the efficiency of magnetized clinoptilolite zeolite with Fe3O4 nanoparticles on the removal of basic violet 16 (BV16) dye from aqueous solutions. J. Dispers. Sci. Technol. 2021, 1–10. [Google Scholar] [CrossRef]
  72. Dargahi, A.; Hasani, K.; Mokhtari, S.A.; Vosoughi, M.; Moradi, M.; Vaziri, Y. Highly effective degradation of 2,4-Dichlorophenoxyacetic acid herbicide in a three-dimensional sono-electro-Fenton (3D/SEF) system using powder activated carbon (PAC)/Fe3O4 as magnetic particle electrode. J. Environ. Chem. Eng. 2021, 9, 105889. [Google Scholar] [CrossRef]
  73. Seidmohammadi, A.; Vaziri, Y.; Dargahi, A.; Nasab, H.Z. Improved degradation of metronidazole in a heterogeneous photo-Fenton oxidation system with PAC/Fe3O4 magnetic catalyst: Biodegradability, catalyst specifications, process optimization, and degradation pathway. Biomass Convers. Biorefinery 2021, 1–17. [Google Scholar] [CrossRef]
  74. Seabra, A.B.; Pelegrino, M.T.; Haddad, P.S. Antimicrobial Applications of Superparamagnetic Iron Oxide Nanoparticles: Perspectives and Challenges; Elsevier Inc.: Amsterdam, The Netherlands, 2017. [Google Scholar]
  75. Blachowicz, T.; Ehrmann, A. Magnetization reversal in bent nanofibers of different cross sections. J. Appl. Phys. 2018, 124, 152112. [Google Scholar] [CrossRef] [Green Version]
  76. Chaparro, C.M.; Suchdev, P.S. Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries. Ann. N. Y. Acad. Sci. 2019, 1450, 15–31. [Google Scholar] [CrossRef] [Green Version]
  77. Elshemy, M.A. Iron Oxide Nanoparticles Versus Ferrous Sulfate In Treatment of Iron Deficiency Anemia In Rats. Egypt. J. Vet. Sci. 2018, 49, 103–109. [Google Scholar] [CrossRef]
  78. Wang, A.; Bagalkot, V.; Vasilliou, C.C.; Gu, F.; Alexis, F.; Zhang, L.; Shaikh, M.; Yuet, K.; Cima, M.J.; Langer, R.; et al. Superparamagnetic Iron Oxide Nanoparticle-Aptamer Bioconjugates for Combined Prostate Cancer Imaging and Therapy. ChemMedChem 2008, 3, 1311–1315. [Google Scholar] [CrossRef]
  79. Harrison, R.J.; Dunin-Borkowski, R.E.; Putnis, A. Direct imaging of nanoscale magnetic interactions in minerals. Proc. Natl. Acad. Sci. USA 2002, 99, 16556–16561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Wáng, Y.X.J.; Idée, J.M. A comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging. Quant. Imaging Med. Surg. 2017, 7, 88–122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Thorat, N.D.; Bohara, R.A.; Malgras, V.; Tofail, S.A.M.; Ahamad, T.; Alshehri, S.M.; Wu, K.C.-W.; Yamauchi, Y. Multimodal Superparamagnetic Nanoparticles with Unusually Enhanced Specific Absorption Rate for Synergetic Cancer Therapeutics and Magnetic Resonance Imaging. ACS Appl. Mater. Interfaces 2016, 8, 14656–14664. [Google Scholar] [CrossRef]
  82. Jouyandeh, M.; Paran, S.M.R.; Shabanian, M.; Ghiyasi, S.; Vahabi, H.; Badawi, M.; Formela, K.; Puglia, D.; Saeb, M.R. Curing behavior of epoxy/Fe3O4nanocomposites: A comparison between the effects of bare Fe3O4, Fe3O4/SiO2/chitosan and Fe3O4/SiO2/chitosan/imide/phenylalanine-modified nanofillers. Prog. Org. Coat. 2018, 123, 10–19. [Google Scholar] [CrossRef]
  83. Darwish, M.; Kim, H.; Bui, M.; Le, T.-A.; Lee, H.; Ryu, C.; Lee, J.; Yoon, J. The Heating Efficiency and Imaging Performance of Magnesium Iron Oxide@tetramethyl Ammonium Hydroxide Nanoparticles for Biomedical Applications. Nanomaterials 2021, 11, 1096. [Google Scholar] [CrossRef] [PubMed]
  84. Stueber, D.; Villanova, J.; Aponte, I.; Xiao, Z.; Colvin, V. Magnetic Nanoparticles in Biology and Medicine: Past, Present, and Future Trends. Pharmaceutics 2021, 13, 943. [Google Scholar] [CrossRef]
  85. Xu, L.; Zhong, S.; Shi, C.; Sun, Y.; Zhao, S.; Gao, Y.; Cui, X. Sonochemical fabrication of reduction-responsive magnetic starch-based microcapsules. Ultrason. Sonochem. 2018, 49, 169–174. [Google Scholar] [CrossRef]
  86. Kunrath, M.F.; Campos, M.M. Metallic-nanoparticle release systems for biomedical implant surfaces: Effectiveness and safety. Nanotoxicology 2021, 15, 721–739. [Google Scholar] [CrossRef]
  87. Hu, T.; Mei, X.; Wang, Y.; Weng, X.; Liang, R.; Wei, M. Two-dimensional nanomaterials: Fascinating materials in biomedical field. Sci. Bull. 2019, 64, 1707–1727. [Google Scholar] [CrossRef] [Green Version]
  88. Gualdani, R.; Guerrini, A.; Fantechi, E.; Tadini-Buoninsegni, F.; Moncelli, M.R.; Sangregorio, C. Superparamagnetic iron oxide nanoparticles (SPIONs) modulate hERG ion channel activity. Nanotoxicology 2019, 13, 1197–1209. [Google Scholar] [CrossRef]
  89. Tian, F.; Chen, G.; Yi, P.; Zhang, J.; Li, A.; Zhang, J.; Zheng, L.; Deng, Z.; Shi, Q.; Peng, R.; et al. Fates of Fe3O4 and Fe3O4@SiO2 nanoparticles in human mesenchymal stem cells assessed by synchrotron radiation-based techniques. Biomaterials 2014, 35, 6412–6421. [Google Scholar] [CrossRef] [PubMed]
  90. Carmona-Carmona, A.J.; Palomino-Ovando, M.A.; Hernández-Cristobal, O.; Sánchez-Mora, E.; Toledo-Solano, M. Synthesis and characterization of magnetic opal/Fe3O4 colloidal crystal. J. Cryst. Growth 2017, 462, 6–11. [Google Scholar] [CrossRef]
  91. Awada, H.; Al Samad, A.; Laurencin, D.; Gilbert, R.; Dumail, X.; El Jundi, A.; Bethry, A.; Pomrenke, R.; Johnson, C.; Lemaire, L.; et al. Controlled Anchoring of Iron Oxide Nanoparticles on Polymeric Nanofibers: Easy Access to Core@Shell Organic–Inorganic Nanocomposites for Magneto-Scaffolds. ACS Appl. Mater. Interfaces 2019, 11, 9519–9529. [Google Scholar] [CrossRef]
  92. Yazid, N.A.; Joon, Y.C. Co-precipitation synthesis of magnetic nanoparticles for efficient removal of heavy metal from synthetic wastewater Co-precipitation Synthesis of Magnetic Nanoparticles for Efficient Removal of Heavy Metal from Synthetic Wastewater. In AIP Conference Proceedings; AIP Publishing LLC: Melville, NY, USA, 2019; Volume 2124, p. 020019. [Google Scholar]
  93. Daoush, W.M. Co-Precipitation and Magnetic Properties of Magnetite Nanoparticles for Potential Biomedical Applications. J. Nanomed. Res. 2017, 5, 1–6. [Google Scholar] [CrossRef]
  94. Mohammadi, H.; Nekobahr, E.; Akhtari, J.; Saeedi, M.; Akbari, J.; Fathi, F. Synthesis and characterization of magnetite nanoparticles by co-precipitation method coated with biocompatible compounds and evaluation of in-vitro cytotoxicity. Toxicol. Rep. 2021, 8, 331–336. [Google Scholar] [CrossRef] [PubMed]
  95. Cotin, G.; Kiefer, C.; Perton, F.; Ihiawakrim, D.; Blanco-Andujar, C.; Moldovan, S.; Lefevre, C.; Ersen, O.; Pichon, B.; Mertz, D.; et al. Unravelling the Thermal Decomposition Parameters for The Synthesis of Anisotropic Iron Oxide Nanoparticles. Nanomaterials 2018, 8, 881. [Google Scholar] [CrossRef] [Green Version]
  96. Unni, M.; Uhl, A.M.; Savliwala, S.; Savitzky, B.H.; Dhavalikar, R.; Garraud, N.; Arnold, D.P.; Kourkoutis, L.F.; Andrew, J.S.; Rinaldi, C. Thermal Decomposition Synthesis of Iron Oxide Nanoparticles with Diminished Magnetic Dead Layer by Controlled Addition of Oxygen. ACS Nano 2017, 11, 2284–2303. [Google Scholar] [CrossRef]
  97. Lassenberger, A.; Grünewald, T.A.; van Oostrum, P.D.J.; Rennhofer, H.; Amenitsch, H.; Zirbs, R.; Lichtenegger, H.C.; Reimhult, E. Monodisperse Iron Oxide Nanoparticles by Thermal Decomposition: Elucidating Particle Formation by Second-Resolved in Situ Small-Angle X-ray Scattering. Chem. Mater. 2017, 29, 4511–4522. [Google Scholar] [CrossRef] [Green Version]
  98. Torres-Gómez, N.; Nava, O.; Argueta-Figueroa, L.; García-Contreras, R.; Baeza-Barrera, A.; Vilchis-Nestor, A.R. Shape tuning of magnetite nanoparticles obtained by hydrothermal synthesis: Effect of temperature. J. Nanomater. 2019, 1–15. [Google Scholar] [CrossRef] [Green Version]
  99. Ansar, M.Z.; Atiq, S.; Riaz, S.; Naseem, S. Magnetite Nano-crystallites for Anti-cancer Drug Delivery. Mater. Today Proc. 2015, 2, 5410–5414. [Google Scholar] [CrossRef]
  100. Sharafi, Z.; Bakhshi, B.; Javidi, J.; Adrangi, S. Synthesis of Silica-coated Iron Oxide Nanoparticles: Preventing Aggregation without Using Additives or Seed Pretreatment. Iran. J. Pharm. Res. IJPR 2018, 17, 386–395. [Google Scholar] [PubMed]
  101. Omelyanchik, A.; Salvador, M.; D’orazio, F.; Mameli, V.; Cannas, C.; Fiorani, D.; Musinu, A.; Rivas, M.; Rodionova, V.; Varvaro, G.; et al. Magnetocrystalline and surface anisotropy in cofe2o4 nanoparticles. Nanomaterials 2020, 10, 1288. [Google Scholar] [CrossRef]
  102. Na, K.-H.; Kim, W.-T.; Park, D.-C.; Shin, H.-G.; Lee, S.-H.; Park, J.; Song, T.-H.; Choi, W.-Y. Fabrication and characterization of the magnetic ferrite nanofibers by electrospinning process. Thin Solid Film 2018, 660, 358–364. [Google Scholar] [CrossRef]
  103. Rajarao, G.K.; Lakshmanan, R.; Okoli, C.; Boutonnet, M.; Ja, S. Microemulsion prepared magnetic nanoparticles for phosphate removal: Time efficient studies. J. Environ. Chem. Eng. 2014, 2, 185–189. [Google Scholar]
  104. Kekalo, K.; Koo, K.; Zeitchick, E.; Baker, I. Microemulsion Synthesis of Iron Core/Iron Oxide Shell Magnetic Nanoparticles and Their Physicochemical Properties. MRS Proc. 2012, 1416, 9–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Salvador, M.; Gutiérrez, G.; Noriega, S.; Moyano, A.; Blanco-López, M.C.; Matos, M. Microemulsion Synthesis of Superparamagnetic Nanoparticles for Bioapplications. Int. J. Mol. Sci. 2021, 22, 427. [Google Scholar] [CrossRef]
  106. Wang, Y.; Nkurikiyimfura, I.; Pan, Z. Sonochemical Synthesis of Magnetic Nanoparticles. Chem. Eng. Commun. 2014, 202, 616–621. [Google Scholar] [CrossRef]
  107. Fuentes-garc, A.; Alavarse, A.C.; Carolina, A.; Maldonado, M.; Ibarra, M.R.; Fabia, G. Simple Sonochemical Method to Optimize the Heating E ffi ciency of Magnetic Nanoparticles for Magnetic Fluid Hyperthermia. ACS Omega 2020, 5, 26357–26364. [Google Scholar] [CrossRef]
  108. Holland, H.; Yamaura, M. Synthesis of Magnetite Nanoparticles by Microwave Irradiation and Characterization. In Proceedings of the Conference: International Latin-American Conference on Powder Technology, Atibaia, Brazil, 8–10 November 2009; pp. 434–442. [Google Scholar]
  109. Aivazoglou, E.; Metaxa, E.; Hristoforou, E. Microwave-assisted synthesis of iron oxide nanoparticles in biocompatible organic environment. AIP Adv. 2018, 8, 048201. [Google Scholar] [CrossRef] [Green Version]
  110. Khan, A.A.; Khan, S.; Khan, S.; Rentschler, S.; Laufer, S.; Deigner, H.-P. Biosynthesis of iron oxide magnetic nanoparticles using clinically isolated Pseudomonas aeruginosa. Sci. Rep. 2021, 11, 1–10. [Google Scholar] [CrossRef] [PubMed]
  111. Elblbesy, M.A.; Madbouly, A.K.; Hamdan, T.A. Bio-synthesis of magnetite nanoparticles by bacteria. Am. J. Nano Res. Appl. 2014, 2, 98–103. [Google Scholar]
  112. Balakrishnan, G.S.; Rajendran, K.; Kalirajan, J. Microbial synthesis of magnetite nanoparticles for arsenic removal. J. Appl. Biol. Biotechnol. 2020, 8, 70–75. [Google Scholar]
  113. Lina, S.; Tejeda-benitez, L.; Hinestroza, J.; Pati, D.; Herrera, A. Green synthesis of iron oxide nanoparticles using Cymbopogon citratus extract and sodium carbonate salt: Nanotoxicological considerations for potential environmental applications. Environ. Nanotechnol. Monit. Manag. 2020, 14, 100377. [Google Scholar]
  114. Kiwumulo, H.F.; Muwonge, H.; Ibingira, C.; Lubwama, M.; Kirabira, J.B.; Ssekitoleko, R.T. Green synthesis and characterization of iron-oxide nanoparticles using Moringa oleifera: A potential protocol for use in low and middle income countries. BMC Res. Notes 2022, 15, 1–8. [Google Scholar] [CrossRef] [PubMed]
  115. Bhuiyan, M.S.H.; Miah, M.Y.; Paul, S.C.; Aka, T.D.; Saha, O.; Rahaman, M.M.; Sharif, M.J.I.; Habiba, O.; Ashaduzzaman, M. Green synthesis of iron oxide nanoparticle using Carica papaya leaf extract: Application for photocatalytic degradation of remazol yellow RR dye and antibacterial activity. Heliyon 2020, 6, e04603. [Google Scholar] [CrossRef]
  116. Wu, W.; Wu, Z.; Yu, T.; Jiang, C.; Kim, W.-S. Recent progress on magnetic iron oxide nanoparticles: Synthesis, surface functional strategies and biomedical applications. Sci. Technol. Adv. Mater. 2015, 16, 023501. [Google Scholar] [CrossRef] [PubMed]
  117. Schwaminger, S.; Syhr, C.; Berensmeier, S. Controlled Synthesis of Magnetic Iron Oxide Nanoparticles: Magnetite or Maghemite? Crystals 2020, 10, 214. [Google Scholar] [CrossRef]
  118. Iconaru, S.L.; Guégan, R.; Popa, C.L.; Motelica-Heino, M.; Ciobanu, C.S.; Predoi, D. Magnetite (Fe3O4) nanoparticles as adsorbents for As and Cu removal. Appl. Clay Sci. 2016, 134, 128–135. [Google Scholar] [CrossRef]
  119. Klencsár, Z.; Ábrahám, A.; Szabó, L.; Szabó, E.G.; Stichleutner, S.; Kuzmann, E.; Homonnay, Z.; Tolnai, G. The effect of preparation conditions on magnetite nanoparticles obtained via chemical co-precipitation. Mater. Chem. Phys. 2018, 223, 122–132. [Google Scholar] [CrossRef]
  120. Darwish, M.S.A.; Kim, H.; Lee, H.; Ryu, C.; Yoon, J. Synthesis of Magnetic Ferrite Nanoparticles with High Hyperthermia Performance via a Controlled Co-Precipitation Method. Nanomaterials 2019, 9, 1176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Maity, D.; Ding, J.; Xue, J.-M. Synthesis Of Magnetite Nanoparticles By Thermal Decomposition: Time, Temperature, Surfactant And Solvent Effects. Funct. Mater. Lett. 2008, 1, 189–193. [Google Scholar] [CrossRef]
  122. Vangijzegem, T.; Stanicki, D.; Panepinto, A.; Socoliuc, V.; Vekas, L.; Muller, R.N.; Laurent, S. Influence of Experimental Parameters of a Continuous Flow Process on the Properties of Very Small Iron Oxide Nanoparticles (VSION) Designed for T1-Weighted Magnetic Resonance Imaging (MRI). Nanomaterials 2020, 10, 757. [Google Scholar] [CrossRef] [Green Version]
  123. Mourdikoudis, S.; Menelaou, M.; Fiuza-Maneiro, N.; Zheng, G.; Wei, S.; Pérez-Juste, J.; Polavarapu, L.; Sofer, Z. Oleic acid/oleylamine ligand pair: A versatile combination in the synthesis of colloidal nanoparticles. Nanoscale Horiz. 2022, 7, 941–1015. [Google Scholar] [CrossRef] [PubMed]
  124. Hydrothermal Synthesis Method for Nanoparticle Synthesis—Techinstro. Available online: https://www.techinstro.com/hydrothermal-synthesis-method-for-nanoparticle-synthesis/ (accessed on 23 February 2022).
  125. Gan, Y.X.; Jayatissa, A.H.; Yu, Z.; Chen, X.; Li, M. Hydrothermal Synthesis of Nanomaterials. J. Nanomater. 2020, 2020, 1–3. [Google Scholar] [CrossRef] [Green Version]
  126. Darr, J.A.; Zhang, J.; Makwana, N.M.; Weng, X. Continuous Hydrothermal Synthesis of Inorganic Nanoparticles: Applications and Future Directions. Chem. Rev. 2017, 117, 11125–11238. [Google Scholar] [CrossRef] [Green Version]
  127. Hyun, J.; Osman, I.; Saadullah, G. Magnetite Fe3O4 (111) Surfaces: Impact of Defects on Structure, Stability, and Electronic Properties. Chem. Mater. 2015, 27, 5856–5867. [Google Scholar]
  128. Richard, B.; Lemyre, J.-L.; Ritcey, A.M. Nanoparticle Size Control in Microemulsion Synthesis. Langmuir 2017, 33, 4748–4757. [Google Scholar] [CrossRef]
  129. Kimura, K. Magnetic Properties of Magnetite Ultrafine Particles Prepared by W/O Microemulsion Method. Jpn. J. Appl. Phys. 1987, 26, 713. [Google Scholar]
  130. Gautam, R.K.; Chattopadhyaya, M.C. Functionalized Magnetic Nanoparticles: Adsorbents and Applications BT—Nanomaterials for Wastewater Remediation. In Nanomater. Wastewater Remediat; Elsevier Inc.: Amsterdam, The Netherlands, 2016; pp. 139–159. [Google Scholar]
  131. Singla, R.; Grieser, F.; Ashokkumar, M. Kinetics and Mechanism for the Sonochemical Degradation of a Nonionic Surfactant. J. Phys. Chem. A 2009, 113, 2865–2872. [Google Scholar] [CrossRef]
  132. Liu, H.; Ji, S.; Yang, H.; Zhang, H.; Tang, M. Ultrasonic-assisted ultra-rapid synthesis of monodisperse meso-SiO2@Fe3O4 microspheres with enhanced mesoporous structure. Ultrason. Sonochem. 2014, 21, 505–512. [Google Scholar] [CrossRef] [PubMed]
  133. Perelshtein, I.; Perkas, N.; Gedanken, A. The Sonochemical Functionalization of Textiles; Elsevier Ltd.: Amsterdam, The Netherlands, 2018; pp. 161–198. [Google Scholar]
  134. Choi, J.; Khim, J.; Neppolian, B.; Son, Y. Enhancement of sonochemical oxidation reactions using air sparging in a 36 kHz sonoreactor. Ultrason. Sonochemistry 2018, 51, 412–418. [Google Scholar] [CrossRef] [PubMed]
  135. Ruan, Q.; Zhu, Y.; Zeng, Y.; Qian, H.; Xiao, J.; Xu, F.; Zhang, L.; Zhao, D. Ultrasonic-Irradiation-Assisted Oriented Assembly of Ordered Monetite Nanosheets Stacking. J. Phys. Chem. B 2009, 113, 1100–1106. [Google Scholar] [CrossRef] [PubMed]
  136. Chikan, V.; McLaurin, E.J. Rapid Nanoparticle Synthesis by Magnetic and Microwave Heating. Nanomaterials 2016, 6, 85. [Google Scholar] [CrossRef] [Green Version]
  137. Yang, G.; Park, S.-J. Conventional and Microwave Hydrothermal Synthesis and Application of Functional Materials: A Review. Materials 2019, 12, 1177. [Google Scholar] [CrossRef] [Green Version]
  138. Kostyukhin, E.; Kustov, L.M. Microwave-assisted synthesis of magnetite nanoparticles possessing superior magnetic properties. Mendeleev Commun. 2018, 28, 559–561. [Google Scholar] [CrossRef]
  139. Shu, G.; Wang, H.; Zhao, H.-X.; Zhang, X. Microwave-Assisted Synthesis of Black Titanium Monoxide for Synergistic Tumor Phototherapy. ACS Appl. Mater. Interfaces 2018, 11, 3323–3333. [Google Scholar] [CrossRef]
  140. Strachowski, T.; Grzanka, E.; Mizeracki, J.; Chlanda, A.; Baran, M.; Małek, M.; Niedziałek, M. Microwave-Assisted Hydrothermal Synthesis of Zinc-Aluminum Spinel ZnAl2O4. Materials 2021, 15, 245. [Google Scholar] [CrossRef]
  141. Eugênia, M.; Brollo, F.; Veintemillas-verdaguer, S.; Salván, C.M.; Morales, P. Key Parameters on the Microwave Assisted Synthesis of Magnetic Nanoparticles for MRI Contrast Agents. Contrast Media Mol. Imaging 2017, 1–13. [Google Scholar]
  142. Kostyukhin, E.M.; Nissenbaum, V.D.; Abkhalimov, E.V.; Kustov, A.L.; Ershov, B.G.; Kustov, L.M. Microwave-Assisted Synthesis of Water-Dispersible Humate-Coated Magnetite Nanoparticles: Relation of Coating Process Parameters to the Properties of Nanoparticles. Nanomaterials 2020, 10, 1558. [Google Scholar] [CrossRef]
  143. Schneider, T.; Löwa, A.; Karagiozov, S.; Sprenger, L.; Gutiérrez, L.; Esposito, T.; Marten, G.; Saatchi, K.; Häfeli, U.O. Facile microwave synthesis of uniform magnetic nanoparticles with minimal sample processing. J. Magn. Magn. Mater. 2017, 421, 283–291. [Google Scholar] [CrossRef]
  144. Fernández-Barahona, I.; Muñoz-Hernando, M.; Herranz, F. Microwave-Driven Synthesis of Iron-Oxide Nanoparticles for Molecular Imaging. Molecules 2019, 24, 1224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Chin, S.F.; Azman, A.; Pang, S.C. Size Controlled Synthesis of Starch Nanoparticles by a Microemulsion Method. J. Nanomater. 2014, 2014, 1–7. [Google Scholar] [CrossRef] [Green Version]
  146. Roh, Y.; Liu, S.V.; Li, G.; Huang, H.; Phelps, T.J.; Zhou, J. Isolation and Characterization of Metal-Reducing Thermoanaerobacter Strains from Deep Subsurface Environments of the Piceance Basin, Colorado. Appl. Environ. Microbiol. 2002, 68, 6013–6020. [Google Scholar] [CrossRef] [Green Version]
  147. Batool, F.; Iqbal, M.S.; Khan, S.-U.; Khan, J.; Ahmed, B.; Qadir, M.I. Biologically synthesized iron nanoparticles (FeNPs) from Phoenix dactylifera have anti-bacterial activities. Sci. Rep. 2021, 11, 1–9. [Google Scholar] [CrossRef]
  148. Gareev, K.G.; Grouzdev, D.S.; Kharitonskii, P.V.; Kosterov, A.; Koziaeva, V.V.; Sergienko, E.S.; Shevtsov, M.A. Magnetotactic Bacteria and Magnetosomes: Basic Properties and Applications. Magnetochemistry 2021, 7, 86. [Google Scholar] [CrossRef]
  149. Perotti, G.F.; Da Costa, L.P. Biological Materials. In RSC Nanoscience and Nanotechnology; Royal Society of Chemistry: London, UK, 2021; Volume 2021, pp. 316–332. [Google Scholar]
  150. Vargas, G.; Cypriano, J.; Correa, T.; Leão, P.; Bazylinski, D.A.; Abreu, F. Applications of Magnetotactic Bacteria, Magnetosomes and Magnetosome Crystals in Biotechnology and Nanotechnology: Mini-Review. Molecules 2018, 23, 2438. [Google Scholar] [CrossRef] [Green Version]
  151. Usov, N.; Gubanova, E. Application of Magnetosomes in Magnetic Hyperthermia. Nanomaterials 2020, 10, 1320. [Google Scholar] [CrossRef]
  152. Baker, I. Magnetic Nanoparticle Synthesisp; Elsevier Ltd.: Amsterdam, The Netherlands, 2018. [Google Scholar]
  153. Yew, Y.P.; Shameli, K.; Miyake, M.; Kuwano, N.; Khairudin, N.B.B.A.; Mohamad, S.E.B.; Lee, K.X. Green Synthesis of Magnetite (Fe3O4) Nanoparticles Using Seaweed (Kappaphycus alvarezii) Extract. Nanoscale Res. Lett. 2016, 11, 1–7. [Google Scholar] [CrossRef] [Green Version]
  154. Koczkur, K.M.; Mourdikoudis, S.; Polavarapu, L.; Skrabalak, S.E. Polyvinylpyrrolidone (PVP) in nanoparticle synthesis. Dalton Trans. 2015, 44, 17883–17905. [Google Scholar] [CrossRef] [Green Version]
  155. Makarov, V.V.; Love, A.J.; Sinitsyna, O.V.; Makarova, S.S.; Yaminsky, I.V.; Taliansky, M.E.; Kalinina, N.O. ‘Green’ nanotechnologies: Synthesis of metal nanoparticles using plants. Acta Nat. 2014, 6, 35–44. [Google Scholar] [CrossRef]
  156. Parajuli, K.; Sah, A.K.; Paudyal, H. Green Synthesis of Magnetite Nanoparticles Using Aqueous Leaves Extracts of Azadirachta indica and Its Application for the Removal of As(V) from Water. Green Sustain. Chem. 2020, 10, 117–132. [Google Scholar] [CrossRef]
  157. Prasad, C.; Murthy, P.K.; Krishna, R.H.; Rao, R.S.; Suneetha, V.; Venkateswarlu, P. Bio-inspired green synthesis of RGO/Fe3O4 magnetic nanoparticles using Murrayakoenigii leaves extract and its application for removal of Pb(II) from aqueous solution. J. Environ. Chem. Eng. 2017, 5, 4374–4380. [Google Scholar] [CrossRef]
  158. Yusefi, M.; Shameli, K.; Yee, O.S.; Teow, S.-Y.; Hedayatnasab, Z.; Jahangirian, H.; Webster, T.J.; Kuča, K. Green Synthesis of Fe3O4 Nanoparticles Stabilized by a Garcinia mangostana Fruit Peel Extract for Hyperthermia and Anticancer Activities. Int. J. Nanomed. 2021, 16, 2515–2532. [Google Scholar] [CrossRef] [PubMed]
  159. Tyagi, P.K.; Gupta, S.; Tyagi, S.; Kumar, M.; Pandiselvam, R.; Daştan, S.D.; Sharifi-Rad, J.; Gola, D.; Arya, A. Green Synthesis of Iron Nanoparticles from Spinach Leaf and Banana Peel Aqueous Extracts and Evaluation of Antibacterial Potential. J. Nanomater. 2021, 2021, 1–11. [Google Scholar] [CrossRef]
  160. Nasiri, J.; Rahimi, M.; Hamezadeh, Z.; Motamedi, E.; Naghavi, M.R. Fulfillment of green chemistry for synthesis of silver nanoparticles using root and leaf extracts of Ferula persica: Solid-state route vs. solution-phase method. J. Clean. Prod. 2018, 192, 514–530. [Google Scholar] [CrossRef]
  161. Pilati, V.; Gomide, G.; Gomes, R.C.; Goya, G.F. Colloidal Stability and Concentration Effects on Nanoparticle Heat Delivery for Magnetic Fluid Hyperthermia. Langmuir 2021, 37, 1129–1140. [Google Scholar] [CrossRef]
  162. Cortés-Llanos, B.; Ocampo, S.M.; de la Cueva, L.; Calvo, G.F.; Belmonte-Beitia, J.; Pérez, L.; Salas, G.; Ayuso-Sacido, Á. Influence of Coating and Size of Magnetic Nanoparticles on Cellular Uptake for In Vitro MRI. Nanomaterials 2021, 11, 2888. [Google Scholar] [CrossRef]
  163. Zhang, H.; Hortal, M.; Dobon, A.; Jorda-Beneyto, M.; Bermudez, J.M. Selection of Nanomaterial-Based Active Agents for Packaging Application: Using Life Cycle Assessment (LCA) as a Tool. Packag. Technol. Sci. 2016, 30, 575–586. [Google Scholar] [CrossRef]
  164. Bobba, S.; Deorsola, F.A.; Blengini, G.A.; Fino, D. LCA of tungsten disulphide (WS 2 ) nano-particles synthesis: State of art and from-cradle-to-gate LCA. J. Clean. Prod. 2016, 139, 1478–1484. [Google Scholar] [CrossRef]
  165. Zhang, Z.; Guan, Y.; Xia, T.; Du, J.; Li, T.; Sun, Z.; Guo, C. Influence of exposed magnetic nanoparticles and their application in chemiluminescence immunoassay. Colloids Surf. A Physicochem. Eng. Asp. 2017, 520, 335–342. [Google Scholar] [CrossRef]
  166. Dembski, S.; Schneider, C.; Christ, B.; Retter, M. Core-Shell Nanoparticles and Their Use for In Vitro and In Vivo Diagnostics; Elsevier Ltd.: Amsterdam, The Netherlands, 2018. [Google Scholar]
  167. Ahmadpoor, F.; Masood, A.; Feliu, N.; Parak, W.J.; Shojaosadati, S.A. The Effect of Surface Coating of Iron Oxide Nanoparticles on Magnetic Resonance Imaging Relaxivity. Front. Nanotechnol. 2021, 3, 1–12. [Google Scholar] [CrossRef]
  168. Wu, K.; Su, D.; Liu, J.; Saha, R.; Wang, J.-P. Magnetic nanoparticles in nanomedicine: A review of recent advances. Nanotechnology 2019, 30, 502003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Heuer-Jungemann, A.; Feliu, N.; Bakaimi, I.; Hamaly, M.; Alkilany, A.; Chakraborty, I.; Masood, A.; Casula, M.F.; Kostopoulou, A.; Oh, E.; et al. The Role of Ligands in the Chemical Synthesis and Applications of Inorganic Nanoparticles. Chem. Rev. 2019, 119, 4819–4880. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Tarkistani, M.; Komalla, V.; Kayser, V. Recent Advances in the Use of Iron–Gold Hybrid Nanoparticles for Biomedical Applications. Nanomaterials 2021, 11, 1227. [Google Scholar] [CrossRef]
  171. Zaloga, J.; Janko, C.; Agarwal, R.; Nowak, J.; Müller, R.; Boccaccini, A.R.; Lee, G.; Odenbach, S.; Lyer, S.; Alexiou, C. Different Storage Conditions Influence Biocompatibility and Physicochemical Properties of Iron Oxide Nanoparticles. Int. J. Mol. Sci. 2015, 16, 9368–9384. [Google Scholar] [CrossRef]
  172. Widdrat, M.; Kumari, M.; Tompa, É.; Pósfai, M.; Hirt, A.M.; Faivre, D. Keeping Nanoparticles Fully Functional: Long-Term Storage and Alteration of Magnetite. Chem. Plus Chem. 2014, 79, 1225–1233. [Google Scholar] [CrossRef] [Green Version]
  173. Shubayev, V.I.; Pisanic, T.R.; Jin, S. Magnetic nanoparticles for theragnostics. Adv. Drug Deliv. Rev. 2009, 61, 467–477. [Google Scholar] [CrossRef] [Green Version]
  174. López-Campos, F.; Candini, D.; Carrasco, E.; Francés, M.A.B.; Candini, D. Nanoparticles applied to cancer immunoregulation. Rep. Pract. Oncol. Radiother. 2019, 24, 47–55. [Google Scholar] [CrossRef]
  175. Mourdikoudis, S.; Kostopoulou, A.; LaGrow, A.P. Magnetic Nanoparticle Composites: Synergistic Effects and Applications. Adv. Sci. 2021, 8, 1–57. [Google Scholar] [CrossRef]
  176. Singh, G.; Rani, S.; Sharma, G.; Kalra, P.; Singh, N.; Verma, V. Coumarin–derived Organosilatranes: Functionalization at magnetic silica surface and selective recognition of Hg2+ ion. Sens. Actuators B Chem. 2018, 266, 861–872. [Google Scholar] [CrossRef]
  177. Pham, X.-H.; Hahm, E.; Kim, H.-M.; Son, B.S.; Jo, A.; An, J.; Thi, T.A.T.; Nguyen, D.Q.; Jun, B.-H. Silica-Coated Magnetic Iron Oxide Nanoparticles Grafted onto Graphene Oxide for Protein Isolation. Nanomaterials 2020, 10, 117. [Google Scholar] [CrossRef] [Green Version]
  178. Stöber, W.; Fink, A.; Bohn, E. Controlled growth of monodisperse silica spheres in the micron size range. J. Colloid Interface Sci. 1968, 26, 62–69. [Google Scholar] [CrossRef]
  179. Park, J.C.; Gilbert, D.A.; Liu, K.; Louie, A.Y. Supporting information Microwave enhanced silica encapsulation of magnetic nanoparticles. J. Mater. Chem. 2012, 22, 8449–8454. [Google Scholar] [CrossRef] [Green Version]
  180. Malhotra, N.; Audira, G.; Chen, J.-R.; Siregar, P.; Hsu, H.-S.; Lee, J.-S.; Ger, T.-R.; Hsiao, C.-D. Surface Modification of Magnetic Nanoparticles by Carbon-Coating Can Increase Its Biosafety: Evidences from Biochemical and Neurobehavioral Tests in Zebrafish. Molecules 2020, 25, 2256. [Google Scholar] [CrossRef]
  181. Baykal, A.; Senel, M.; Unal, B.; Karaoğlu, E.; Sözeri, H.; Toprak, M. Acid Functionalized Multiwall Carbon Nanotube/Magnetite (MWCNT)-COOH/Fe3O4 Hybrid: Synthesis, Characterization and Conductivity Evaluation. J. Inorg. Organomet. Polym. Mater. 2013, 23, 726–735. [Google Scholar] [CrossRef]
  182. Moreno-Bárcenas, A.; Zapata, J.A.A.; Alcalá, M.E.; Ramírez, J.T.; Hernández, A.M.; García-García, A. Evolution of Nanostructured Carbon Coatings Quality via RT-CVD and Their Tribological Behavior on Nodular Cast Iron. Metals 2022, 12, 517. [Google Scholar] [CrossRef]
  183. Kyesmen, P.I.; Nombona, N.; Diale, M. A Promising Three-Step Heat Treatment Process for Preparing CuO Films for Photocatalytic Hydrogen Evolution from Water. ACS Omega 2021, 6, 33398–33408. [Google Scholar] [CrossRef]
  184. Chen, Z.; Dai, X.J.; Lamb, P.R.; du Plessis, J.; Leal, D.R.D.C.; Magniez, K.; Fox, B.L.; Wang, X. Coating and Functionalization of Carbon Fibres Using a Three-Step Plasma Treatment. Plasma Process. Polym. 2013, 10, 1100–1109. [Google Scholar] [CrossRef]
  185. Schwaminger, S.P.; Bauer, D.; Fraga-García, P.; Wagner, F.E.; Berensmeier, S. Oxidation of magnetite nanoparticles: Impact on surface and crystal properties. Cryst. Eng. Comm. 2017, 19, 246–255. [Google Scholar] [CrossRef] [Green Version]
  186. Sanchez, L.M.; Alvarez, V.A. Advances in Magnetic Noble Metal/Iron-Based Oxide Hybrid Nanoparticles as Biomedical Devices. Bioengineering 2019, 6, 75. [Google Scholar] [CrossRef]
  187. Ortega, G.; Reguera, E. Biomedical Applications of Magnetite Nanoparticles; Elsevier Inc.: Amsterdam, The Netherlands, 2019. [Google Scholar]
  188. Shiri, M.S.Z.; Henderson, W.; Mucalo, M.R. A Review of The Lesser-Studied Microemulsion-Based Synthesis Methodologies Used for Preparing Nanoparticle Systems of The Noble Metals, Os, Re, Ir and Rh. Materials 2019, 12, 1896. [Google Scholar] [CrossRef] [Green Version]
  189. Slimani, S.; Concas, G.; Congiu, F.; Barucca, G.; Yaacoub, N.; Talone, A.; Smari, M.; Dhahri, E.; Peddis, D.; Muscas, G. Hybrid Spinel Iron Oxide Nanoarchitecture Combining Crystalline and Amorphous Parent Material. J. Phys. Chem. C 2021, 125, 10611–10620. [Google Scholar] [CrossRef]
  190. Mylkie, K.; Nowak, P.; Rybczynski, P.; Ziegler-Borowska, M. Polymer-Coated Magnetite Nanoparticles for Protein Immobilization. Materials 2021, 14, 248. [Google Scholar] [CrossRef]
  191. Smit, M.; Lutz, M. Polymer-coated magnetic nanoparticles for the efficient capture of Mycobacterium tuberculosis (Mtb). SN Appl. Sci. 2020, 2, 1–12. [Google Scholar] [CrossRef]
  192. Mirshahghassemi, S.; Cai, B.; Lead, J.R. Evaluation of polymer-coated magnetic nanoparticles for oil separation under environmentally relevant conditions: Effect of ionic strength and natural organic macromolecules. Environ. Sci. Nano 2016, 3, 780–787. [Google Scholar] [CrossRef]
  193. Kim, D.; Yu, M.K.; Lee, T.S.; Park, J.J.; Jeong, Y.Y.; Jon, S. Amphiphilic polymer-coated hybrid nanoparticles as CT/MRI dual contrast agents. Nanotechnology 2011, 22, 155101. [Google Scholar] [CrossRef]
  194. Huang, Y.-F.; Liu, Q.-H.; Li, K.; Li, Y.; Chang, N. Magnetic iron(III)-based framework composites for the magnetic solid-phase extraction of fungicides from environmental water samples. J. Sep. Sci. 2017, 41, 1129–1137. [Google Scholar] [CrossRef]
  195. Sommertune, J.; Sugunan, A.; Ahniyaz, A.; Bejhed, R.S.; Fornara, A. Polymer / Iron Oxide Nanoparticle Composites—A Straight Forward and Scalable Synthesis Approach. Int. J. Mol. Sci. 2015, 16, 19752–19768. [Google Scholar] [CrossRef] [Green Version]
  196. Li, Y.; Wang, N.; Huang, X.; Li, F.; Davis, T.P.; Qiao, R.; Ling, D. Polymer-Assisted Magnetic Nanoparticle Assemblies for Biomedical Applications. ACS Appl. Bio Mater. 2019, 3, 121–142. [Google Scholar] [CrossRef] [Green Version]
  197. Beyou, E.; Bourgeat-Lami, E. Organic–inorganic hybrid functional materials by nitroxide-mediated polymerization. Prog. Polym. Sci. 2021, 121, 101434. [Google Scholar] [CrossRef]
  198. Behrens, S.; Appel, I. Magnetic nanocomposites. Curr. Opin. Biotechnol. 2016, 39, 89–96. [Google Scholar] [CrossRef]
  199. Demirelli, M.; Karaoglu, E.; Baykal, A.; Sozeri, H. M-hexaferrite–APTES/Pd(0) Magnetically Recyclable Nano Catalysts (MRCs). J. Inorg. Organomet. Polym. Mater. 2013, 23, 1274–1281. [Google Scholar] [CrossRef]
  200. Karaoglu, E.; Baykal, A. CoFe2O4–Pd (0) Nanocomposite: Magnetically Recyclable Catalyst. J. Supercond. Nov. Magn. 2014, 27, 2041–2047. [Google Scholar] [CrossRef]
  201. Junejo, Y.; Baykal, A.; Sözeri, H. Simple hydrothermal synthesis of Fe3O4-PEG nanocomposite. Open Chem. 2013, 11, 1527–1532. [Google Scholar] [CrossRef]
  202. Watt, J.; Collins, A.M.; Vreeland, E.C.; Montaño, G.A.; Huber, D.L. Magnetic Nanocomposites and Their Incorporation into Higher Order Biosynthetic Functional Architectures. ACS Omega 2018, 3, 503–508. [Google Scholar] [CrossRef]
  203. Alveroǧlu, E.; Sözeri, H.; Baykal, A.; Kurtan, U.; Şenel, M. Fluorescence and magnetic properties of hydrogels containing Fe3O4 nanoparticles. J. Mol. Struct. 2013, 1037, 361–366. [Google Scholar] [CrossRef]
  204. Demir, A.; Baykal, A.; Sözeri, H.; Topkaya, R. Low temperature magnetic investigation of Fe3O4 nanoparticles filled into multiwalled carbon nanotubes. Synth. Met. 2014, 187, 75–80. [Google Scholar] [CrossRef]
  205. Akal, Z.; Alpsoy, L.; Baykal, A. Biomedical applications of SPION@APTES@PEG-folic acid@carboxylated quercetin nanodrug on various cancer cells. Appl. Surf. Sci. 2016, 378, 572–581. [Google Scholar] [CrossRef]
  206. Hulla, J.E.; Sahu, S.C.; Hayes, A.W. Nanotechnology: History and future. Hum. Exp. Toxicol. 2015, 34, 1318–1321. [Google Scholar] [CrossRef] [Green Version]
  207. Bayda, S.; Adeel, M.; Tuccinardi, T.; Cordani, M.; Rizzolio, F. The History of Nanoscience and Nanotechnology: From Chemical–Physical Applications to Nanomedicine. Molecules 2020, 25, 112. [Google Scholar] [CrossRef] [PubMed]
  208. Wei, W.; Zhang, X.; Zhang, S.; Wei, G.; Su, Z. Biomedical and bioactive engineered nanomaterials for targeted tumor photothermal therapy: A review. Mater. Sci. Eng. C 2019, 104, 109891. [Google Scholar] [CrossRef]
  209. Hose, R.C. Prof. Richard Zsigmondy. Nature 1929, 124, 845–846. [Google Scholar]
  210. Weissig, V.; Pettinger, T.K.; Murdock, N. Nanopharmaceuticals (part 1): Products on the market. Int. J. Nanomed. 2014, 9, 4357–4373. [Google Scholar] [CrossRef] [Green Version]
  211. Schwaminger, S.P.; Bauer, D.; Fraga-García, P. Gold-iron oxide nanohybrids: Insights into colloidal stability and surface-enhanced Raman detection. Nanoscale Adv. 2021, 3, 6438–6445. [Google Scholar] [CrossRef]
  212. Kah, J.; Yeo, E.; He, S.; Engudar, G. Gold Nanorods in Photomedicine in Applications of Nanoscience in Photomedicine; Elsevier Inc.: Amsterdam, The Netherlands, 2015; pp. 221–248. [Google Scholar] [CrossRef]
  213. Kandasamy, G.; Maity, D. Recent advances in superparamagnetic iron oxide nanoparticles (SPIONs) for in vitro and in vivo cancer nanotheranostics. Int. J. Pharm. 2015, 496, 191–218. [Google Scholar] [CrossRef]
  214. Vemulkar, T.; Mansell, R.; Petit, D.C.M.C.; Cowburn, R.P.; Lesniak, M.S. Highly tunable perpendicularly magnetized synthetic antiferromagnets for biotechnology applications. Appl. Phys. Lett. 2015, 107, 012403. [Google Scholar] [CrossRef] [Green Version]
  215. Panahi, H.A.; Alaei, H.S. β-Cyclodextrin/thermosensitive containing polymer brushes grafted onto magnetite nano-particles for extraction and determination of venlafaxine in biological and pharmaceutical samples. Int. J. Pharm. 2014, 476, 178–184. [Google Scholar] [CrossRef]
  216. Hu, X.; Wang, Y.; Zhang, L.; Xu, M.; Zhang, J.; Dong, W. Design of a pH-sensitive magnetic composite hydrogel based on salecan graft copolymer and Fe3O4@SiO2nanoparticles as drug carrier. Int. J. Biol. Macromol. 2018, 107, 1811–1820. [Google Scholar] [CrossRef]
  217. Otero-Lorenzo, R.; Dávila-Ibáñez, A.B.; Comesaña-Hermo, M.; Correa-Duarte, M.A.; Salgueiriño, V. Synergy effects of magnetic silica nanostructures for drug delivery applications. J. Mater. Chem. B 2014, 2, 2645–2653. [Google Scholar] [CrossRef]
  218. Testa-Anta, M.; Ramos-Docampo, M.A.; Comesaña-Hermo, M.; Rivas-Murias, B.; Salgueiriño, V. Raman spectroscopy to unravel the magnetic properties of iron oxide nanocrystals for bio-related applications. Nanoscale Adv. 2019, 1, 2086–2103. [Google Scholar] [CrossRef] [PubMed]
  219. Alphandéry, E. Biodistribution and targeting properties of iron oxide nanoparticles for treatments of cancer and iron anemia disease. Nanotoxicology 2019, 13, 573–596. [Google Scholar] [CrossRef] [PubMed]
  220. Del Sol-Fernández, S.; Portilla-Tundidor, Y.; Gutiérrez, L.; Odio, O.F.; Reguera, E.; Barber, D.F.; Morales, M.P. Flower-like Mn-Doped Magnetic Nanoparticles Functionalized with αvβ3-Integrin-Ligand to Efficiently Induce Intracellular Heat after Alternating Magnetic Field Exposition, Triggering Glioma Cell Death. ACS Appl. Mater. Interfaces 2019, 11, 26648–26663. [Google Scholar] [CrossRef]
  221. Xu, K.; Yao, H.; Hu, J.; Zhou, J.; Zhou, L.; Wei, S. Pre-drug Self-assembled Nanoparticles: Recovering activity and overcoming glutathione-associated cell antioxidant resistance against photodynamic therapy. Free Radic. Biol. Med. 2018, 124, 431–446. [Google Scholar] [CrossRef]
  222. Berry, C.C.; Wells, S.; Charles, S.; Curtis, A.S. Dextran and albumin derivatised iron oxide nanoparticles: Influence on fibroblasts in vitro. Biomaterials 2003, 24, 4551–4557. [Google Scholar] [CrossRef]
  223. Gupta, A.K.; Curtis, A.S. Lactoferrin and ceruloplasmin derivatized superparamagnetic iron oxide nanoparticles for targeting cell surface receptors. Biomaterials 2003, 25, 3029–3040. [Google Scholar] [CrossRef]
  224. Pöttler, M.; Fliedner, A.; Schreiber, E.; Janko, C.; Friedrich, R.P.; Bohr, C.; Döllinger, M.; Alexiou, C.; Dürr, S. Impact of Superparamagnetic Iron Oxide Nanoparticles on Vocal Fold Fibroblasts: Cell Behavior and Cellular Iron Kinetics. Nanoscale Res. Lett. 2017, 12, 1–9. [Google Scholar] [CrossRef] [Green Version]
  225. Ramchandran, V.; Gernand, J.M. Examining the in vivo pulmonary toxicity of engineered metal oxide nanomaterials using a genetic algorithm-based dose-response-recovery clustering model. Comput. Toxicol. 2019, 13, 100113. [Google Scholar] [CrossRef]
  226. Sadeghi, L.; Babadi, V.Y.; Espanani, H.R. Toxic effects of the Fe2O3 nanoparticles on the liver and lung tissue. Bratisl. Med. J. 2015, 116, 373–378. [Google Scholar] [CrossRef]
  227. Parivar, K.; Fard, F.M.; Bayat, M.; Alavian, S.M.; Motavaf, M. Evaluation of Iron Oxide Nanoparticles Toxicity on Liver Cells of BALB/c Rats. Iran. Red Crescent Med. J. 2016, 18, e28939. [Google Scholar] [CrossRef] [Green Version]
  228. Osman, N.M.; Sexton, D.; Saleem, I.Y. Toxicological assessment of nanoparticle interactions with the pulmonary system. Nanotoxicology 2019, 14, 21–58. [Google Scholar] [CrossRef] [PubMed]
  229. Omidkhoda, A.; Mozdarani, H.; Movasaghpoor, A.; Pour Fatholah, A.A. Study of apoptosis in labeled mesenchymal stem cells with superparamagnetic iron oxide using neutral comet assay. Toxicol. Vitr. 2007, 21, 1191–1196. [Google Scholar] [CrossRef] [PubMed]
  230. Li, X.; Wei, Z.; Lv, H.; Wu, L.; Cui, Y.; Yao, H.; Li, J.; Zhang, H.; Yang, B.; Jiang, J. Iron oxide nanoparticles promote the migration of mesenchymal stem cells to injury sites. Int. J. Nanomed. 2019, 14, 573–589. [Google Scholar] [CrossRef] [Green Version]
  231. Huang, D.-M.; Hsiao, J.-K.; Chen, Y.-C.; Chien, L.-Y.; Yao, M.; Chen, Y.-K.; Ko, B.-S.; Hsu, S.-C.; Tai, L.-A.; Cheng, H.-Y.; et al. The promotion of human mesenchymal stem cell proliferation by superparamagnetic iron oxide nanoparticles. Biomaterials 2009, 30, 3645–3651. [Google Scholar] [CrossRef] [PubMed]
  232. Balas, M.; Din, I.P.; Hermenean, A.; Cinteza, L.; Dinischiotu, A. Exposure to Iron Oxide Nanoparticles Coated with Phospholipid-Based Polymeric Micelles Induces Renal Transitory Biochemical and Histopathological Changes in Mice. Materials 2021, 14, 2605. [Google Scholar] [CrossRef]
  233. Hataminia, F.; Noroozi, Z.; Eslam, H.M. Investigation of iron oxide nanoparticle cytotoxicity in relation to kidney cells: A mathematical modeling of data mining. Toxicol. Vitr. 2019, 59, 197–203. [Google Scholar] [CrossRef]
  234. Serkova, N.J.; Renner, B.; Larsen, B.A.; Stoldt, C.R.; Hasebroock, K.M.; Bradshaw-Pierce, E.L.; Holers, V.M.; Thurman, J.M. Renal Inflammation: Targeted Iron Oxide Nanoparticles for Molecular MR Imaging in Mice. Radiology 2010, 255, 517–526. [Google Scholar] [CrossRef] [Green Version]
  235. Zhang, W.; Cao, S.; Liang, S.; Tan, C.H.; Luo, B.; Xu, X.; Saw, P.E. Differently Charged Super-Paramagnetic Iron Oxide Nanoparticles Preferentially Induced M1-Like Phenotype of Macrophages. Front. Bioeng. Biotechnol. 2020, 8, 1–10. [Google Scholar] [CrossRef]
  236. Gu, Z.; Liu, T.; Tang, J.; Yang, Y.; Song, H.; Tuong, Z.K.; Fu, J.; Yu, C. Mechanism of Iron Oxide-Induced Macrophage Activation: The Impact of Composition and the Underlying Signaling Pathway. J. Am. Chem. Soc. 2019, 141, 6122–6126. [Google Scholar] [CrossRef]
  237. Yarjanli, Z.; Ghaedi, K.; Esmaeili, A.; Rahgozar, S.; Zarrabi, A. Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci. 2017, 18, 1–12. [Google Scholar] [CrossRef] [Green Version]
  238. Yang, Z.; Liu, Z.W.; Allaker, R.P.; Reip, P.; Oxford, J.; Ahmad, Z.; Ren, G. A review of nanoparticle functionality and toxicity on the central nervous system. Nanotechnol. Brain Future 2013, 7, 313–332. [Google Scholar]
  239. Hajsalimi, G.; Taheri, S.; Shahi, F.; Attar, F.; Ahmadi, H.; Falahati, M. Interaction of iron nanoparticles with nervous system: An in vitro study. J. Biomol. Struct. Dyn. 2017, 36, 928–937. [Google Scholar] [CrossRef] [PubMed]
  240. Apopa, P.L.; Qian, Y.; Shao, R.; Guo, N.L.; Schwegler-Berry, D.; Pacurari, M.; Porter, D.; Shi, X.; Vallyathan, V.; Castranova, V.; et al. Iron oxide nanoparticles induce human microvascular endothelial cell permeability through reactive oxygen species production and microtubule remodeling. Part. Fibre Toxicol. 2009, 6, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  241. Duan, J.; Du, J.; Jin, R.; Zhu, W.; Liu, L.; Yang, L.; Li, M.; Gong, Q.; Song, B.; Anderson, J.M.; et al. Iron oxide nanoparticles promote vascular endothelial cells survival from oxidative stress by enhancement of autophagy. Regen. Biomater. 2019, 6, 221–229. [Google Scholar] [CrossRef]
  242. Wen, T.; Du, L.; Chen, B.; Yan, D.; Yang, A.; Liu, J.; Gu, N.; Meng, J.; Xu, H. Iron oxide nanoparticles induce reversible endothelial-to-mesenchymal transition in vascular endothelial cells at acutely non-cytotoxic concentrations. Part. Fibre Toxicol. 2019, 16, 1–13. [Google Scholar] [CrossRef] [Green Version]
  243. Villanueva, A.; Cañete, M.; Roca, A.G.; Calero, M.; Veintemillas-Verdaguer, S.; Serna, C.J.; Morales, M.D.P.; Miranda, R. The influence of surface functionalization on the enhanced internalization of magnetic nanoparticles in cancer cells. Nanotechnology 2009, 20, 115103. [Google Scholar] [CrossRef]
  244. Yang, J.-X.; Tang, W.-L.; Wang, X.-X. Superparamagnetic iron oxide nanoparticles may affect endothelial progenitor cell migration ability and adhesion capacity. Cytotherapy 2010, 12, 251–259. [Google Scholar] [CrossRef]
  245. Cochran, D.B.; Wattamwar, P.P.; Wydra, R.; Hilt, J.Z.; Anderson, K.W.; Eitel, R.E.; Dziubla, T.D. Suppressing iron oxide nanoparticle toxicity by vascular targeted antioxidant polymer nanoparticles. Biomater. 2013, 34, 9615–9622. [Google Scholar] [CrossRef]
  246. Mahmoudi, M.; Hofmann, H.; Rothen-Rutishauser, B.; Petri-Fink, A. Assessing the In Vitro and In Vivo Toxicity of Superparamagnetic Iron Oxide Nanoparticles. Chem. Rev. 2011, 112, 2323–2338. [Google Scholar] [CrossRef] [Green Version]
  247. Schimpel, C.; Resch, S.; Flament, G.; Carlander, D.; Vaquero, C.; Bustero, I.; Falk, A. A methodology on how to create a real-life relevant risk profile for a given nanomaterial. ACS Chem. Health Saf. 2018, 25, 12–23. [Google Scholar] [CrossRef] [Green Version]
  248. Sarpong-Kumankomah, S.; Gibson, M.A.; Gailer, J. Organ damage by toxic metals is critically determined by the bloodstream. Co-Ord. Chem. Rev. 2018, 374, 376–386. [Google Scholar] [CrossRef]
  249. Krug, H.F. Nanosafety Research-Are We on the Right Track? Angew. Chem. Int. Ed. Engl. 2014, 53, 12304–12319. [Google Scholar] [CrossRef] [PubMed]
  250. Motayagheni, N. Modified Langendorff technique for mouse heart cannulation: Improved heart quality and decreased risk of ischemia. MethodsX 2017, 4, 508–512. [Google Scholar] [CrossRef]
  251. Tipton, C.M.; Matthes, R.D.; Tcheng, T.; Dowell, R.T.; Vailas, A.C. The use of the Langendorff preparation to study the bradycardia of training. Med. Sci. Sport. 1977, 9, 220–230. [Google Scholar]
  252. Bell, R.M.; Mocanu, M.M.; Yellon, D.M. Retrograde heart perfusion: The Langendorff technique of isolated heart perfusion. J. Mol. Cell Cardiol. 2011, 50, 940–950. [Google Scholar] [CrossRef]
  253. Zimmer, H.-G. The Isolated Perfused Heart and Its Pioneers. Physiology 1998, 13, 203–210. [Google Scholar] [CrossRef] [Green Version]
  254. Stone, V.; Johnston, H.; Schins, R.P.F. Development of in vitro systems for nanotoxicology: Methodological considerations in vitro methods for nanotoxicology Vicki Stone et al. Crit. Rev. Toxicol. 2009, 39, 613–626. [Google Scholar] [CrossRef]
  255. Erofeev, A.; Gorelkin, P.; Garanina, A.; Alova, A.; Efremova, M.; Vorobyeva, N.; Edwards, C.; Korchev, Y.; Majouga, A. Novel method for rapid toxicity screening of magnetic nanoparticles. Sci. Rep. 2018, 8, 1–11. [Google Scholar] [CrossRef] [Green Version]
  256. Yuen, H.-W.; Becker, W. Iron Toxicity; StatPearls Publishing: Florida, FL, USA, 2019. [Google Scholar]
  257. Jaishankar, M.; Tseten, T.; Anbalagan, N.; Mathew, B.B.; Beeregowda, K.N. Toxicity, mechanism and health effects of some heavy metals. Interdiscip. Toxicol. 2014, 7, 60–72. [Google Scholar] [CrossRef] [Green Version]
  258. Wong, V.; Lerner, E. Nitric oxide inhibition strategies. Futur. Sci. OA 2015, 1, 1. [Google Scholar] [CrossRef]
  259. Li, Q.; Yon, J.-Y.; Cai, H. Mechanisms and Consequences of eNOS Dysfunction in Hypertension. J. Hypertens. 2015, 33, 1128–1136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  260. Zhao, Y.; Vanhoutte, P.M.; Leung, S.W. Vascular nitric oxide: Beyond eNOS. J. Pharmacol. Sci. 2015, 129, 83–94. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  261. Förstermann, U.; Sessa, W.C. Nitric oxide synthases: Regulation and function. Eur. Heart J. 2012, 33, 829–837. [Google Scholar] [CrossRef] [PubMed]
  262. Skrzypiec-Spring, M.; Grotthus, B.; Szeląg, A.; Schulz, R. Isolated heart perfusion according to Langendorff—Still viable in the new millennium. J. Pharmacol. Toxicol. Methods 2007, 55, 113–126. [Google Scholar] [CrossRef] [PubMed]
  263. Manuel, A.R.-L.; Martinez-Cuevas, P.P.; Rosas-Hernandez, H.; Oros-Ovalle, C.; Bravo-Sanchez, M.; Martinez-Castañon, G.A.; Gonzalez, C. Evaluation of vascular tone and cardiac contractility in response to silver nanoparticles, using Langendorff rat heart preparation. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 1507–1518. [Google Scholar] [CrossRef]
  264. Vargas, J.R.; Harald, O.; Carmen, N.B.; Karen, G. Magnetic nanoparticle behavior evaluation on cardiac tissue contractility through Langendorff rat heart technique as a nanotoxicology parameter. Appl. Nanosci. 2021, 11, 2383–2396. [Google Scholar] [CrossRef]
  265. Thorat, N.D.; Otari, S.V.; Patil, R.M.; Bohara, R.A.; Yadav, H.M.; Koli, V.B.; Chaurasia, A.K.; Ningthoujam, R.S. Synthesis, Characterization and Biocompatibility of Chitosan functionalized superparamagnetic nanoparticles for heat activated curing of cancer cells Published. Dalton Trans. 2014, 43, 17343–17351. [Google Scholar] [CrossRef]
  266. Kumar, P.; Nagarajan, A.; Uchil, P. Analysis of Cell Viability by the Lactate Dehydrogenase Assay. Cold Spring Harb. Protoc. 2018, 2018, 465–469. [Google Scholar] [CrossRef]
  267. Kumar, A.; Gupta, M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 2005, 26, 3995–4021. [Google Scholar]
  268. Spirou, S.V.; Lima, S.A.C.; Bouziotis, P.; Vranješ-Djurić, S.; Efthimiadou, E.; Laurenzana, A.; Barbosa, A.I.; Garcia-Alonso, I.; Jones, C.; Jankovic, D.; et al. Recommendations for In Vitro and In Vivo Testing of Magnetic Nanoparticle Hyperthermia Combined with Radiation Therapy. Nanomaterials 2018, 8, 306. [Google Scholar] [CrossRef] [Green Version]
  269. Jespersen, B.; Tykocki, N.R.; Watts, S.W.; Cobbett, P.J. Measurement of smooth muscle function in the isolated tissue bath-applications to pharmacology research. J. Vis. Exp. 2015, 95, e52324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  270. Gonzalez, C.; Corbacho, A.M.; Eiserich, J.P.; Garcia, C.; Lopez-Barrera, F.; Morales-Tlalpan, V.; Barajas-Espinosa, A.; Diaz-Muñoz, M.; Rubio, R.; Lin, S.-H.; et al. 16K-Prolactin Inhibits Activation of Endothelial Nitric Oxide Synthase, Intracellular Calcium Mobilization, and Endothelium-Dependent Vasorelaxation. Endocrinology 2004, 145, 5714–5722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  271. Bachler, G.; von Goetz, N.; Hungerbühler, K. A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles. Int. J. Nanomed. 2013, 8, 3365–3382. [Google Scholar]
  272. Al-Jamal, K.T.; Bai, J.; Wang, J.T.-W.; Protti, A.; Southern, P.; Bogart, L.; Heidari, H.; Li, X.; Cakebread, A.; Asker, D.; et al. Magnetic Drug Targeting: Preclinical in Vivo Studies, Mathematical Modeling, and Extrapolation to Humans. Nano Lett. 2016, 16, 5652–5660. [Google Scholar] [CrossRef] [Green Version]
  273. Corá, L.; Romeiro, F.; Stelzer, M.; Américo, M.; Oliveira, R.; Baffa, O.; Miranda, J. AC biosusceptometry in the study of drug delivery. Adv. Drug Deliv. Rev. 2005, 57, 1223–1241. [Google Scholar] [CrossRef]
  274. Prospero, A.G.; Fidelis-De-Oliveira, P.; Soares, G.A.; Miranda, M.F.; Pinto, L.A.; Dos Santos, D.C.; Silva, V.D.S.; Zufelato, N.; Bakuzis, A.F.; Miranda, J.R. AC biosusceptometry and magnetic nanoparticles to assess doxorubicin-induced kidney injury in rats. Nanomedicine 2020, 15, 511–525. [Google Scholar] [CrossRef]
  275. Alphandéry, E. Bio-synthesized iron oxide nanoparticles for cancer treatment. Int. J. Pharm. 2020, 586, 119472. [Google Scholar] [CrossRef]
  276. Wei, H.; Hu, Y. Superparamagnetic Iron Oxide Nanoparticles: Cytotoxicity, Metabolism, and Cellular Behavior in Biomedicine Applications. Int. J. Nanomed. 2021, 16, 6097. [Google Scholar] [CrossRef]
  277. Khan, L.U.; Petry, R.; Paula, A.J.; Knobel, M.; Ste, D. Protein Corona Formation on Magnetic Nanoparticles Conjugated with Luminescent Europium Complexes. ChemNanoMat 2018, 4, 1202–1208. [Google Scholar] [CrossRef]
  278. Nedyalkova, M.; Donkova, B.; Romanova, J.; Tzvetkov, G.; Madurga, S.; Simeonov, V. Iron oxide nanoparticles—In vivo/in vitro biomedical applications and in silico studies. Adv. Colloid Interface Sci. 2017, 249, 192–212. [Google Scholar] [CrossRef] [Green Version]
  279. Kostal, J. Computational Chemistry in Predictive Toxicology: Status Quo et Quo Vadis? 1st ed.; Elsevier: Amsterdam, The Netherlands, 2016; Volume 10. [Google Scholar]
  280. Antonelli, A.; Sfara, C.; Weber, O.; Pison, U.; Manuali, E.; Salamida, S.; Magnani, M. Characterization of ferucarbotran-loaded RBCs as long circulating magnetic contrast agents. Nanomedicine 2016, 11, 2781–2795. [Google Scholar] [CrossRef] [PubMed]
  281. European Commission. Nanoreg Data Logging Templates for the Environmental, Health and Safety Assessment of Nanomaterials; European Commission: Luxembourg, 2013. [Google Scholar]
  282. European Union. Regulation (Eu) No 1169/2011 of the European Parliament; European Union: Luxembourg, 2011. [Google Scholar]
  283. ISO 14577-1:2015; Metallic Materials—Instrumented Indentation Test for Hardness and Materials Parameters–Part 1: Test Method. ISO: Geneva, Switzerland, 2015. Available online: https://www.iso.org/obp/ui/#iso:std:iso:14577:-1:ed-2:v1:en (accessed on 24 August 2022).
  284. National Science and Technology Council Committee on Technology. National Nanotechnology Initiative: Strategic Plan National Science and Technology Council Subcommittee on Nanoscale Science, Engineering, and Technology Committee on Technology About the National Science and Technology Council; National Science and Technology Council Committee on Technology: Washington, DC, USA, 2014. [Google Scholar]
  285. FDA. Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. Biotechnol. Law Rep. 2011, 30, 613–616. [Google Scholar] [CrossRef]
  286. ECHA. Appendix R7-1 for Nanoforms Applicable to Chapter R7a Endpoint Specific Guidance; ECHA: Helsinki, Finland, 2021. [Google Scholar]
  287. Canadian Enviromental Protection Act. Framework for the Risk Assessment of Manufactured Nanomaterials under the Canadian Environmental Protection Act, 1999 Draft Environment and Climate Change Canada Health Canada Draft June 2022 Executive Summary; Canadian Enviromental Protection Act: Victoria, BC, Canada, 2022. [Google Scholar]
  288. European Chemicals Agency. Understanding REACH—ECHA. 2018. Available online: https://echa.europa.eu/regulations/reach/understanding-reach (accessed on 26 September 2018).
  289. Sukhanova, A.; Bozrova, S.; Sokolov, P.; Berestovoy, M.; Karaulov, A.; Nabiev, I. Dependence of Nanoparticle Toxicity on Their Physical and Chemical Properties. Nanoscale Res. Lett. 2018, 13, 44. [Google Scholar] [CrossRef] [Green Version]
  290. Sharma, G.; Kodali, V.; Gaffrey, M.; Wang, W.; Minard, K.R.; Karin, N.J.; Teeguarden, J.G.; Thrall, B.D. Iron oxide nanoparticle agglomeration influences dose rates and modulates oxidative stress-mediated dose-response profiles in vitro. Nanotoxicology 2014, 8, 663–675. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  291. Gao, X.; Lowry, G.V. Progress towards standardized and validated characterizations for measuring physicochemical properties of manufactured nanomaterials relevant to nano health and safety risks. NanoImpact 2018, 9, 14–30. [Google Scholar] [CrossRef]
  292. Barik, B.K.; Mishra, M. Nanoparticles as a potential teratogen: A lesson learnt from fruit fly. Nanotoxicology 2018, 13, 258–284. [Google Scholar] [CrossRef]
  293. Yu, X.; Hong, F.; Zhang, Y.-Q. Bio-effect of nanoparticles in the cardiovascular system. J. Biomed. Mater. Res. Part A 2016, 104, 2881–2897. [Google Scholar] [CrossRef]
  294. Abdelsattar, A.S.; Dawoud, A.; Helal, M.A. Interaction of nanoparticles with biological macromolecules: A review of molecular docking studies. Nanotoxicology 2020, 15, 66–95. [Google Scholar] [CrossRef]
  295. Simeonidis, K.; Mourdikoudis, S.; Kaprara, E.; Mitrakas, M.; Polavarapu, L. Inorganic engineered nanoparticles in drinking water treatment: A critical review. Environ. Sci. Water Res. Technol. 2015, 2, 43–70. [Google Scholar] [CrossRef]
Figure 1. MNPs’ biomedical applications.
Figure 1. MNPs’ biomedical applications.
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Figure 2. Graphical representation of the available synthesis routes used to produce MNPs.
Figure 2. Graphical representation of the available synthesis routes used to produce MNPs.
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Figure 3. Different shapes can be obtained when synthesizing MNPs, changing their physicochemical properties.
Figure 3. Different shapes can be obtained when synthesizing MNPs, changing their physicochemical properties.
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Figure 4. Representative micro-domains of the two immersible phases in microemulsions.
Figure 4. Representative micro-domains of the two immersible phases in microemulsions.
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Figure 5. Size comparison of a red blood cell and a 70 nm nanoparticle.
Figure 5. Size comparison of a red blood cell and a 70 nm nanoparticle.
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Figure 6. Toxicological assays and protocols help researchers to better understand the impact of novel pharmaceutical agents and materials: (a) in vitro, (b) ex vivo, and (c) in vivo.
Figure 6. Toxicological assays and protocols help researchers to better understand the impact of novel pharmaceutical agents and materials: (a) in vitro, (b) ex vivo, and (c) in vivo.
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Table 1. Comparison between synthesis routes for the formation of MNPs *.
Table 1. Comparison between synthesis routes for the formation of MNPs *.
Synthesis
Route
Temperature (°C)EnvironmentTimeSize ControlShape ControlEfficiency OutputMagnetite (XRD Pattern)Ref.
Aqueous routesCoprecipitation<100Insert atmosphereMinutesRelatively broadBadHighPrecursor-dependent[92,93,94]
Thermal decomposition100–300Insert atmosphereHours to daysExcellentExcellentHighOxygen-dependent[95,96,97]
Hydrothermal150–200High pressureHours to daysExcellentExcellentHighTemperature-dependent[98]
Sol–gel100–300AmbientHoursGoodGoodMediumPoor magnetite presence[99,100,101,102]
Microemulsion<100AmbientHoursGoodGoodLowPoor magnetite presence[103,104,105]
Assisted routesSonochemical assisted<50AmbientMinutesGoodBadMediumCavitation- and frequency-dependent[106,107]
Microwaved assisted100–200AmbientMinutes to hoursMediumGoodMediumHigh magnetite presence[108,109]
Biologic routesBacteria drivenRoom temp.AmbientHours to daysBroadBadLowBiologic-assistant-dependent[110,111,112]
GreenRoom temp.AmbientMinutesRelatively goodGoodLowMedium magnetite presence. Leaves nature-dependent[113,114,115]
* Table modified from [116].
Table 2. Different biological assays in MNPs *.
Table 2. Different biological assays in MNPs *.
TissueConcentrationMorphologySizeCoatingMethodologyEffectRef.
Fibroblast (hTERT human)0.1–0.02 mg/mLSpherical7.8–9.6 nmDextran, albumin
Lactoferrin, ceruloplasmin
BrdU assayCellular death[222,223,224]
Lung cells (A549)20–40 mg/kgSpherical20–107.7 nmBareTB staining, ROS, CometEnhancement of free radicals and reduction in the GSH
DNA oxidative injuries (Comet)
Low—no toxicity (TB, ROS)
Increased TP and LDH
Non-biomechanical damage
Cell Young’s modulus decreased (25–28%)
[225,226]
Liver rat cell (BAL3A rat)20–40 mg/kg
25, 50, 75, 150, 300 µg/g
Spherical107.7 nm
20–30 nm
Bare
Liposomes
PEG
MTT, LDHNontoxic below 75 µgmL−1
Nonalcoholic fatty liver disease (NAFLD) inflammation
LDH leaking
Iron overload affected by NAFLD
[226,227,228]
Mesenchymal mother cell (MSC human)50, 100, 250 mg/mL
25, 50, 100, 150 µg/mL
Spherical80–150 nm
48 nm
Protamine sulfate
PDA
CometNo significant effect
Increased proliferation index and migration ability
[229,230,231]
Kidney cells (Cos-7 monkey)15 mg/kg
1–100 µg/mL
Spheric-like
Ferrofluid
13–122 nm
9.7 nm
Phospholipid-based polymeric micelles
DOX
MTT, MTSCell viability reduced
Particle charge (+)-induced high cytotoxicity
Oxidative stress, reverted by tissue
[232,233,234]
Macrophage (human)2.73 mg/mLFerrofluid
Ellipsoidal
320–490 nmBare
SiO2
MTS, BrdU assayTime-dependent cell viability (7 days, 20%)
Induced M1 activation
[235,236]
Nervous system cells (human, PC12)0–1000 µg/mLSpherical
Hollow spheres
5–100 nmPGA
SiO2
Dextran
Bare
MTS, LDHMTS increased production
DNA fragmentation, apoptotic
Conformational changes in Tau protein
Oxidative stress
[237,238,239]
Endothelial cells (BAECs, HUVECs)50 µg/mL
0–100 µg/mL
0, 300, 600 µg/mL
Spherical
Spherical–like
50–600 nm
5–10 nm
10 nm
Bare
Dextran
PSC
PI staining, RedoxCellular intake
Cell viability 80 ± 3%
Promotes cell survival by autophagy
Peroxidase-like activity
[240,241,242]
Cancer (multiple)50, 100, 500 µg/mLSpherical–like6 nmDMSAMTTHigh cell viability >90%
Trigger immune response
High ROS activity
[240,241,242,243]
Vascular system (A10 rat)50, 100, 200, 400 µg/mLSpherical–like150–160 nmBare
Citric acid
Redox, MTTDecreased cell viability
Increased actin and calponin expression
Concentration-dependent toxicity
Migration of EPC reduced
[242,244,245]
* Table modified from [246]. BrdU—bromodeoxyuridine, TB—trypan blue, ROS—reactive oxygen species, GSH—glutathione, TP—total protein, LDH—lactate dehydrogenase, MTT—3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide, MTS—3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, PI—propidium iodide, PEG—polyethylene glycol, PDA—polydopamine, DOX—doxorubicin, PSC—polyglucose sorbitol carboxymethyl ether, DMSA—dimercaptosuccinic acid.
Table 3. Biological assessment of treatments for MNPs.
Table 3. Biological assessment of treatments for MNPs.
Biological StudiesType of AssayAssays in MNPsRef.
In vitroSuspension (HL60, K562) Monolayers (MCF-7, U87MG)
Cultured
CCK8, MTT, TB, LDH, Comet[268,278]
Ex vivoLangendorff isolated system, in silico studies Perfusion pressure, protein expression, mediator count, liver, spleen, lungs, heart [250,264,279]
In vivoBiodistribution, histological stainingVIP, liver, spleen, lungs, heart[268,280]
CCK8—cell counting, VIP—vacuum filtration process.
Table 4. Definitions of nanomaterials of different global organizations.
Table 4. Definitions of nanomaterials of different global organizations.
OrganizationNanomaterial Definition *StatusLast Meeting/ProposalRef.
NANoREG (European Union, EU, European Commission, EC)Taken from EC: “Any intentionally produced material that has one or more dimensions of the order of 100 nm or less or that is composed of discrete functional parts, either internally or at the surface, many of which have one or more dimensions of the order of 100 nm or less”.Toxicological data gathering2014, updated by NanoFATE in 2022[281,282]
International Organization for Standardization (ISO)“Any material with any external dimension in the nanoscale or having an internal structure or surface in the nanoscale”.Terms and vocabulary for nano-objects2017[283]
FDA (United States of America, National Nanotechnology Initiative, NNI)Taken from the NNI: “The understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications”.Nonbinding recommendations for manufacturers2014[284,285]
ECHA (European Union)“A natural, incidental, or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in size range 1 nm–100 nm”.Guidance for terms, vocabulary, and sample dispersion and aggregation of nanoformsDraft 2021[286]
CEPA (Canada)“Any manufactured substance or product, as well as any component material, ingredient, device, or structure, if it has at least one external dimension that is at or within the nanoscale, or if it has internal or surface structure that is at the nanoscale, or if it has all dimensions that are smaller or larger than the nanoscale and exhibits at least one nanoscale property or phenomenon”.Guidance framework for adapting nanomaterials to existing practicesDraft 2022[287]
* The definition was extracted literally from each organization manuscript cited in the reference column.
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Vargas-Ortiz, J.R.; Gonzalez, C.; Esquivel, K. Magnetic Iron Nanoparticles: Synthesis, Surface Enhancements, and Biological Challenges. Processes 2022, 10, 2282. https://doi.org/10.3390/pr10112282

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Vargas-Ortiz JR, Gonzalez C, Esquivel K. Magnetic Iron Nanoparticles: Synthesis, Surface Enhancements, and Biological Challenges. Processes. 2022; 10(11):2282. https://doi.org/10.3390/pr10112282

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Vargas-Ortiz, Jesús Roberto, Carmen Gonzalez, and Karen Esquivel. 2022. "Magnetic Iron Nanoparticles: Synthesis, Surface Enhancements, and Biological Challenges" Processes 10, no. 11: 2282. https://doi.org/10.3390/pr10112282

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