Early disease detection is highly desirable to improve health outcomes and reduce social-economic burdens (1-3). Specifically, rapid and sensitive characterization of disease biomarkers will not only be of immediate value for diagnostic screening, but also facilitates monitoring of disease progression and treatment efficacy (4,5). Recently, diagnostic strategies based on magnetic nanoparticles (NPs) have received considerable attention (6-9). These magnetic approaches experience little interference from native biological samples, as biological specimens typically have negligible magnetic susceptibilities, making them transparent to the external magnetic field even in the absence of extensive sample preparation. Central to these diagnostic approaches, new generations of magnetic nanomaterials have been specifically designed and developed for biomedical applications (10-13). These diverse magnetic nanomaterials not only possess high biocompatibility, but also support efficient image contrast and enable versatile surface modifications. Importantly, based on their unique applications in different detection modalities—as in vivo probes of magnetic imaging or ex vivo labels of biosensing assays—new nanomaterials could be specifically designed to fulfill new diagnostic needs (Figure 1).
Over the years, various magnetic detection technologies have been developed. As one of the most powerful diagnostic technologies among various imaging tools, magnetic resonance imaging (MRI) can provide pathophysiological information, through the generation of anatomical and functional images at a high spatial resolution. To further improve the imaging sensitivity as well as to analyze specific anatomical sites of interest, various inorganic magnetic nanomaterials have been developed and employed as MRI contrast agents (14,15). These materials possess not only exceptional potency in accelerating the spin relaxation time of water protons (image contrast), but also excellent colloidal stability, biocompatibility, and long circulation time for in vivo applications (16-19). More recently, with the advancement of MRI technologies, responsive agents which can react to local biological environments have been developed to provide functional and molecular information (20-22).
Beyond in vivo imaging, magnetic nanomaterials have also been applied to establish new generations of diagnostic assays for ex vivo detection. To quantify biologically relevant signals through magnetic nanomaterials, various detection technologies have been developed. These include techniques that use nuclear magnetic resonance (NMR) detectors to measure changes in the relaxation rate of surrounding water molecules, akin to the detection mechanism of MRI (7,9), as well as the applications of magnetometers [e.g., magneto-resistive sensors (23,24), Hall sensors (25,26)] to quantify magnetic fields directly from labeled biological targets. Through specific integration of nanomaterials with miniaturized detection platforms, these magnetic diagnostic assays have shown promising potential to provide robust, sensitive platform for point-of-care diagnostic applications.
By developing optimized magnetic nanomaterials, the detection sensitivities and capabilities of MRI and other magnetic sensors have been significantly improved. To date, various magnetic biosensors have been designed to quantify a wide range of targets, including proteins (27,28), extracellular vesicles (29-31), bacteria (32,33), and mammalian cells (34,35). This review focuses on the design and preparation of magnetic NPs as well as their applications for in vivo imaging and point-of-care sensors.
Magnetic properties and material synthesis
The classification of a material’s magnetic properties is based on its magnetic susceptibility (χ), which is defined by the ratio of the induced magnetization (M) to the applied magnetic field (H). While in ferri- and ferromagnetic materials, magnetic moments align parallel to H. Coupling interactions between the electrons of the material result in ordered magnetic states. At small particle sizes (in the order of tens of nanometers), ferri- or ferromagnetic materials, such as magnetic NPs, become single magnetic domains and therefore maintain one large magnetic moment. However, at sufficiently high temperature, thermal energy can induce free rotation of the particles, resulting in a loss of net magnetization in the absence of an external field. This superparamagnetic property ensures that magnetic NPs do not spontaneously aggregate under physiological solutions (36).
By producing local magnetic dipoles with strong spatial dependence, magnetic NPs efficiently destroy the coherence in the spin-spin relaxation of water protons. The net effect is a change in magnetic resonance signal measured as (I) T1 longitudinal relaxation, which results in longitudinal magnetization recovery, and (II) T2 transverse relaxation, which involves transverse magnetization decay originating from the loss of phase coherence and dephasing between the proton nuclear spins. The capacities of magnetic NPs to decrease T2 and T1 are defined as their transverse (r2) and longitudinal (r1) relaxivities, respectively. As a result of these intrinsic properties, magnetic NPs can be used as contrast agents in MRI studies and as labeling and signal transducers in biosensing studies. Several factors could be considered in controlling the magnetic properties of these nanomaterials, including their material composition, size-dependent magnetism, shape and structure, as well as surface coating. Here, we briefly introduce several typical NPs, their synthesis methods as well as their magnetic properties.
Magnetic NPs have been prepared in chemical precipitation process (37), hydrothermal process (38), ball milling (39), microemulsion (40), and Sol-Gel method (41,42). The formation mechanism of monodisperse NPs can be explained by the “LaMer model” which systematically describes NPs formation and growth during particle synthesis (43). Specifically, this model involves three different steps, namely nucleation, crystal growth, and Ostwald ripening (Figure 2). By optimizing the conditions at these steps, NPs with variable sizes, shapes, and components can be prepared in a controlled manner.
Magnetic metal NPs
Iron (Fe) is one of the most common ferromagnetic materials used for magnetic applications (44). To date, many methods have been used to synthesize Fe NPs. These methods include reduction of iron salts in aqueous solutions, in the presence of reducing agents such as sodium borohydride. In order to ensure particle uniformity, Fe NPs can also be synthesized by thermal decomposition of Fe(CO)5 based on a polymer matrix (45). Additionally, by changing the precursors to Fe[N(SiMe3)2]2, the overall synthesis yield can be improved and by-product formation is reduced (46).
In addition to Fe, cobalt (Co) is another commonly used material. In the synthesis of Co nanomaterials [as well as Ni and FeM (Co, Pt) composite materials], organic phase preparation has been widely adopted (47-49). In this synthesis approach, surfactants play a key role in controlling the particle size. Specifically, surfactants control the formation of droplets of varying sizes; these droplets define the templates in which nucleation and NPs growth will happen. For example, tributylphosphine (TBP) has been frequently used to control Co nucleation and growth, while oleic acid is used for particle stabilization (50). Alternatively, Co NPs can also be prepared by reducing cobalt(II) bis(2-ethylhexyl)sulfosuccinic acid [Co-(AOT)2] with NaBH4 (51) or directly synthesized by reducing Co(CH3COO)2·4H2O under high temperature (52).
In addition to the traditional face-centered cubic (fcc) and hexagonal-close-packed (hcp) structures, Co NPs also have a special structure—ε-structure which is mainly formed by reducing CoCl2 with hydride (53). There is a strong correlation between crystal structure and the magnetic properties of cobalt. By changing the state of the metastable ε-Co NPs, the corresponding soft magnetic properties can also be tuned.
Magnetic oxide NPs
Magnetic oxide NPs are attractive due to their strong magnetic properties and chemical stabilities. Among them, Fe3O4 has cubic-closest-packed inverse spinel structure and semi-metallic properties, showing great potential in magnetic separation and biomedical fields (54,55). One of the conventional methods to synthesize Fe3O4 NPs is using a simple solvothermal reduction system based on Fe complexes (56). However, this method cannot effectively control the surface energy and ensure uniform growth of magnetic iron oxide NPs. Therefore, organic phase methods have been explored to prepare NPs with uniform sizes. Researchers have also used different concentrations of precursor components and dopants to prepare different nanostructures (57). For example, Zeng et al. tuned surfactant/metal precursor ratios to obtain cubic and polyhedral structures of Fe3O4 (58). Different morphologies of magnetic NPs show different magnetic properties. For example, compared with the cubic structured ferrite, the room temperature coercivity (Hc) of hexagonal barium ferrite (BaFe) NPs became much higher (over 4k Oe) by appropriately adjusting the proportion of the components (59). In addition, antiferromagnetic NPs [such as FeO (60), NiO (61), and MnO NPs (62)] can also be prepared by this kind of thermal decomposition based on suitable metal precursors.
Multicomponent magnetic NPs
As compared to single-component NPs, multicomponent NPs do not only realize multifunctionalities but also provide novel functions that are not available in single-component materials or structures. In addition, it can achieve enhanced properties and overcome the natural constraints of single materials. The progress on the design and synthesis of multifunctional NPs has been summarized in several recent comprehensive review articles (63-65). Here, we highlight two main kinds of multifunctional NPs (core/shell and dumbbell-like NPs), including their structures and magnetic properties.
Core/shell NPs are the most common type of multicomponent NPs and have been studied extensively. Core/shell structures were first realized in semiconductor NPs (66), expanded to prevent the oxidation of metal, especially Fe which has extremely high reactivity. Lee et al. recently prepared hybrid magnetic NPs (Fe/Fe3O4) with a large Fe core and a thin ferrite shell. Briefly, iron (0) pentacarbonyl [Fe(CO)5] was thermally decomposed into Fe core. The mixture was then treated with oxygen, resulting in a thin protective ferrite shell while retaining a larger Fe core. This material showed enhanced sensitivity for the detection of bacterial cells with r2 relaxivity of up to 260 (s·mM Fe)−1 (67). Moreover, the ferrite shell could be further engineered (Fe@MFe2O4, M = Fe, Mn, Co) (68) (Figure 3). The resultant particles showed high relaxivity and remained mono-dispersed with little particle aggregation. Fe@MFe2O4 could sensitively detect proteins and individual cancer cells in the picomolar range. Another interesting core-shell structure is core/shell Fe/FexC NPs prepared through thermal decomposition of Fe(CO)5 under argon or hydrogen (69). The magnetic properties of these nanostructures are shown to be improved as compared to Fe3O4 or core-shell Fe/Fe3O4 NPs even after oxidation.
Besides Fe metal core, FePt@Fe3O4 offers another important functional improvement. For example, in the previously synthesized FePt seed solution, Fe(acac)3 could be thermally decomposed to form FePt@Fe3O4 NPs (70). It is noteworthy that the particles with 0.5 nm Fe3O4 shell have Hc of 5 kOe, while those with 3 nm shell have a Hc value of only 1.4 kOe, indicating the dependence of Hc over the thickness of the Fe3O4 shell. Furthermore, through the addition of the shell component onto the magnetic cores, the magnetic properties of these core/shell NPs can be effectively adjusted due to the energy conversion efficiency and the thermal energy changes at the core/shell interface. As a typical representative which took advantage of the plasmon resonance properties of noble metals in magnetic systems, Au@Fe3O4 NPs were explored. It exhibited both superparamagnetic of Fe3O4 NPs and plasmonic properties of gold (71), while the magnetic properties of Fe3O4 were affected by the interactions between Au and Fe3O4. In order to synthesize multicomponent NPs with specific size and morphology, seed-mediated growth methods are often used. For example, Ge et al. illustrated a strategy called “packaging and etching” (72). These core/shell NPs are particularly suitable as multifunctional probes for biomedical applications. In addition to regulating the composition of nanomaterials, particle morphology and structure can also be tuned to improve their magnetic properties. For example, Gao et al. selected FePt NPs as seeds to prepare FePt@CoS2 egg yolk-shell nanocrystals by oxidation of FePt NPs (73).
Unlike the core/shell NPs which are typically formed by coating a uniform shell on the seed NPs, dumbbell NPs are usually formed by anisotropic nucleation and growth of one or even more discrete components on the surface of the seeds. The most studied dumbbell NPs are precious metal-magnetic oxide NPs (74). For instance, Au-Fe3O4 dumbbell NPs were obtained by the thermal decomposition of Fe(CO)5 on the surface of prefabricated Au NPs followed by air oxidation (Figure 4A,B,C) (75). Similarly, Fe(acac)3 and Fe-oleate were also used to synthesize Au-Fe3O4 dumbbell NPs via thermal decomposition reaction in high boiling point non-coordinating solvents (e.g., 1-octadecene) (71,77). Typically, during the growth process, the template material is gradually oxidized and the precious metal on the surface continuously grows. The anisotropic growth of dumbbell NPs is closely related to the polarity of the solvent and the surfactant; the polarity of the solvent or the surfactant could be regulated to control the size and morphology of the resultant NPs (78). By combining two different components, the physical and chemical properties of the dumbbell NPs can be significantly different from their single component counterparts. For example, the absorption peak of Au-Fe3O4 NPs is red-shifted from 520 to 538 nm owing to the light absorption of Fe3O4. Like the Fe3O4 NPs, the dumbbell particles are superparamagnetic at room temperature. The 3–14 nm dumbbell particles show loops similar to the 14 nm Fe3O4 NPs with saturation moment reaching 80 emu/g. The NPs are thus useful as dual optical/magnetic probe for diagnostic and therapeutic applications (75).
More complex dumbbell NPs can be synthesized using preformed two-component dumbbell NPs as seeds, for example Au2-Au1-Fe3O4 NPs (Figure 4D,E). The growth mechanism is related to the non-uniform strain-energy distribution caused by lattice distortion and failure criterion. In the Au1-Fe3O4 solution, when Au1 is small, the lattice distortion is large, and Au2 prefers to grow as individual Au NPs. For the larger Au1, the strain energy is located at the interface of Au1-Fe3O4 NPs, and the lattice distortion at the far end of Au1 is small. This favors the growth of Au2 on Au1 to form more complex structures (76). The author further identified that the interactions between Fe3O4 Au1 and A2 have important influences on the magnetic properties of Fe3O4.
Magnetic resonance imaging (MRI)
MRI measures the spin relaxation of water protons and is widely used in clinical imaging. As a non-invasive imaging tool, MRI enables a high spatial resolution at the cellular level (~10 µm) and deep tissue penetration without any ionizing irradiation, thereby offering good soft tissue contrast in normal and disease physiology. These distinct advantages make MRI one of the most powerful tools in clinical diagnostics, real-time treatment monitoring, and post-therapy evaluation. Furthermore, through the administration of exogenous contrast agents, which can accelerate the relaxation of water protons by causing local magnetic fields, the MRI sensitivity and signal-to-noise ratio can be greatly enhanced to favor accurate molecular imaging (15,79). Clinically, >30% of all MRI scans are performed with the assistance of MRI agents. These contrast agents are either paramagnetic or superparamagnetic, with diameters ranging from a few nanometers to several hundred nanometers. They can be categorized into different groups according to their working mechanisms.
T2 contrast agents
T2 agents, which are also called negative contrast agents, are usually paramagnetic NPs in the form of various ion oxides (80). T2 agents work by shortening T2 of water protons, thereby generating negative (dark) images (81). Under the induction of external magnetic field, the T2 agents can generate a local magnetic field which perturbs the spin-spin relaxation process of water protons nearby. As such, the contrast-enhancing capability of T2 agents is highly related to their corresponding superparamagnetic properties and the applied external magnetic field.
As mentioned previously, the NPs’ size and magnetic doping to form MFe2O4 (M = Co, Ni, Mn) have significant influence on the superparamagnetic properties. In addition, new studies have also shown that the particle morphology, as well as the inclusion of chelating agents can affect the T2 image contrast capacity. For instance, Zhao and coworkers synthesized octapod iron oxide NPs and found that the material showed an ultrahigh transverse relaxivity (r2) of 679.3±30 mM−1s−1, which was over 5 times higher than spherical iron oxide particles of similar geometric volumes (18). By preparing six different morphologies of manganese-doped iron oxide NPs, namely spheres, cubes, plates, tetrahedra, rhombohedra and octapod of the same volume, Yang et al. showed that the effective radii of the nanomaterials are crucial factors in affecting the T2 relaxation rates of nearby protons (82). In addition, chelating agents have also been found to affect the transverse relaxation time by influencing the inhomogeneity of induced local magnetic field of magnetic NPs (83).
T1 contrast agents
In comparison, T1 agents or positive contrast agents are mainly paramagnetic NPs which work by shortening the longitudinal relaxation time (T1) of water protons, thus producing positive (bright) images. While current clinical T1 agents are primarily gadolinium (Gd) complexes, these agents have several disadvantages, including toxicity resulted from the leaching of Gd3+ from the complexes. In addition, the agents’ relatively low in vivo circulation time further limits their clinical potential.
To overcome these disadvantages of Gd-based T1 agents and develop new generations of magnetic T1 agents for ultrasensitive imaging and early diagnosis, Mn and Fe-based T1 MRI contrast agents have been extensively researched in recent years (19,21,84). In particular, the transition manganese metal ion (Mn2+) is antiferromagnetic with five unpaired electrons and an essential element in human body. These features render the material a good T1 candidate for in vivo usage. At present, a series of Mn-based NPs [e.g., MnO (85), Mn3O4 (86) and hollow MnO2 NPs (87)] has been successfully developed for T1 contrast imaging.
With five unpaired electrons, Fe-based NPs also show potential as T1 contrast agents. A critical parameter in determining if the contrast agents can be considered as T1 or T2 agents is their ratio of relaxivity (i.e., r2/r1). An ideal T1 contrast agent should exhibit high r1/r2 ratio to maximize their T1 contrast effect, while suppress the influence of T2 contrast. Generally, iron oxide NPs with a diameter >5 nm are not good for T1 imaging due to their high r2 value (i.e., large r2/r1 ratio). Specifically, recent studies have suggested that iron oxide NPs <5 nm can be highly desirable T1 imaging (88). To enhance the material’s T1 contrast efficiency, iron oxide NPs could be modeled as core/shell structures. This type of material typically consists of a magnetic core to contribute to its T2 performance as well as a magnetically disordered shell for improving its T1 contrast. By decreasing the particle size, the magnetic core can be greatly reduced and thereby dramatically suppressing its magnetic moment. This reduction in particle size further improves the surface effect, which increases the dangling bonds of Fe3+ and the spin canting effect. These effects act in synergy to increase the particles’ r1 relaxivity while reducing their r2 relaxivity.
Responsive MRI agents
Responsive MRI agents are activatable magnetic agents which are not only able to enhance the signal-to-noise imaging ratio at the sites of interest, but also produce simultaneous readouts of specific anatomical and physiological conditions (20,46,89-91). Specifically, new generations of responsive MRI agents can detect a wide range of stimuli, including hypoxia, redox states, enzymes, nucleic acids, metabolites, or changes in redox states and pH. As T1 and T2 relaxation times are mainly affected by two physiochemical factors of MRI contrast agents, namely water accessibility and superparamagnetism, new research has been focusing on developing activatable MRI agents through changing their hierarchical organization (e.g., assembly or disassembly of NPs to influence the degree of water accessibility or the magnitude of the superparamagnetism) (92,93). For example, Chen and co-workers have recently designed a T1-MRI contrast agent based on Mn2+ ions for efficient imaging of acidic tumor microenvironment (21). The prepared MnOx encased in hollow mesoporous silica can be dissolved under weak acidic environment to release Mn2+ ions. This release significantly increases the relaxation rate r1 of probes, achieving a 11-fold signal as compared to measurements with the neutral condition.
As previously described, the T2 performance of MRI agents is tightly related to their superparamagnetic property, which is positively correlated to the size of the magnetic nanomaterials. Levering on this design principle, Wang et al. recently developed ultra small iron oxide NPs with the size of 3.5 nm (94). In acidic tumor environment, these NPs can assemble into clusters and hence improve the T2 signal. Aside from this T1 to T2 contrast switching to sense the local pH, the magnetic clustering also facilitates the retention of the nanomaterials in the tumor, thereby improving the functional performance of the imaging system. In addition to pH, enzymatic activity can also be a triggering factor to cause (dis)aggregation of magnetic NPs. Recently, Gao et al. established a glutathione (GSH)-responsive MRI agent, which could enhance image contrast through cross-linking of adjacent Fe3O4 NPs (22). In the presence of GSH within the tumor microenvironment, the particles aggregated through in situ reaction between thiol groups and melamine moieties on the NPs. The aggregated particles showed a higher saturation magnetization and thus substantially improved the T2 contrast.
Due to their high sensitivity, compact instrumentation, and flexible integration, magnetic biosensors have emerged as excellent detection devices for point-of-care diagnostics. In recent years, a number of sensitive magnetic detection devices have been developed such as, magnetoresistive sensors (95), spin-valves (96), anisotropic magneto resistive-based sensors (97), superconducting quantum interference devices (SQUIDs) (98), Hall sensors (99), giant magneto-impedance based sensors (100), and micro-NMR sensors (101). In this section, we will use two sensing mechanisms, namely giant magnetoresistance (GMR) and NMR, to illustrate magnetic detection.
The GMR effect is a change in electrical conductivity in a system that comprises multiple metallic layers. Under the influence of an external magnetic field, the magnetization of the ferromagnetic layers changes relative to one another, thereby changing the overall electrical conductivity of the system. In terms of sensor functionality and fabrication, GMR sensors possess many advantages, such as high sensitivity, low power, easy fabrication, and good compatibility with standard silicon-based integrated circuit technology. Hence, these sensors have demonstrated promising potential as sensing elements for biomarker detection (102). Specifically, recent studies have employed GMR sensors, in combination with magnetic beads as molecular labels, for diverse biomedical sensing applications (100,103-105). In these applications, GMR sensors were used to quantify magnetic fields directly from the labeled biological targets.
NMR is another powerful magnetic phenomenon. Unlike the direct detection of magnetic moments by GMR sensors, NMR sensors detect via changes in the spin relaxation induced by magnetic fields (34,106). Aside from its application in MRI, the sensing mechanism can also be applied for ex vivo detection. Depending on the size of the target biomarker, there are two forms of magnetic NMR assays. For detecting small analytes, such as metabolites, oligonucleotides, and proteins, magnetic relaxation switching (MRSw) effect can be exploited. MRSw relies on the changes in organizational state of magnetic NPs in solution (107). Magnetic NPs switching between dispersed and aggregated states are associated with changes in the spin-spin relaxation time (T2) (Figure 5A). MRSw assays are performed without removing excess unbound magnetic NPs and thereby facilitate the detection of small molecules. On the other hand, larger biological targets (e.g., cellular components, bacteria, and mammalian cells) can be tagged with functional magnetic NPs, while the unbound magnetic NPs are removed. This gain of magnetic signal (change of 1/T2) is proportional to the number of bound magnetic NPs and indicates the abundance of relevant biomarkers (Figure 5B) (7,108). To facilitate these different assay formats, miniaturized NMR detectors have been developed (Figure 6). These systems offer distinctive advantages. First, they lower the detection limit by reducing the sample volumes and hence effectively increase the analyte concentrations (109). Second, miniaturized NMR probes (coils) produce much stronger radio-frequency (RF) magnetic fields per unit current, leading to higher signal-to-noise per unit sample volume (101). Third, with smaller RF coils, the requirement for spatial homogeneity of static magnetic fields becomes less stringent, making it possible to use small, portable magnets (34). Through these integrated advances, NMR sensors could be used to detect a wide variety of biological targets, thereby extending its applications for point-of-care biomedical diagnostics.
Magnetic NPs and their detection strategies have recently received considerable attention. In combination, these magnetic diagnostic systems offer unique advantages over conventional detection methods. Specifically, because biological samples exhibit negligible magnetic background, magnetic nanomaterials can be used directly for both deep tissue imaging as well as point-of-care diagnostics. Through recent progress in material design and synthesis, new generations of magnetic NPs can be precisely engineered to fulfill new functional needs. For in vivo imaging, novel magnetic NPs not only enable strong image contrast of targeted anatomical sites, but can also sense the local molecular environments to catalyze contrast switching. For ex vivo diagnostics, magnetic nanomaterials are seamlessly incorporated into miniaturized biosensing platforms, thereby enabling the detection of rare and diverse molecular targets without requiring for extensive sample preparation. Through these synergistic developments, it is likely that magnetic detection will have broad applications in biomedical research as well as clinical translation.
This work was supported in part by funding from NUS Research Scholarship, MOE, NMRC, A*STAR IMCB Independent Fellowship and NUS Early Career Research Award.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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