Abstract
The study of tiny particles and their applications have emerged as an important area of research in recent years. In particular, magnetic nanoparticles have attracted considerable attention due to their unique properties that make the particles useful in numerous applications. Accordingly, the present review investigates the synthesis, characterization, and biomedical applications of magnetic nanoparticles. The introduction section examines recent advances in nanotechnology and explains the significance of magnetic nanoparticles in scientific research. The section on results and discussion presents the findings of various researchers with a focus on the magnetic properties, synthesis, characterization, and biomedical applications of magnetic nanoparticles. Particularly, the study notes that the reduction of size in multi-domain substances forms single-domain materials, which generate the effect of superparamagnetism. Accordingly, superparamagnetism is one of the most important characteristics of magnetic nanoparticles utilized in various applications. The section on the synthesis of magnetic nanoparticles explains the solid-, gas-, and liquid-phase methods. Next, the paper discusses the different methods of characterization that are employed to preserve magnetic properties and improve the biomedical applications of nanoparticles. Finally, the review concludes that magnetic nanoparticles have different characteristics from the bulk scale, which makes the particles useful for biomedical applications.
Keywords: Nanoparticles, synthesis, characterization, biomedical applications
Nanoscience is an emerging scientific field that employs interdisciplinary approaches to study tiny particles. Accordingly, nanotechnology development involves the improvement of techniques for molecular and atomic based examination of materials in nanoscale. Nanotechnology employs the concept that minute materials have a high surface area that increases surface reactivity, as well as quantum-associated effects. Issa et al. (2013) explained that the decrease in the size of nanoparticles increases the “surface-to-volume ratio (and consequently the fraction of the surface atoms with respect to the bulk ones).” The nanoparticles’ large surface-to-volume ratios are primary determinants of the particles’ unique mechanical, chemical, and physical properties when compared to the features that correspond to bulk materials. Notable physical properties of nanoparticles include magnetic, electric, and optical characteristics (Issa et al., 2013). Chemical properties include the reactivation rate whereas mechanical properties include hardness and strength. The properties increase the usefulness of nanoparticles in various biomedical applications (Gupta et al., 2013). Moreover, they create opportunities for the future application of nanoparticles to life sciences. As a result, the novel properties of nanoparticles attract the attention of investigators in scientific fields like medicine and biology. The exclusive efficacy and properties of nanoparticles are associated with attributes such as the equal size of biomolecules and nanoparticles. As such, nanoparticles provide a novel interaction with biomolecules inside and on the surface of cells, which facilitates the development of cancer treatment and diagnosis. In particular, magnetic nanoparticles (MNPs) have been utilized widely in environmental fields, material science, engineering, biotechnology, and biomedicine (Faraji et al., 2010). MNPs are nanoparticles that show response to the application of a magnetic field. Since particle size affects surface-to-volume ratio, a large ratio increases the number of atoms residing on the particle’s surface in comparison to the number of atoms at the core. For example, about 0.2% of the atoms in a nanoparticle with a diameter of one μm occur on its surface whereas approximately 20% of the atoms of a particle with a diameter of six nm occur on the particle’s surface (Issa et al., 2013). Thus, synthesis of nanocrystals is important because the nanocrystals’ properties depend on the dimensions of the particles. Synthesizing uniform-sized nanoparticles with manageable sizes promotes the characterization of size-dependent properties of the particles. Consequently, different methods have been introduced to prepare MNPs. The techniques include thermal decomposition, microemulsion, and chemical coprecipitation. Although the methods can synthesize monodispersed MNPs, investigators continue to face challenges when controlling the surface, shape, and size of the nanoparticles. However, the generation of nanocrystals is crucial to realizing numerous nanotechnological applications and useful nanoscale devices. For instance, “color sharpness of semiconductor nanocrystalbased optical devices and biomedical imaging probes” depends on the nanocrystals’ uniformity (Faraji et al., 2010, p.1). Furthermore, biomedical applications utilize nanoparticle properties such as high values of magnetization, sizes that are smaller than one hundred nm, and narrow size distribution. Given the significance of nanoparticles in many fields, the present critical review explores the synthesis and characterization of MNPs and discusses their biomedical applications.
Results and Discussion
Magnetic Property
Materials are often classified according to their response to external magnetic fields. Also, orientations of materials’ magnetic moments facilitate the identification of different types of magnetism, including ferrimagnetism, antiferromagnetism, ferromagnetism, paramagnetism, and diamagnetism (Faraji et al., 2010). Spins pointing in similar directions occur in domains separated by walls that possess characteristic energy and width (Kolhatkar et al., 2013). The movement of the walls is often utilized while reversing magnetization. Experiments focusing on coercivity’s dependence on the size of particles have demonstrated a similar effect (Fig. 1). The reduction of size in multi-domain substances forms single-domain materials that create the effect of superparamagnetism.
Figure 1. Particle Size versus Coercivity (Faraji et al., 2010). The figure shows a schematic representation of the effect of particle size on coercivity. In particular, its demonstration of coercivity’s dependence on the size of particles reveals that the movements of domain walls can to be employed to reverse magnetization.
Basically, superparamagnetism is associated with the movement of a nanoparticle’s magnetic moments away from a preferred crystallographic axis due to the effect of thermal fluctuations (Kolhatkar et al., 2013). Each particle adopts paramagnetic tendencies while maintaining large magnetic moments because of the existence of magnetic order in nanoparticles. Superparamagentic materials show intrinsic nonmagnetic properties although external magnetic fields can readily magnetize the materials (Kolhatkar et al., 2013). Faraji et al. (2010) noted that different particles have different critical radii, which are determined by crystalline magnetoanisotrophy, temperature, and shape.
Synthesis
Over the last decade, significant effort has been made to enhance the production of magnetic nanoparticles. Researchers have succeeded in synthesizing MNPs with different phases and compositions, including metal alloys like CoPt and FePt (Mandal & Chaudhuri, 2016), ferrites like MFe2O4 (where M represents metals such as Mg, Mn, Ni, and Cu), metal oxides like Fe3o4, and pure metals such as Ni, Co and Fe (Faraji et al., 2010). Over the years, numerous studies have described different methods of attaining highly stable and shape-controlled MNPs (Kang et al., 2013; Li et al., 2015). In particular, popular methods have included laser pyrolysis, carbon arc, combustion synthesis, chemical vapor deposition, microwave-assisted, sonochemical, solvothermal, microemulsion, and co-precipitation techniques (Faraji et al., 2010).
Liquid Phase Synthesis
The principles employed in the preparation of monodisperse particles are often presented in a LaMer diagram (Fig. 2). The diagram explains that homogenous precipitations experience an increase in concentration that exceeds the saturation point to allow the occurrence of nucleation. Faraji et al. (2010) suggested that particle growth “transpires by a combination of the diffusion of atoms onto the nuclei and with irreversible aggregation of nuclei” (p. 3).
Figure 2. The LaMer Diagram (Source: Faraji et al., 2010). The figure illustrates the requirement for achieving monodispersity. As such monodispersity has requirements such as high nucleation rate and rapid growth of nuclei.
Figure 2 demonstrates several requirements for the achievement of monodispersity. First, nucleation rate should be high to stop the concentration from increasing. Instead, bursts of nuclei occur in a limited time (τ short). Secondly, the nuclei should grow at a rapid rate to ensure that the concentration does not exceed the point of nucleation concentration. As a result, few particles are produced. Thirdly, the growth rate should not be excessively fast in order to ensure that the period of growth is longer than the period of nucleation (Faraji et al., 2010). Consequently, the distribution size resulting from a finite period of nucleation is narrowed. The control of such factors allows researchers to synthesize MNPs with varying sizes efficiently.
Gas Phase Synthesis
Gas phase techniques for preparing magnetic nanoparticles depend on reactions such as oxidation, disproportionation, hydrolysis, reduction, and thermal decomposition to induce the precipitation of solids from a gas phase. Gas phase techniques include chemical vapor deposition (CVD), arc discharge, and laser pyrolysis. In the process of CVD, a system of gas delivery moves a stream of gas with precursors to reaction chambers that are maintained at temperatures exceeding 900 degrees Celsius (Faraji et al., 2010). The reactions occurring in the chambers generate products that combine forming clusters of nanoparticles. Agglomeration and growth of the nanoparticles are mitigated through a rapid expansion of two-phase streams of gas at the outlets of reaction chambers. Next, the synthesized powder of nanoparticles undergoes heat treatment in different high-purity streams of gas to ensure structural and compositional modifications that include particle crystallization and purification, in addition to the transformation of particles into a desirable morphology, composition, and size. CVD process is often used in the deposition of iron oxide by reacting a halide like iron trichloride with H20 at a temperature of between 800 and 1000 degrees Celsius (Faraji et al., 2010). The technique’s effectiveness is influenced by the low concentration of precursors in a carrier gas and the rapid expansion that is followed by quenching of nucleated clusters as they leave the reactors. In recent years, “catalytically assisted chemical vapor deposition (CCVD)” has been employed widely due to its capacity for scalable generation (Faraji et al., 2010, p.9). Nonetheless, there is a need to overcome several obstacles in order to realize CCVD’s potential. The challenges include the “relatively low productivity, the existence of complex phases, and the difficulty in separating carbon-encapsulated superparamagnetic” nanoparticles from impurities (Faraji et al., 2010, p.9).
Solid Phase Synthesis
Several solid-phase techniques are used to prepare carbon-encapsulated MNPs (CEMNPs). The approaches include methods based on the “high-temperature annealing of materials such as Fe2O3 plus C powders, elementary Fe plus C powders, and Co NPs plus copolymers” (Faraji et al., 2010, p.10). In such techniques, nonetheless, magnetic properties and size of final products are hard to control. In addition, superparamagnetic particles are difficult to obtain because the starting size of the particles often exceeds 10 nm. One example of a solid-phase technique involves the application of combustion syntheses to the generation of CEMNPs. Investigators have used the approach to produce crystalline nanoparticles, CoFe2O4, and cobalt ferrite (Faraji et al., 2010). In the process, exothermic carbon oxidation generates thermal reaction waves that propagate through “solid reactants mixture of CoO and Fe2O3 converting it to cobalt ferrite” (Faraji et al., 2010, p.10). Furthermore, the extensive CO2 emission increases the friability and porosity of products. The researchers also found that a full conversion to a “ferrite CoFe2O4 structure” can only be achieved for “carbon concentrations exceeding 12% wt” (Faraji et al., 2010, p.10). Normally, a solid-state interaction between FeO and CoO involving the growth of cobalt ferrite crystals starts at an early combustion phase and continues into the zone of post-combustion. Also, the average size of the particles increases with the increase in combustion temperatures (Faraji et al., 2010). Other investigations have demonstrated that CESNs (carbon-encapsulated superparamagnetic nanoparticles) can be synthesized into particles with different magnetic characteristics and sizes through the annealing of Fe-C solution at varying temperatures. The heat treatment occurs at a low temperature of about 600°C with most nanoparticles being embedded in amorphous carbon matrices and having a size estimated at 8nm (Faraji et al., 2010). Researchers have applied the annealing method to synthesize iron nanoparticles with carbon and boron nitride nanocoatings (Faraji et al., 2010). In the experiment, the investigators employed mixtures of carbon or boron with α-Fe2O3 as starting materials. The powder was then annealed at a temperature “above 1273 K in a nitrogen atmosphere” (Faraji et al., 2010, p.10). Benefits of using a solid-phase technique include excellent control of particle size and, hence, efficient regulation of superparamagnetism. Additionally, the approach generates few impurities, which makes it appropriate for large-scale generation of magnetic nanoparticles.
Typically, MNPs have high sensitivity to agglomeration and oxidation because they have high chemical reactivates and possess a large surface area. The surfaces of the nanoparticles undergo rapid oxidation under an ambient condition (Wiedwald et al., 2010), which leads to the development of a thin oxide layer that dramatically changes the characteristics of the particles. Another problem facing the preparation of the materials involves the nanoparticles’ natural agglomeration into bigger clusters. Consequently, researchers have proposed the use of encapsulation procedures to preserve the magnetic properties of nanoparticles and protect them from agglomeration and oxidation (Faraji et al., 2010). Nanoparticles have been encapsulated successfully using materials such as surfactants, organic polymers, metal oxides, precious metals, silica, and carbon.
Characterization
Different applications and magnetic properties of MNPs are influenced by surface functional groups, structure, morphology, and size of prepared nanoparticles. As a result, several characterization methods have been employed to preserve magnetic properties and improve the applications of MNPs.
Morphology and Size
The core size of a particle is routinely determined using transmission electron microscopy (TEM), which reports the size of amorphous and crystalline parts of the core and allows the acquisition of number-weighted average values. In addition, the technique offers details about shape and size distribution (Fig. 3). Nonetheless, the method requires image treatment to ensure excellent analysis. Also, it should be carried out using a significantly large number of nanoparticles.
Figure 3. TEM Images (Faraji et al., 2010). The figure shows TEM images of various particles. In particular, (a) shows Fe3O4 nanoparticles, image (b) depicts “Fe3O4@nSiO2,” images (c-e) show “Fe3O4@nSiO2@mSiO2 microspheres,” and image (f) depicts “Fe3O4@nSiO2@mSiO2 microspheres” (Faraji et al., 2010, p.14).
Another technique, “high-resolution transmission electron microscopy (HR-TEM)” allows researchers to access a material’s atomic arrangement (Faraji et al., 2010, p.16). The method facilitates the study of local microstructures like screw axes, glide plane, lattice fringe, defects, and lattice vacancies, as well as the crystalline nanoparticles’ surface atomic arrangement. SEM (scanning electron microscopy) is also widely utilized in determining the size distribution and morphology of particles in scales ranging from nano to micro. However, SEM lacks efficiency when characterizing a nanoparticle’s core or shell because the technique gives reports of the total size of the particle (Fig. 3). Additionally, SEM is inefficient for nanoparticles that are lower than twenty nm and provides a lower resolution than TEM. Another popular technique for determining the size of nanoparticles is the “photon correlation spectroscopy (PCS), also called dynamic light scattering (DLS)” (Faraji et al., 2010, p.16). In the method, the nanoparticles’ diffusion coefficient is determined in solution to provide the hydrodynamic radii of corresponding spheres and the colloidal solution’s polydispersity.
Elemental and Structural Analysis
EDXD (Energy dispersive X-ray diffraction) technique can be performed on a given suspension and helps in the understanding of fine details about the structure of nanoparticles. Moreover, EDXD allows researchers to carry out elemental analyses and determine chemical compositions of prepared MNPs (Faraji et al., 2010). Also, the data obtained through the use of EDXD helps in estimating the ratio of elements found in the structure of a nanoparticle. Another technique involves the utilization of XRD spectra to determine phase purity and crystallographic identity of synthesized materials. It also allows the calculation of the average particle size using the “broadening of the most prominent peak in the XRD profile” (Faraji et al., 2010, p.18).
Magnetic Properties
Numerous techniques have been developed to measure magnetic properties associated with MNPs. In particular, powerful tools like VSM (vibrating sample magnetometry) and SQUID magnetometry have been employed in the measurement of the net magnetization of various samples. Like the majority of traditional magnetization probes, the two techniques measure the entire magnetization instead of being element specific (Faraji et al., 2010).
Surface Characterization
XPS (X-Ray photoelectron spectroscopy) has been used extensively to study the mechanisms involved in the reactions occurring on the surfaces of MNPs. Generally, XPS spectra help to determine the characteristics associated with the bond between different elements. Moreover, the technique facilitates the confirmation of the speciation and structure of elements occurring in MNPs’ chemical compositions (Faraji et al., 2010). Another useful method of surface characterization is the application of FT-IR spectroscopy to the study of an organic molecule’s functional group. FT-IR helps in confirming the attachment of various functional groups during the process of functionalization (Faraji et al., 2010).
Biomedical Applications of MNPs
MNPs have been used in disciplines such as spintronics (Singamaneni et al., 2011), information storage, biomedicine (Vallejo-Fernandez et al., 2013), catalysis, magnetic fluids, and storage of magnetic energy. In medical fields, MNPs can be utilized as contrast agents, which improve the contrast of images in MRI. They are also used in tumor treatment where healthcare practitioners introduce the nanoparticles selectively into tumor cells (Issa et al., 2013). The temperature of the particles is then increased to about 43°C using oscillating magnetic fields, which increases the sensitivity of tumor cells to treatment modalities such as radiation. In addition, MNPs can be employed as “site-specific drug delivery agents, which involves immobilizing the drug on magnetic materials under the action of external magnetic field” (Issa et al., 2013). In the past, nanoparticle ferrofluids were used to treat solid tumors and later employed as magnetoliposomes in peptide delivery and drugs, as well as in the treatment and diagnosis of various diseases.
Properties utilized in Biomedical Application
Size reduction causes nanoparticles to display deviations from the bulk magnetic characteristics. The new features can be attributed to the effects of finite size and surface magnetization. In the biomedical application of nanoparticles, several key properties are required in biomedical applications of magnetic nanoparticles. First, MNPs should be non-toxic and biocompatible (Issa et al., 2013). Secondly, the particles should have a sufficient size of about ten to fifty nm to ensure resistance to aggregation and the preservation of colloidal stability when the particle’s magnetic interaction undergoes a reduction. In addition, a small size increases surface area of the particles, which leads to better targeting and prevention of biological clearance. Small nanoparticles also remain in circulation after being injected into the blood stream and can pass through capillaries without causing vessel embolism (Issa et al., 2013). Thirdly, saturation magnetization of MNPs should be high to ensure the effective control of the nanoparticles’ movement in the blood, as well as to guide their movement towards the targeted tissue.
Use of MNPs in Cancer Therapy and Diagnosis
The use of nanotechnology in cancer diagnosis is an emerging medical field. The technology includes features such as the noninvasive detection of cancer that benefits patients in various ways (Yigit et al., 2012). For example, noninvasive imaging obviates the requirement for obtaining tissue samples through biopsy and, hence, reduces the patient’s physical burden. Additionally, slight modifications of the nanoparticles to include therapeutic moiety can provide the “possibility of combining diagnosis with an initial drug delivery step” (Yigit et al., 2012). Currently, image-guided treatment has become an active area of research in the application of MNPs to biomedicine. New discoveries of novel cancer markers are also likely to ameliorate the identification of the genes that cause invasiveness, proliferation, and progression of cancer. Thus, the discovery of effective cancer therapeutics will attract the attention of many drug companies in the near future.
Presently, chemotherapy, radiotherapy, and surgery form the primary components of the methods used to treat cancer. Chemotherapy is often expensive and associated with numerous adverse side effects. However, the use of nanodrug delivery and nanoimaging systems can help to target cancer cells selectively and, hence, reduce undesirable drug toxicity. FDA has already approved liposomes and several other nanoparticle-based systems of drug delivery for treating certain cancers. Moreover, the most extensively used magnetic nanoparticles in cancer treatment are “magnetite Fe3O4 and maghemite γ-Fe2O3” (Gobbo et al., 2015). According to Sadeghi-Aliabadi et al. (2013), “soft magnetic oxides, MFe2O4, where M is a divalent cation, have a spinel structure” called spinel ferrites. Nanoparticles of such magnetic oxides possess different characteristics when compared to their bulk forms. As such, the characteristics allow the use of MNPs in the generation of hyperthermia during tumor therapy whereas the bulk forms are used mainly in electronics and telecommunication.
Conclusion
This review has explored the synthesis and characterization of MNPs. In addition, it has discussed the application of MNPs to biomedicine. In particular, the study has presented the use of methods such as laser pyrolysis and chemical vapor deposition in the synthesis of the nanoparticles. Since surface functional groups affect the properties of MNPs, several characterization approaches are used to preserve MNPs’ magnetic properties and improve their applications. Such properties of MNPs have been utilized in a variety of disciplines, including information storage and biomedicine. In biomedical practice, MNPs are introduced selectively into tumor cells during treatment. Thus, magnetic nanoparticles have different characteristics from the bulk scale, which makes them useful for biomedical applications.
References
Faraji, M., Yamini, Y., & Rezaee, M. (2010). Magnetic nanoparticles: Synthesis, stabilization, functionalization, characterization, and applications. Journal of the Iranian Chemical Society, 7(1), 1-37.
Gobbo, O. L., Sjaastad, K., Radomski, M. W., Volkov, Y., & Prina-Mello, A. (2015). Magnetic nanoparticles in cancer theranostics. Theranostics, 5(11), 1249–1263. doi:10.7150/thno.11544.
Gupta, V., Gupta, A. R., & Kant, V., 2013. Synthesis, characterization and biomedical applications of nanoparticles. Science International, 1, 167-174. doi:10.5567/sciintl.2013.167.174.
Issa, B., Obaidat, I. M., Albiss, B. A., & Haik, Y. (2013). Magnetic nanoparticles: Surface effects and properties related to biomedicine applications. International Journal of Molecular Sciences, 14(11), 21266–21305. doi:10.3390/ijms141121266.
Kang, J., Lee, H., Kim, Y.-N., Yeom, A., Jeong, H., Lim, Y. T., & Hong, K. S. (2013). Size-regulated group separation of CoFe2O4 nanoparticles using centrifuge and their magnetic resonance contrast properties. Nanoscale Research Letters, 8(1), 376. doi:10.1186/1556-276X-8-376.
Kolhatkar, A. G., Jamison, A. C., Litvinov, D., Willson, R. C., & Lee, T. R. (2013). Tuning the magnetic properties of nanoparticles. International Journal of Molecular Sciences, 14(8), 15977–16009. doi:10.3390/ijms140815977.
Li, M., Li, X., Qi, X., Luo, F., & He, G. (2015). Shape-controlled synthesis of magnetic Iron Oxide@SiO2–Au@C particles with core–shell nanostructures. Langmuir, 31(18), 5190–5197. doi:10.1021/acs.langmuir.5b00800.
Mandal, S., & Chaudhuri, K. (2016). Engineered magnetic core shell nanoprobes: Synthesis and applications to cancer imaging and therapeutics. World Journal of Biological Chemistry, 7(1), 158–167. doi:10.4331/wjbc.v7.i1.158.
Sadeghi-Aliabadi, H., Mozaffari, M., Behdadfar, B., Raesizadeh, M., & Zarkesh-Esfahani, H. (2013). Preparation and cytotoxic evaluation of magnetite (Fe3O4) nanoparticles on breast cancer cells and its combinatory effects with doxorubicin used in hyperthermia. Avicenna Journal of Medical Biotechnology, 5(2), 96–103. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689562/
Singamaneni, S., Bliznyuk, V. N., Binekc, C., & Tsymbalc, E.Y. (2011). Magnetic nanoparticles: Recent advances in synthesis, self-assembly and applications. Journal of Materials Chemistry, 21, 16819–16845.
Vallejo-Fernandez, G., Whear, O., Roca, A.G., Hussain, S., Timmis, J., Patel, V., & O’Grady, K. (2013). Mechanisms of hyperthermia in magnetic nanoparticles. Journal of Physics D: Applied Physics, 46(31), 1-6.
Wiedwald, U., Han, L., Biskupek, J., Kaiser, U., & Ziemann, P. (2010). Preparation and characterization of supported magnetic nanoparticles prepared by reverse micelles. Beilstein Journal of Nanotechnology, 1, 24–47. doi:10.3762/bjnano.1.5.
Yigit, M. V., Moore, A., & Medarova, Z. (2012). Magnetic nanoparticles for cancer diagnosis and therapy. Pharmaceutical Research, 29(5), 1180–1188. doi:10.1007/s11095-012-0679-7.
