Magnetic Nanomaterials for Biomedical and Pharmaceutical Applications: Fundamentals, Functionalization, and Therapeutic Potential

Modern biomedical and pharmaceutical sciences have undergone a radical revolution brought about by nanotechnology that allows the design and production of materials at nanoscale with new physical, chemical and biological characteristics. Nanometer-engineered materials exhibit some of the most unusual properties that are not otherwise found in bulk materials because of quantum confinement, larger surface-area, and modified electronic structures. Such nanoscale properties have provided new possibilities in the development of new diagnostic apparatus, targeted therapeutic systems, and multifunctional biomedical apparatuses [1]. Magnetic nanomaterials are one of the various classes of nanomaterials that have attracted a lot of attention because they can respond to external magnetic fields and at the same time remain at nanoscale size that can be used in biological interactions. The magnetic nanomaterials can be widely defined as nanoparticles made of magnetic components or materials including iron, cobalt, nickel or their oxides and ferrites that have magnetic features when subjected to an external magnetic field. The reason behind this is the fact that these particles usually have sizes in the range of 1-100 nanometres hence can interact with biomolecules, cells and tissues in complex biological environments in a unique manner due to the distinctive physicochemical and magnetic characteristics that these materials develop with the nanoscale [2]. Superparamagnetic is one of the greatest properties of magnetic nanoparticles whereby nanoparticles are highly magnetized when an external magnetic field is applied upon the nanoparticles instead of magnetic remanence being maintained once the external magnetic field is removed. This property is especially beneficial in biomedical systems since it prevents the aggregation of the particles and provides colloidal stability in the physiological systems [3]. Moreover, due to high surface-volume ratio of nanoparticles, these particles can be easily functionalized on their surfaces with polymers, ligands and biomolecules, which improve their stability, targeting ability and other biological systems [4]. The magnetic nanomaterials have a few benefits over the traditional therapeutic and diagnostic materials, as well. They can be magnetically responsive, which means that external magnetic fields can direct nanoparticles to their target anatomic locations and thus create magnetically targeted drug delivery systems to decrease systemic toxicity and enhance therapeutic efficacy. Besides, magnetic nanoparticles may be used as contrast agents in a magnetic resonance imaging model, which offers increased sensitivity to image and spatial resolution in the diagnosis of disease [5]. They have also been applied in magnetic hyperthermia therapy wherein local heating of magnetic nanoparticles within the alternating magnetic fields can be used to selectively kill cancer cells without damaging the nearby healthy tissues [6]. Besides these, magnetic nanomaterials are also showing potentials in biosensing, bioseparation, tissue engineering, gene delivery and regenerative medicine. Their versatility enables them to be used in diagnostic and therapeutic applications on the same nanoscale platform and thus the creation of enhanced theranostic systems that enable disease diagnosis and targeted therapy in one platform [7]. The growing interdisciplinary research in the areas of materials science, nanotechnology, chemistry, biology, and medicine has boosted the creation of new magnetic nanomaterials with better physicochemical properties and improved biological activities. Nonetheless, even with these encouraging developments, various challenges are still present in regards to the stability of nanoparticles, possible toxicity, large scale production, and clinical approval of magnetic nanomaterials use [2,6].Accordingly, the key to successful translation of magnetic nanomaterials into clinical and pharmaceutical use is a thorough insight into the fundamentals of the concept, production methods, functionalization, characterization, and regulatory approval of nanomaterials use. This review aims at discussing in detail the basic principles of magnetism of the magnetic nanomaterials, the different types of magnetic nanoparticles employed in biomedical research, synthesis methods, surface engineering approaches, characterization of the nanoparticles and the different biomedical and pharmaceutical applications. Besides, the review also points out the aspects of toxicity, the limitations that are present, and the future trends in the development of magnetic nanomaterials in advanced medical practices.

Figure 1. Graphical diagram of the multifunctional biomedical uses of magnetic nanomaterials such as drug delivery, magnetic resonance imaging, biosensing and hyperthermia therapy.

The Figure 1. Publications that the biomedical multifunctional uses of magnetized nanomaterials. Magnetic nanoparticles are the flexible nanoplatforms, which can be used in magnetic guided drug delivery, in addition to contrast in magnetic resonance imaging (MRI), in sensitive biosensing and diagnostics, and in production of local heat in magnetic hyperthermia therapy of cancer.

2. Fundamental Principles Of Magnetic Nanomaterials

The magnetic nanomaterials are characterized by special magnetic properties which develop due to overall interaction of electrons and atomic magnetic moments within the Nano compositions. On smaller sizes, the magnetic properties are highly dependent on the size of the particles, morphology, crystal structure and surface effects. The basic magnetic concepts in magnetic nanomaterials must be understood so as to maximize the use of magnetic nanomaterials in biomedical and pharmaceutical applications including targeted drug delivery, imaging and magnetic hyperthermia therapy. The magnetic behaviour of nanoparticles is determined by parameters including magnetic moment, magnetization, susceptibility, coercivity, and anisotropy, all of which are significantly influenced by nanoscale phenomena and interparticle interactions [8]. Magnetic nanoparticles exhibit distinctive behaviour compared with bulk materials because of quantum confinement effects and the increasing dominance of surface atoms. When the particle size approaches the nanometre range, a large proportion of atoms reside at the surface, which significantly alters electronic structure and magnetic ordering. Such size dependent changes may frequently result in increased magnetic susceptibility, change in coercivity and the development of superparamagnetic behavior which is especially significant in biomedical use since superparamagnetic behavior eliminates magnetic remanence and reduces aggregation of the nanoparticles in physiological conditions [9].

2.1 Basic Concepts of Magnetism

The sources of magnetism are motion of electric charges and natural magnetic moment of electron spin and orbital angular momentum. The overall orientation of the atomic magnetic moments in these materials leads to the development of observable magnetic properties as in magnetic materials. The strength and orientation of a magnetic source are described by the magnetic moment and normally given in a form of a vector. On exposing magnetic nanoparticles to external magnetic field, the magnetic moments exhibit the alignment with the applied field and lead to magnetization of the material. Magnetization can be characterized as the measure of magnetic response of a substance in unit volumes and is the summation of the magnetic response of the substance when the substance is expounded to an external magnetic field. The extent of magnetization is determined by the makeup of the material, temperature and structural features of the nanoparticles. Magnetic susceptibility refers to the degree to which a substance is magnetized in an external magnetic field. Highly magnetic susceptible materials have high magnetic responses and hence are very desirable in biomedical processes that require magnetic manipulation and imaging [10]. The other important magnetic parameter is that of coercivity which is the ability of a magnetic material to resist demagnetization. High-coercivity materials maintain a high level of magnetization despite the loss of an exogenous field and low-coercivity materials de-magnetize quickly. Low-coercivity nanoparticles with superparamagnetic properties are desirable in biomedical biology since they do not exhibit undesired aggregation and magnetic interactions in the body [11]. Magnetic anisotropy is the dependence of magnetic characteristics in a substance in a directional manner. Magnetic anisotropy in nanoparticles is due to crystal structure, particle shape and surface effect. Large magnetic anisotropy helps to stabilize magnetic moments and affects the energy barrier to be overcome in order to reverse the magnetization. This aspect is very important in defining the magnetic relaxation behavior and heating efficiency of nanoparticles in magnetic hyperthermia therapy [12].

2.2 Types of Magnetic Behavior

There are a number of categories of the magnetic materials according to the position and interaction of the atomic magnetic moments. These are diamagnetism, paramagnetism, ferromagnetism, ferrimagnetism and superparamagnetism. The material is found to have particular electronic configurations and magnetic interactions that cause each kind of magnetic behavior. Diamagnetic materials are those that respond to magnetic forces with very low magnetic responds and create induced magnetic field which acts in the opposite direction of the applied magnetic field. The materials only have paired electrons and hence they do not have permanent magnetic moments. Even though, the effects of diamagnetism are usually weak, they contribute to the magnetic behavior of biological tissues and their immediate surroundings in biomedical imaging systems [8]. Unpaired electrons that give rise to the tiny magnetic moments are found in paramagnetic materials. These magnetic moments are partially aligned to the external magnetic field producing a weak positive magnetic susceptibility. This alignment is however disturbed by thermal energy when the external field is taken off leaving the magnetization to vanish. Ferromagnetic materials have a high magnetic interaction because of parallel alignment of the atomic magnetic moments by exchange interaction. It is this alignment that causes magnetic domains to form and causes it to be permanently magnetized even when the external magnetic field is removed. Despite the high magnetization levels of the ferromagnetic materials, there is a restriction of their application in biomedical applications owing to the risk of aggregation and the possibility of being toxic. Ferrimagnetism is a property of a material when magnetic moments are oriented opposite to each other but have unequal magnitudes and create a net magnetic moment. Magnetite and maghemite are iron oxide nanoparticles that behave like ferrimagnetic in bulk and find extensive application in the biomedical field because of their stability and high magnet response [13]. Superparamagnetism is a special magnetic phenomenon that occurs on a nanoscale and especially when the size of particles is smaller than a critical size which is usually a range of 20 nanometers. In this condition, every nanoparticle acts as one magnetic domain with a high magnetic moment. Thermal fluctuations cause rapid randomization of magnetic orientation in the absence of an external magnetic field, eliminating residual magnetization. This property is extremely advantageous in biomedical applications because it prevents particle aggregation and enables reversible magnetic manipulation using external magnetic fields [14]

Figure 2. Simulation of various magnetic properties such as diamagnetism, paramagnetism, ferromagnetism, ferrimagnetism and superparamagnetism that are found in magnetic nanomaterials.

Figure 2. The illustration of various magnetic behaviors in magnetic nanomaterials at an external magnetic field. The orientation of the magnetic moments of diamagnetism, paramagnetism, ferromagnetism, ferrimagnetism and superparamagnetism was represented using the diagram. Each of these behaviors is different in its spin arrangements and magnetic responses and affects the magnetic properties and biomedical performance of nanoscale materials significantly. Due to the size dependence of the magnetic properties, the magnetic performance of nanodispersions was studied among different materials and surfaces using unique geometries. The magnetic performance of nanodispersions between various materials and surfaces were investigated based on different geometries due to the size dependence of the magnetic properties. Nanoparticles are strongly affected by particle size, shape and surface structure to determine their magnetic properties. When the particle size drops to the nanometer level, there is a great change in the magnetic domain structures. In bulk ferromagnetic substances, different magnetic domains are present in order to reduce the magnetic energy. But at a small enough size of the particle the multi domain formation becomes energy prohibited leading to the single domain nanoparticles. Single domain nanoparticles have a homogenous magnetization of the particle, increased magnetic responsiveness is observed. Such nanoparticles usually exhibit a high coercivity and better magnetic stability than multidomain particles. Further reduction in the particle size equates thermal energy to the magnetic anisotropy energy leading to the superparamagnetic state whereby magnetic moments move about swiftly [15]. The role of surface effects is also important as it determines the magnetic behavior on nanoscale. The nanoparticles contain a greater fraction of atoms on surfaces, which have broken symmetry and reduced coordination resulting in changed magnetic interactions. Magnetic anisotropy and saturation magnetization can be affected by surface spin disorder and structural defects thus impacting on the overall magnetic performance of the nanoparticles to be used in biomedical applications. Superparamagnetic phenomenon is especially significant to biomedical fields including targeted drug delivery and magnetic resonance imaging. The SPNPs have a high level of magnetization in the presence of a magnetic field but with zero remanent magnetization once the magnetic field is removed. This reversible magnetism enables the exact outside handling of nanoparticles without aggregation and irreversible magnetization in biological systems [9,14].

Table 1. Magnetic behaviors of materials and their key characteristics

3. Types of Magnetic Nanomaterials Used In Biomedical Applications

Magnetic nanomaterials used in biomedical and pharmaceutical sciences are diverse inorganic and hybrid nanostructures, which have controllable magnetic characteristics and high surface reactivity. These are materials intended to be coupled effectively with biological systems as well as being highly magnetic responsive to the external magnetic fields. The most applied magnetic nanomaterials are iron oxide nanoparticles, ferrite nanoparticles, metallic magnetic nanoparticles, and multifunctional magnetic nanocomposites. The categories have unique magnetic properties, structural stability and biocompatibility profiles, which affect their application in certain biomedical tasks including drug delivery, diagnostic imaging, biosensing and cancer therapy [16]. Saturation magnetization, magnetic anisotropy, chemical stability, surface functionality, and toxicity are some of the parameters that highly determine the selection of magnetic nanomaterial. Among the obtainable magnetic nanomaterials, iron oxide nanoparticles are the ones the most widely studied because of their good safety profile and good magnetic properties. Nevertheless, the recent advancement in nanotechnology has also come up with ferrite-based nanoparticles, metallic magnetic nanoparticles and hybrid magnetic nanocomposites, which have better multifunctional characteristics and better therapeutic performance [17].

3.1 Iron Oxide Nanoparticles

The most noticeable category of magnetic nanomaterials used in biomedical studies is that of iron oxide nanoparticles. These nanoparticles are normally found in two main crystalline forms which include magnetite (Fe 3 O 4 ) and maghemite ( gamma Fe 2 O 3 ). Both forms are ferrimagnetic in bulk form but they exhibit superparamagnetic behavior when produced in nanoscale sizes of less than about twenty nanometers. This is especially beneficial to use in biomedical fields, as it is possible to achieve high magnetic responsiveness in an external field and avoids permanent magnetization of the sample once the field is removed [1,13]. The magnetite nanoparticles have an inverse spinel arrangement structure which is made of Fe 2 and 3 ions that are organized in tetrahedral and octahedral positions. The distinctive structure generates high saturation magnetization induced by the strong magnetic interactions. Maghemite nanoparticles are produced by the oxidation of magnetite and have cation vacancies which preserve a similar spinel structure containing Fe 3 + ions. Both the magnetite and the maghemite nanoparticles exhibit outstanding magnetic characteristics along with the chemical stability under the aqueous conditions hence they can be very useful in biomedical purposes. The use of iron oxide nanoparticles as a contrast agent in magnetic resonance imaging is a well-sketched research topic because iron oxide nanoparticles can vary the proton relaxation time in biological tissues. The superparamagnetic characteristics of them improve the T 2 relaxation signals which allow higher imaging contrast and diagnostic precision. Moreover, therapeutic agents, targeting ligands or polymers can be incorporated on to these nanoparticles in order to develop magnetically directed drug delivery systems that have the ability to deliver drugs to particular tissues in the presence of an external magnetic field [5,14]. Besides imaging and drug delivery, iron oxide nanoparticles were also shown to have a bright future in magnetic hyperthermia therapy. These nanoparticles produce localized heat on exposing them to alternating magnetic fields due to the Néel and Brownian relaxation processes. The resultant thermal energy can selectively trigger either apoptosis or necrosis in cancer cells with minimum harm to the surrounding healthy tissues [6].

Figure 3. Magnetism and crystal structures of iron oxide nanoparticles such as magnetite and maghemite in biomedical applications.

The Figure 3. Demonstrates the crystal structures and magnetic properties of iron oxide nanoparticles that are in common use in biomedical applications. The diagram depicts the spinel structure of the magnetite (Fe 3 O 4 ) and maghemite ( 8-Fe 2 O 3 ), which is ferrimagnetic and superparamagnetic on a nanoscale. Their magnetic characteristics allow them to be used in biomedical practice in targeted drug delivery, magnetic resonance imaging (MRI), and magnetic hyperthermia treatment.

3.2 Ferrite Nanoparticles

Another significant type of magnetic nanomaterials is ferrite nanoparticles with the general chemical formula MFe 2 O 4 where M is a divalent metal ion: cobalt, nickel, zinc, or manganese. These nanoparticles assume spinel crystal structures as that of iron oxide nanoparticles yet they have altered magnetic properties relative to the metal ion incorporated. Various metal cations have an effect on an magnetic anisotropy, saturation magnetization, and magnetic relaxation behavior [17]. Cobalt ferrite nanoparticles are highly anisotropic and coercive in nature and can be used in applications where magnetic properties are needed to remain constant like in magnetic hyperthermia therapy or magnetic data storage. The nanoparticles of ferrite containing nickel exhibit an average magnetic behavior and a good chemical stability that enable them to be used as biosensing and catalytic proteins in biomedical. The nanoparticles of zinc ferrite exhibit comparatively less magnetic anisotropy but have a greater biocompatibility and chemical stability that has prompted the interest in using them in drug delivery and diagnostic imaging systems. The high magnetic anisotropy of ferrite nanoparticles has made them popular in hyperthermia therapy due to their high efficiency in the generation of heat when they are exposed to alternating magnetic fields. Nevertheless, their surface alteration and toxicity should be carefully done and assessed to make their use safe in the biomedical settings because metal ions can be released when they degrade.

3.3 Metallic Magnets Nanoparticles.

Transitional metals of iron, cobalt and nickel are found in metallic magnetic nanoparticles, which have very high saturation magnetization values in comparison to metal oxide-based nanoparticles. Such nanoparticles are highly magnetic-responsive and possess high efficiency on heating in application of magnetic hyperthermia. The large magnetic moment allows them to be further manipulated with external magnetic fields which is useful in targeted drug delivery and in the magnetic separation processes [18]. Although they are very attractive with regard to their magnetism nature, metallic magnetic nanoparticles encounter a number of challenges associated with chemical stability and possible cytotoxicity. Such nanoparticles are very prone to oxidation at the presence of air or aqueous conditions and hence form surface oxide layers which change their magnetic properties. In addition, the direct exposure of biological tissues to metallic nanoparticles could cause oxidative stress and inflammation. To address these drawbacks, metallic magnetic nanoparticles are in most cases coated with protective shell made out of polymers, silica, or carbon building blocks. These protective layers improve chemical stability, prevent oxidation, and biocompatibility as well as high magnetic responsiveness. Encapsulation methods have made it possible to create multifunctional nanoparticles that integrate high magnification of magnets of metal cores, stability, and safety of protective surfaces.

3.4 Magnetic Nanocomposites and Hybrid Nanomaterials.

Magnetic nanocomposites are a new type of multifunctional materials that can be developed by the addition of magnetic nanoparticles to organic/inorganic materials like polymers, silica, gold or carbon-based nanostructures. The following hybrid systems are constructed to incorporate several functional properties in one nanoplatform, and therefore they improve their usage in biomedical and pharmaceutical biomedical use [7]. The magnetic nanocomposites based on polymers are popular in use as drug delivery system due to the fact that polymer matrices are biocompatible, flexible and have the ability to deliver drug in a controlled manner. Polyethylene glycol, chitosan and polycaprolactone are the most common polymers used to coat magnetic nanoparticles to enhance the colloidal stability and extend circulation time in the blood. Magnetic nanoparticles coated with silica have become of significant interest with regard to their superior chemical stability and the ability to be functionalized on their surface easily. The silica shell offers a protective coating that prevents agglomeration of nanoparticles and enables the biomolecule binding, antibodies, peptides and nucleic acids, to be attached to the nanoparticles and therapeutically targeted. Carbon based magnetic nanomaterials such as graphene and carbon nanotube composite are some new hybrid systems with unusual electronic and mechanical characteristics. Such materials provide extensive surface areas to drug loading and have a high potential of biosensing, imaging and photothermal therapy. Nanomedicine Multifunctional magnetic nanocomposites have tremendously increased the scope that magnetic nanomaterials have. These hybrid systems are capable of diagnostic imaging, targeted drug delivery and therapeutic capabilities in parallel and this has resulted in integrated theranostic platforms with the ability to enhance disease diagnosis and treatment efficacy [8].

Table 2. Major categories of magnetic nanomaterials used in biomedical applications

4. Synthesis Methods of Magnetic Nanomaterials

The magnetic nanomaterials synthesis is important in defining their structural properties, magnetic properties, surface chemistry and biocompatibility. The size, morphology, crystallinity, and surface functionality of nanoparticles can only be optimized by having precise control over particle size, morphology, crystallinity and functionality. During the last several decades, hundreds of synthetic methods have been established in order to obtain magnetic nanoparticles with controlled characteristics that can be used in medical imaging, targeted drug delivery, biosensing, and cancer therapy [19]. In general, magnetic nanomaterials can be produced by three primary methods such as chemical synthesis processes, physical manufacturing processes, as well as biological or green synthesis processes. Chemical methods are the most popular because they are simple to use, scalable and can be used to generate nanoparticles with a size distribution. Physical procedures are very pure and crystalline and can be very energy-demanding and instrument intensive. Recently, the biological and green synthesis methods have become one of the environmentally friendly alternatives that involve using microorganisms, or plant derived compounds to produce biocompatible nanoparticles [20]. Various factors including the desired particle size, magnetic properties, functionality, and biomedical application among others determine the selection of an appropriate synthesis technique. The benefits and drawbacks of each of the synthesis methods are unique, and should be closely taken into account when designing magnetic nanomaterials to be used in a clinical or pharmaceutical context.

4.1 Chemical Synthesis Methods

The most widely used methods of synthesizing magnetic nanoparticles are those involving chemical synthesis because they have rather simple procedures and allow a great deal of control in the size and composition of particles. Co-precipitation, thermal decomposition, hydrothermal synthesis, and sol-gel are also some of the most common methods of synthesizing iron oxide and ferrite nanoparticles [21]. One of the simplest and most commonly used techniques of synthesis of iron oxide nanoparticles is co-precipitation. It is done by the concomitant precipitation of ferrous and ferric ions in an aqueous alkaline solution. Their nucleation and growth will take place when iron salts like FeCl 2 and FeCl 3 are combined in a basic medium leading to the production of magnetites nanoparticles. The reaction parameters such as pH, temperature, ionic concentration, and rate of stirring have a great effect on the size and morphology of nanoparticles. Although co-precipitation method has the advantage of being simple and scaling up, the method typically produces nanoparticles of relatively large size distribution and mediocre crystallinity. Another chemical method that has been extensively utilized that yields highly uniform magnetic nanoparticles with narrow size distributions is thermal decomposition. The organometallic precursors, which are used in this process, include iron acetylacetonate which is decomposed at high temperatures in organic solvents under the influence of the surfactants. The surfactants used include oleic acid and oleylamine which are stabilizing agents that prevent aggregation of nanoparticles and provide the opportunity to control the growth of particles accurately. Thermal decomposition is normally used to obtain very crystalline nanoparticles with high magnetism, but the need of organic solvents, as well as, high reaction temperatures makes the process very complicated and expensive. Hydrothermal synthesis is a chemical reaction which takes place in aqueous solutions but under high temperatures and pressure in closed autoclave reactors. This method facilitates the production of extremely crystalline nanoparticles with regulated morphology and enhanced magnetism. Hydrothermal environment encourages slow and slow growth and nucleation, which are capable of producing nanoparticles that have a well-defined shape, either a sphere, rod or cube. Another chemical process that is employed in the synthesis of magnetic nanomaterials involves sol-gel in which the metal precursors undergo hydrolysis and condensations reactions to form the nanomaterial. During this process, the metal alkoxides or salts are subjected to hydrolysis to generate a colloidal suspension that then gets converted to a gel system. Further drying and heating results in the development of magnetic nanoparticles of controlled composition and uniform dispersion in a solid matrix. Sol-gel technique is especially employed in the production of magnetic nanocomposites and hybrid materials to use in biomedical applications [22].

Figure 4. Diagnostic diagram of frequent chemical synthesis strategies of magnetic nanoparticles such as co-precipitation, thermal decomposition, hydrothermal synthesis and solgel.

The Figure 4, indicates the chemical synthesis methods of the magnetic nanoparticles preparation. The diagram identifies four common methods such as co-precipitation, thermal decomposition, hydrothermal synthesis and sol-gel process all of which exhibit varying reaction conditions as well as reaction mechanisms through which the nanoparticle size, crystallinity and magnetic properties can be established.

4.2 Physical Synthesis Methods

Physical synthesis methods entail the creation of magnetic nanoparticles by mechanical or physical methods which are not based on chemical reactions in solution. The approaches usually produce nanoparticles that are highly pure and crystalline, which is appealing to some of the current technological and biomedical applications [23]. Ball milling is one of the most common examples of physical means and entails the mechanical grinding of bulk magnetic materials into nanoscale particles with high energy milling devices. In this operation, a collusion between the milling balls and the bulk material into smaller nanoscale particles happens repeatedly. The benefit of ball milling is that no elaborate reagents are needed in the process, but, the milling media may leave structural defects and contaminate the product. Another physical method of the synthesized magnetic nanoparticles is laser ablation. In this procedure, the high energy beam of laser is focused on a solid metal target which is placed into a liquid media. The high intensity laser energy melts away minute amounts of the target material to create plasma that quickly cools and condenses to nanoparticles. The benefit of laser ablation is that the method of generating nanoparticle purity is of high merit without any chemical contaminants, but the technology is expensive, and the instrumentation used is both complex and expensive to operate. Physical vapor deposition is another significant physical process in which atoms of metal are vaporized; this is done by vaporizing a solid material, thereafter condensing it onto a substrate to produce structures of nanoscale. Thin films and nanostructured magnetic materials with remarkably controlled composition and thickness have been produced using variants of this technique including sputtering and evaporation. However, physical methods of synthesis have enjoyed benefits of purity and crystallinity and are typically not as common in biomedical applications as chemical methods because of limitations in large scale generation and ability to functionalise the surfaces.

4.3 Green Synthesis and Biological.

The magnetic nanoparticles produced biologically have been receiving growing interest as a sustainable and eco-friendly substitute of traditional chemical and physical procedures. In these methods, biological systems such as microorganisms, plant extracts, and biomolecules are used to promote the formation of nanoparticle using naturally occurring biochemical systems [24]. Microorganisms like the bacteria, fungi and algae have been able to produce magnetic nanoparticles by enzymatic reduction and biomineralization. Some magnetotactic bacteria synthesize magnetic nanoparticles (called magnetosomes) that are magnetite nanoparticles that fulfill the role of internal magnetic sensors and work to orient orient the bacteria within geomagnets. Such biologically synthesized nanoparticles are of a very homogeneous size and have good magnetic properties. Another green method that has potential of manufacturing magnetic nanoparticles involves plant mediated synthesis. Under this technique, plant extracts of phytochemicals (polyphenols, flavonoids and alkaloids) are used as reducing and stabilizing agents in the formation of nanoparticles with metal salts. Plant based synthesis can prove to be quite beneficial in a number of ways such as; it is cheap, eco-friendly and toxic chemical reagents are removed. Biocompatibility: Biologically synthesized magnetic nanoparticles in many ways have increased biocompatibility because of the presence of natural biomolecules on the surfaces of the nanoparticles. These biomolecules make nanoparticles more stable and their ability to interact with biological systems, which is useful in biomedical applications, including drug delivery, biosensing, and imaging. Irrespective of these benefits, biological synthesis procedures continue to have issues associated with reproducibility, scalability, and control of nanoparticle size and morphology. Current studies are striving to streamline these procedures to allow production of high amounts of high quality magnetic nanomaterials that can be used in clinical applications on a large scale.

Table 3. Comparison of major synthesis methods for magnetic nanoparticles

5. Surface Functionalization and Modification of Magnetic Nanoparticles

The surface functionalization is one of the most important procedures in the evolution of magnetic nanoparticles in the field of biomedical uses. Even though magnetic nanoparticles have the appropriate magnetic characteristics, their direct application into biological systems is frequently hampered by factors such as aggregation, low colloidal stability, fast elimination by the blood system, and even cytotoxicity. The technologies that are instead used to increase the nanoparticle stability, biocompatibility and targeting ability without altering their magnetic responsiveness are surface modification strategies [25]. Magnetic nanoparticles have many active platforms due to its high surface to volume ratio. Nanoparticles can be functionalized by applying suitable surface engineering such as coating them with polymers, inorganic substances, biomolecules, or targeting ligand to promote their reactivity with a biological environment. These functional surfaces not only help to avoid aggregation of nanoparticles; they also give functional groups where drugs can be loaded, imaging agent, or targeting molecule [26]. The functionalization of surface is also significant in the regulation of pharmacokinetics and biodistribution of the magnetic nanoparticles in body. Hydrophilic and biocompatible molecules can be used to modify the surface of the nanoparticles to avoid recognition by the reticuloendothelial system and increase the time of circulation in the bloodstream. Such prolonged circulation enhances the efficiency of drug delivery and imaging use.

5.1 Polymer Coating

One of the most popular strategies of the magnetic nanoparticles surface modification is the polymer coating. Biocompatible polymers coating the surface of nanoparticles enhance colloidal stability and aggregation prevention of nanoparticles in physiological conditions. Polymer functional groups can also be used to provide functional groups that allow the attachment of a therapeutic agent or targeting ligands. Polyethylene glycol is also one of the polymers that have been extensively employed as a functional group in nanoparticles because of its high biocompatibility and the capacity to inhibit nonspecific adsorption of proteins. Magnetic nanoparticles that have polyethylene glycol coating exhibit an increased level of circulation time in blood owing to the fact that the macrophages of the immune system cannot recognize or absorb the nanoparticles due to the presence of a hydrophilic polymer coating. This is also known as the stealth effect and this greatly enhances the efficacy of the nanoparticle-based drug delivery systems [27]. Chitosan and dextran are some of the naturally occurring polymers that are extensively used in coating magnetic nanoparticles. Chitosan is a biodegradable polysaccharide that is a form of chitin with good biocompatibility and antimicrobial characteristics. Magnetic nanoparticles coated with chitosan demonstrate enhanced stability and are readily functionalized with drugs or nucleic acids to be used in application in gene therapy and delivery of drugs. Dextran coated magnetic nanoparticles have been widely researched in the field of clinical imaging, especially as contrast agents in magnetic resonance imaging. The dextran coating increases the dispersion of the nanoparticles in the aqueous media and predisposes them better to the biological tissues. Moreover, dextran has numerous hydroxyl groups which can further be functionalized chemically.

Figure 5. Diagrammatic representation of a polymer covered magnetic nanoparticle by indicating drug loading and targeting ligand functionality.

The figure 5 shows that the used to denote the polymer-coated magnetic nanoparticles that were intended to be used in targeted delivery of the drugs. The figure depicts that a magnetic nanoparticle core is covered with biocompatible polymers that allow loading of drugs and controlled release, but target ligands, like antibodies, peptides or aptamers are anatomized onto the surface to allow selective binding to particular cells or receptors to make the nanoparticles more therapeutically effective.

5.2 Silica Coating

The other common surface modification technique to use on magnetic nanoparticles is silica coating. Silica shells offer a number of benefits that include chemical stability, biocompatibility, and the ability to functionalize the surface easily. The layer of silica is a protective layer that prevents oxidation and aggregation of nanoparticles and ensures that magnetic particles are responsive. Tetraethyl orthosilicate is usually reacted to silica to create silica coated magnetic nanoparticles during sol gel processes where the silica material is subjected to hydrolysis and condensation reactions to create a silica shell around the magnetic core. The resulting core shell structure results in the combination of the magnetic properties of the core and the chemical stability of the silica shell [28]. The significant benefits of silica coatings include the inclusion of silanol groups on the surface and this is a feature that enables the addition of other functional molecules by using well established silane chemistry. This allows conjugation of fluorescent dyes, drugs, antibodies or nucleic acids to the nanoparticle surface. Consequently, magnetic nanoparticles containing silica have proven to have extensive uses in targeted drug delivery, biosensing and multimodal imaging. Moreover, some silica shells have porous structure, which enables them to carry a high amount of drugs and therefore these nanoparticles can be used in controlled drug release systems. The release of drugs through silica can be controlled by changing the thickness and porosity of silica and enhance the efficacy of the therapy.

5.3 Ligand functionalization and Targeting Molecules.

The functionalization of ligands is a relevant approach to providing magnetic nanoparticles with a certain biological recognition properties. Nanoparticles can be designed to target a particular cell, tissue or biomarker of disease by conjugation with targeting ligands, including antibodies, peptides, or small molecules. This specific interaction goes a long way in improving effectiveness of nanoparticle based diagnostic and therapeutic systems. The targeting ligand commonly is an antibody because of its high specificity with respect to specific antigens on the surface of the cancer cells or the pathogen microorganisms. Antibody-conjugated magnetic nanoparticles can be targeted to diseased tissues and will therefore be useful in delivering therapeutic agents or better imaging contrast. Nanoparticle targeting is also commonly done using peptide based ligands as these are smaller than antibodies and therefore, can penetrate tissues more easily. Some peptides show high affinity to receptors which are overexpressed on cancer cells allowing them to be used to deliver chemotherapy drugs. Folate folic acid receptors are commonly targeted by small molecule ligands like folic acid that is used on cancer cells. Magnetic nanoparticles functionalized with folic acid can be selectively taken up by tumor cells enhancing targeted delivery system specificity and minimizing toxicity effects on normal tissues. Targeting molecules can thus be functionalized on surfaces to create platforms of nanomedicine of high specificity that can detect and bind a specific biological target.

Table 4. Common surface modification materials used for magnetic nanoparticles

6. Biomedical Applications of Magnetic Nanomaterials

The magnetic nanomaterials have gained a lot of interest in the biomedical and pharmaceutical studies because of their peculiarity to react to the external magnetic field in their interaction with biological systems. These materials are a combination of nanoscale characteristics that include high-surface-areas, manipulable magnetism, and surface-functionalization capabilities that enable them to carry out various functions that include imaging, targeted drug delivery, and therapeutic treatment. Consequently, the magnetic nanoparticles have become powerful agents in nanomedicine and they have greatly enhanced the opportunities of diagnosing and treating several diseases by manipulating them remotely through external magnetic fields [29]. The capability of the magnetic nanoparticles to be manipulated by external magnetic fields is one of the major pros of the magnetic nanoparticles in the context of nanomedicine. This aspect allows them to be accurately controlled in regard to their movement, localization, and therapeutic activity within the body. Also, magnetic nanoparticles may be produced to contain drug, gene or imaging molecules, enabling them to serve as multifunctional nanoplatforms to perform diagnostic and therapeutic functions, commonly known as theragnostic [30]. The magnetic nanomaterials have thus been utilized in the biomedical domain in very many areas such as targeted drug delivery, diagnostic imaging, magnetic hyperthermia cancer treatment, biosensing and regenerative medicine. Nanoparticle engineering further enhanced their performance, safety, and clinical use in further development by continuing to improve their synthesis and surface engineering.

6.1 Magnetic Drug Delivery

One of the most widely researched areas of magnetic nanoparticles application is targeted drug delivery. The traditional drug delivery systems normally lack efficacy in targeting, systemic toxicity and decreased therapeutic efficacies. Magnetic drug delivery systems are trying to address these shortcomings by exploiting the magnetic nanoparticles as carriers, which deliver drugs to precise disease sites with the application of external magnetic fields [31]. In magnetic drug delivery, therapy is introduced through magnetic nanoparticles in which drugs are coated or encapsulated onto the magnetic nanoparticles. On exposure to an external magnetic field through the target tissue, the nanoparticles are magnetically attracted to form a concentration in the target site. This localized drug loaded nanoparticles concentration contributes to the effectiveness of therapeutic action and the decreased exposure of healthy tissues to drugs. Magnetic nanoparticles can also be used to control the release of drugs using a number of stimuli responsive techniques. As an example, localized heating can be raised by the application of alternating magnetic fields, and this heating causes temperature sensitive coating to release drugs. On the same note, PH sensitive polymer-coatings have the ability to deliver drugs in acidic tumor locales, adds an extra targeting specificity. A lot of studies have indicated that magnetic drug delivery systems are effective in cancer, cardiovascular diseases, and neurological disorders treatment. Such systems have enhanced bioavailability of drugs, less dosage, and better therapeutic effects than traditional ways of drug delivery.

Figure 6. Demonstrative diagram of drug delivery through magnetically controlled nanoparticles of magnetically loaded drug delivery via magnetic field and drug-loaded magnetic nanoparticles.

The figure 6, demonstrates that the drug delivery by the magnetic nanoparticles loaded with drug using the magnetic nanoparticles. The nanoparticles are administered throughout the bloodstream and are guided to the target tissue by an external magnet field allowing concentration of nanoparticles in any site and release of drug in the diseased site in a controlled manner and thereby enhancing the therapeutic effect and limiting side effects on the system.

6.2 Magnetic Resonance Imaging (MRI)

The application of magnetic nanoparticles in magnetic resonance imaging, one of the most significant noninvasive diagnostic imaging methods in contemporary medicine has been prevalent as a contrast agent. The magnetic resonance imaging technique gives an in-depth anatomical and functional data of tissues and organs because relaxation of hydrogen nuclei is measured in the presence of a magnetic field [32]. In MRI, superparamagnetic iron oxide nanoparticles are of particular use as T 2 contrast agents. The local magnetic field inhomogeneities formed by these nanoparticles cause all protons in the vicinity of the nanoparticles to transversely relax, leading to a darker signal in MRI images. This provides the increased contrast which can be used to better visualize tissues, tumors and pathological alterations. To enhance the stability and longevity of magnetic nanoparticles that are utilized in MRI, they are frequently coated with biocompatible polymers like dextran or polyethylene glycol. Surface functionalization with targeting ligands also allows selective concentration in a tissue or disease site, enhancing the diagnostic capability. Over the last few years, multifunctional magnetic nanoparticles have been designed that have imaging as well as therapeutic properties. Such theranostic nanoparticles enable the diagnosis of a disease and its treatment simultaneously, and this is an important step towards personalized medicine.

6.3 Magnetically Resonance Hyperthermia in the Treatment of Cancer.

Magnetic hyperthermia is a new method of treatment of cancer, where magnetic nanoparticles are used to produce local heat in the tumor tissue. The magnetic nanoparticles generate thermal energy when subjected to an alternating magnetic field by magnetic relaxation process. The heat generated by the magnetic nanoparticles raises the temperature of the tumor environment usually to around forty two to forty five degrees Celsius which is sufficient to cause the death of cancer cells without destroying the surrounding normal tissues [33]. The efficiency of the heating effect of the magnetic nanoparticles depends on a number of factors such as, particle size, magnetic anisotropy, saturation magnetization, and frequency of the applied magnetic field. The nanoparticles of iron oxide are widely utilized in the process of hyperthermia therapy due to their proper magnetic characteristics and satisfactory biocompatibility. Magnetic hyperthermia may also be used in conjunction with other traditional cancer therapies like chemotherapy and radiotherapy to improve the efficacy of the therapy. Nanoparticles can be useful in enhancing the effect of treatment by heating the tumors locally, making them more sensitive to chemotherapy drugs and radiations. Even a number of clinical trials have proved that magnetic hyperthermia can treat tumor types like glioblastoma and prostate cancer. On-going studies are trying to optimize the parameters of nanoparticle design and treatment with the objective of increasing the safety and utility of this promising treatment mode.

Figure 7. Mechanism of magnetic hyperthermia showing heat generation from magnetic nanoparticles under an alternating magnetic field.