Artificial Cells, Nanomedicine, and Biotechnology, 2015; Early Online: 1–10 Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 2169-1401 print / 2169-141X online DOI: 10.3109/21691401.2014.998832

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Magnetic nanoparticles as potential candidates for biomedical and biological applications Fatemeh Zeinali Sehrig1, Sima Majidi2, Nasrin Nikzamir1, Nasim Nikzamir1, Mohammad Nikzamir1 & Abolfazl Akbarzadeh1,2,3,4 1Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, 2Biotechnology Research Center, Tabriz

University of Medical Sciences, Tabriz, Iran, 3Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, and 4Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran cal ­applications (Yang et al. 2012). MNPs are a main class of nanoscale materials with the potential to revolutionize common clinical diagnostic and therapeutic procedures. Due to their exclusive physical properties and ability to operate at the cellular and molecular levels of biological interactions, MNPs are being actively investigated as the next generation of magnetic resonance imaging contrast agents(Ebrahimnezhad et  al. 2013) and as carriers for targeted drug delivery (Gref et al. 1994, Akbarzadeh et al. 2012). The MNPs demonstrate superparamagnetic behavior because of the infinitely small coercivity arising from the negligible energy barrier in the hysteresis of the magnetization loop of the particles, as predicted by Bloch and Neel (Lian et al. 2003, Sun et al. 2007). Recently, increased investigations with various types of iron oxides have been carried out in the field of MNPs which mostly include Fe3O4 (magnetite, superparamagnetic when the size is less than 15 nm),a-Fe2O3 (hematite, weakly ferromagnetic or antiferro-magnetic), γ-Fe2O3 (maghemite, ferrimagnetic), FeO (wustite, antiferromagnetic), b-Fe2O3 and ε-Fe2O3 (Pourhassan-Moghaddam et  al. 2013), among which magnetite and maghemite are the most favorable and current candidates since their biocompatibility has already been verified (Wu et  al. 2008). Fe3O4 NPs can possibly be used as magnetic targeted drug delivery carriers and magnetic resonance imaging (MRI) contrast agents, owing to their high saturation magnetization, low toxicity, and biocompatibility (Chin et  al. 2011). For biological and biomedical applications, magnetic iron oxide NPs are the most preferred materials of choice due to their biocompatibility, super paramagnetic behavior, and chemical constancy (Nidhin et al. 2008). The nanostructure is based on an inorganic core of iron oxide, such as Fe3O4 and g-Fe2O3, coated with a polymer such as dextran (Mehdizadeh Aghdam et al. 2012), chitosan (Li et  al. 2008), poly (ethylenimine) (PEI) (Yiu et  al. 2010), and poly(ethylene glycol) (PEG) (Ahmadi et  al. 2014, Mahdavi et  al. 2013). Special surface coating of

Abstract Magnetic iron oxide nanoparticles have become the main candidates for biomedical and biological applications, and the application of small iron oxide nanoparticles in in vitro diagnostics has been practiced for about half a century. Magnetic nanoparticles (MNPs), in combination with an external magnetic field and/or magnetizable grafts, allow the delivery of particles to the chosen target area, fix them at the local site while the medication is released, and act locally. In this review, we focus mostly on the potential use of MNPs for biomedical and biotechnological applications, and the improvements made in using these nanoparticles (NPs) in biological applications. Keywords: iron oxide nanoparticles, biotechnological applications, diagnostics, target

Introduction Nanotechnology is beginning to allow scientists, engineers, chemists, and physicians to work at the molecular and cellular levels to create important developments in life sciences and healthcare (Akbarzadeh et al. 2012). NPs are submicron moieties with diameters ranging from 1to 100 nm, as their name conveys, and are made of inorganic or organic materials, with several original properties compared with the bulk materials (LaConte et al. 2005, Wu et al. 2008). Nano materials have been attracting great attention due to their exceptional electrical, optical, magnetic, and catalytic properties. It is well known that the phases, sizes, and morphologies of nano materials have great impact on their properties and potential applications; therefore, the controlled synthesis of nanostructured materials with novel morphologies has recently received much attention (Geng et  al. 2006, Honig and Spalek 1998, Rao et al. 2007, Liu et al. 2013). With the recent progress of nano biotechnology, MNPs have gained increasing attention for use in biomedi-

Correspondence: Dr. Abolfazl Akbarzadeh, Drug Applied Research Center, Tabriz University of Medical Sciences, 5154853431 Tabriz, Iran. Tel/Fax:  984133341933. E-mail: [email protected] (Received 24 November 2014; accepted 6 December 2014)

1

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2  F. Zeinali Sehrig et al. the magnetic particles is required, which has to be not only non-toxic and biocompatible but also allow a targeted delivery with particle localization in a particular area. MNPs can bind to drugs, enzymes, proteins, antibodies, or nucleotides, and can be directed to a tissue, organ, or tumor using an external magnetic field, or can be heated in alternating magnetic fields for use in hyperthermia (Mahdavi et al. 2013). The magnetic properties of MNPs can be tailored by their particle sizes and size distributions. The particle sizes and size distributions of MNPs are affected by the preparation method. For these reasons, several methods of synthesis have been developed to prepare Fe3O4 NPs, in order to achieve desired properties (Chin et al. 2011). MNPs show noticeable novel phenomena such as superparamagnetism, high field irreversibility, high capacity field, extra anisotropic contributions, or shifted rings after field cooling. These phenomena rise from finite size and surface properties that control the magnetic behavior of specific NPs (Batlle and Labarta 2002). Frenkel and Dorfman were the first to predict that a particle of ferromagnetic material, lower than a critical particle size ( 15 nm for the ordinary materials), would consist of a single magnetic field; for instance, a particle that is in a state of uniform magnetization at any field (Khaki-Khatibi et  al. 2013, Bean and Livingston 1959, Tartaj et al. 2003). For exact control of the particles, superparamagnetism is beneficial over ferromagnetism, as superparamagnetic particles have an oriented magnetic moment under a magnetic field but lose this property in the absence of the field; for instance, they do not exhibit remanence or hysteresis. Hence, we expect to observe a consistent response from superparamagnetic materials in an imposed field, in contrast to the expected variable response from ferromagnetic particles. Ferromagnetic materials can be superparamagnetic when they have single domains, typically with small particles of a size below about 20 nm (Rosensweig et  al. 1994, Suh et al. 2012). Based on their exclusive mesoscopic chemical, physical, thermal, and mechanical properties, superparamagnetic NPs offer a high potential for several biomedical applications, (Davaran et al. 2013, Arbab et al. 2003, Pankhurst et  al. 2003) such as: (a) cellular therapy such as cell labelling, targeting, and as a tool for cell biology research to separate and purify cell populations; (b) tissue repair; (c) magnetic field- guided carriers for localizing drugs; (d) magnetic resonance imaging (MRI); (e) tumor hyperthermia; and (f ) magnetofection (Mahdavi et  al. 2013). MNPs have been used to deliver drugs to target tissues and to increase stability against degradation by enzymes. The superparamagnetic NP can be managed by an external magnetic field to lead it to the target tissue (Mahdavi et al. 2013, Ghanbari et  al. 2014). It is important to choose the materials for the creation of nanostructure materials and devices with adjustable chemical and physical properties. To this end, magnetic iron oxide nanoparticles have become the main candidates, and the application of small iron oxide nanoparticles in in vitro diagnostics has been practiced for about half a century (Wu et al. 2008, Gupta and Gupta 2005). Moreover, applications in therapy, biology, and medical diagnosis need the magnetic particles to be stable in water at a pH of 7 and in

a physiological environment. The colloidal constancy of this fluid will depend on the charge and surface chemistry and also depend on the dimensions of the particles (Akbarzadeh et al. 2012, Thakral et al. 2007). In this review, we focus mainly on the possible use of MNPs for biomedical applications and the advantage of using these particles in biological applications.

Biological and biomedical applications MNPs have a wide range of uses in many different applications. These applications make use of MNPs in several forms, e.g. in solution as ferrofluids; as surface-functionalized particles for biosensing applications (Ghasemali et  al. 2013); and as particle arrays in magnetic storage media (Sun et al. 2000, Willard et  al. 2004). Magnetically responsive nano and microparticles have many previously established and potential applications in several areas of biotechnology and biomedicine (Safarik et al. 2011). Magnetic separation has been successfully applied to many features of biomedical and biological research. It has been confirmed to be a highly sensitive technique for the selection of occasional tumor cells from blood, and is particularly well-suited to the separation of low numbers of target cells (Pankhurst et  al. 2003, Liberti et  al. 2001). Biomedical applications of MNPs can be classified based on their application inside or outside the body (in vivo, in vitro) (Akbarzadeh et al. 2012). In vivo applications could be additionally separated into therapeutic (hyperthermia and drugtargeting) and diagnostic applications (nuclear magnetic resonance (NMR) imaging), and for in vitro applications, the main use is diagnostic (separation and selection, and magnetorelaxometry) (Tartaj et al. 2003).

In vivo application Size and surface functionality are main factors which play a significant role in the in vivo applications of MNPs. Even without targeting surface ligands, diameters of superparamagnetic iron oxide nanoparticles (SPIO s) significantly affect in vivo biodistribution. SPIOs with diameters of 10 to 40 nm are important for prolonged blood circulation (Akbarzadeh et al. 2012, Lu et al. 2007).

Therapeutic applications Drug delivery. The main disadvantage of most chemotherapy drugs is that they are relatively non-specific. The therapeutic drugs are managed intravenously, leading to general systemic distribution, resulting in harmful side-effects as the drug attacks normal, healthy cells besides the targeted tumor cells (Figure 1) (Pankhurst et al. 2003). The possibilities of magnetic drug targeting (MDT) applications have increased in recent years (Akbarzadeh et  al. 2012, Kwon et  al. 2007). A key area in drug delivery is the accurate targeting of the drug to the cells or tissue of choice. Drug targeting systems should be able to control the fate of a drug entering the body. Nanotechnology offers here another challenge to come closer to this goal, to transport the drug to the right place at the right time (Kayser et al. 2005, Sadat Tabatabaei Mirakabad et al. 2014). Transportation of drugs

Biomedical and biological applications of magnetic nanoparticles  3

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capillaries (0.05 cm s 1), the magnetic particles are retained at the target site and maybe internalized by the endothelial cells of the target tissue (Tartaj et al. 2003, Joubert 1997). A strategy that could allow active targeting includes the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the targeted cells. Selective interactions of ligand–receptor could allow an exact targeting of the site of interest (Sadat Tabatabaei Mirakabad et al. 2014, Kaparissides et al. 2006).

Figure 1. Concept of magnetic drug targeting (Akbarzadeh et al. 2012, Faraji et al. 2010).

to an exact site can remove side effects and also reduce the dosage required. The surfaces of these particles are usually modified with organic polymers and inorganic metals or oxides to make them biocompatible and appropriate for additional functionalization by the attachment of several bioactive molecules (Berry and Curtis 2003, Faraji et  al. 2010). In the clinical area of human medicine, these particles are mostly being used as delivery systems for chemotherapy drugs, which may represent a new method to treat cancer. In addition, MDT has been used in radiotherapy and immunotherapy (Silva et al. 2012). MNPs for targeted drug delivery must be tailor-made for in vivo applications. In order to prevent dangerous accumulation of the particles in the blood stream, the particles must be of a small size compared to the dimensions of the capillaries, spherical in shape, and have a size distribution of less than 15%. Furthermore, the particles must have a high magnetic moment and change their magnetization quickly and at low fields (Willard et al. 2004). In the application of MDT, the magnetic particle is coated with activated carbon and serves to deliver pharmaceuticals to the target sites. In practice, the managed drug is absorbed to the particle and is localized to a particular site in the body by an external magnetic field. The physical force generated by the external magnetic field acts to transport the particles through the vascular wall, therefore positioning and retaining the drugs in close proximity to the cancer cells. This allows more concentrated doses of the drugs to be delivered to the cancer cells and keeps them on site for longer periods of time (Willard et al. 2004). This process is based on the competition between forces exerted on the particles by the blood compartment, and magnetic forces generated from the applied field. When the magnetic forces surpass the linear blood flow rates in arteries (10 cm s 1) or

Magnetic hyperthermia. Hyperthermia is a therapeutic technique used to increase the temperature of a region of the body affected by malignancy or other growth, which is a part of multimodal oncological strategies and is administered together with other cancer treatments. The foundation is based on a direct cell-killing effect at temperatures above 41–42°C (Tartaj et al. 2003, Wust et al. 2002, Hilger et al. 2005, Jordan et al. 1999, Davaran et al. 2014). This heat conducts into the closely surrounding diseased tissue whereby, if the temperature can be kept above the therapeutic threshold of 42°C for 30 min or more, the cancer is destroyed. Since the majority of hyperthermia devices are limited in their utility due to unacceptable coincidental heating of healthy tissue, magnetic particle hyperthermia is interesting because it offers a way to ensure that only the intended target tissue is heated (Pankhurst et al. 2003). Insertion of SPIO in altering current (AC) magnetic fields randomly flips the magnetization between the parallel and antiparallel directions, allowing the transfer of magnetic energy to the particles in the form of heat, a property that can be used in vivo to raise the temperature of tumor tissues to destroy the pathological cells by hyperthermia, because tumor cells are more sensitive to a temperature increase than healthy ones (Akbarzadeh et al. 2012, Mikhaylova et al. 2004, Kim et al. 2006). The amount of magnetic material required to create the essential temperatures depends to a large extent on the method of administration. For instance, direct injection allows for considerably greater quantities of material to be localized in a tumor than do methods employing intravascular management or antibody targeting, while the latter two can have other benefits. A reasonable assumption is that about 5–10 mg of magnetic material concentrated in each cm3 of tumor tissue is suitable for magnetic hyperthermia in human patients (Pankhurst et al. 2003). Depending on the degree of temperature increase, hyperthermal behavior can be classified into several types. In thermo ablation, a tumor is surrendered to high temperatures of heat,  46°C and up to 56°C, requiring cells to tolerate direct coagulation, tissue necrosis, or carbonization. Moderate hyperthermia (41°C  T  46°C) has several effects both at the cellular and tissue levels. In diathermia, lower temperatures (T  41°C) is used for the treatment of rheumatic diseases in physiotherapy (Silva et al. 2012). The temperature rise required for hyperthermia can be obtained, among other methods, by using fine iron oxide magnetic particles (Gilchrist et  al. 1957). The physical principle for which a magnetic material can be heated by the impact of an external alternating magnetic field are the losses that occur in the process during the redirection of the

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4  F. Zeinali Sehrig et al. magnetization of magnetic materials with low electrical conductivity (Tartaj et al. 2003, Kouhi et al. 2014, Neel 1949). Heat creation can be attributed to two different phenomena: a) relaxation, and b) hysteresis loss. The relaxation is of two types, Brownian and Neel. Brownian relaxation is owing to the physical spin of particles within the medium in which they are placed and is hindered by the viscosity that inclines to counter the movement of particles in the medium. Heat production through Neel relaxation is due to rapidly happening changes in the direction of magnetic moments relative to the crystal lattice. This is delayed by the anisotropic energy that tends to orient the magnetic field in a given direction relative to the crystal lattice. Neel relaxation is the main contributor for heat release in intracellular magnetic fluid hyperthermia (Silva et al. 2012, Hergt and Dutz 2007). Matsuoka et al. have conducted in vivo studies using magnetic hyperthermia. They could develop magnetic cationic liposomes based on SPIO NPs and investigated their in vivo efficacy for hyperthermia treatment of hamster osteosarcoma. In this work, magnetoliposomes were injected directly into the osteosarcoma and then exposed to an alternating magnetic field. The tumor was heated above 42°C. Complete regression was observed in 100% of the treated hamsters. Consequently, these results prove the feasibility of magnetic hyperthermia (Silva et al. 2012, Matsuoka et al. 2004). The advantage of magnetic hyperthermia is that it allows the heating to be limited to the tumor area. Furthermore, the use of MNPs is preferred over micron-sized particles, because nanoparticles absorb much more power at tolerable AC magnetic fields (Jeong et  al. 2007, Hyeon 2003) which is strongly dependent on the particle size and shape. Thus, having well-defined synthetic routes able to prepare uniform particles is essential for a rigorous control of temperature (Akbarzadeh et al. 2012). Tissue engineering. Developments in cell therapy research have given rise to a fast-growing multidisciplinary field that incorporates knowledge of engineering, medicine, and biology. Tissue engineering (TE) is a favorable technology for overcoming the limitations in organ transplantation related to organ donor deficiency. It involves proper use of cells, materials, and physical/biochemical procedures to restore, maintain, or improve tissue function (Silva et al. 2012). The capability to control the location of these particles distally using magnets, and to impel a high concentration in a given tissue or organ, has powerful applications in innovative medicine, including tissue engineering (Corchero and Villaverde 2009). An emerging tissue engineering plan, especially magnetic force-based tissue engineering (Mag-TE), employs cells that have been magnetically labeled with magnetite cationic liposomes (MCLs) (Figure 2). Such MCLlabeled cells can be operated and organized by magnetic force and preserve their functionality, indicating that MCLs are not toxic. In the Mag-TE method, a magnet is applied under the culture plate, attracting and accumulating magneticallylabeled cells. This allows populations of MCL-labeled cells to be successively driven to the surface to generate 2D-patterned or even 3D-multilayered structures. This approach

Figure 2. In magnetic force-based tissue engineering, magnetic nanoparticles are introduced into mammalian cells and their spatial position is controlled by a magnet. The shape of the magnet (planar or cylindrical), defines the layered or tubular morphology of the resulting tissue (Corchero et al. 2010).

has previously been tested with various cell lines, consisting of the human umbilical vein endothelial cells (Akiyama et al. 2009), retinal pigment epithelial cells (Ito et al. 2005), keratinocytes (Ito et al. 2004), mesenchymal stem cells (Shimizu et al. 2007), and cardiomyocytes (Shimizu et al. 2007), with favorable results (Corchero et al. 2010). Furthermore, tubular structures, for example, urinary tissue shaped by urothelial cells or vascular tissues consisting of smooth endothelial cells and muscle cells, can also be produced using the Mag-TE protocol. In this approach, magnetically-labeled cells form a cell sheet, onto which a cylindrical magnet is rolled and then removed after the tubular structure has been shaped (Ito et al. 2005, Corchero et al. 2010). Following a related approach, Frasca and coworkers applied magnetic forces to generate a 3D cell assembly with tunable size and regulated geometry. Cells were magnetically tagged using anionic citrate-coated iron oxide NPs. Focalized magnetic power confirmed an efficient entrapment of the cells in the vicinity of the magnet. This knowledge could be applied with no limitation regarding the physicochemical nature of the substrate, the cell type, or the geometry of the required magnetic constraint (Frasca et  al. 2009). The same group showed that magnetic forceassisted cell seeding provided efficient cell seeding into 3D porous scaffolds. Furthermore, exact 3D cellular organization inside the scaffold could be attained by means of magnetic microtips that progress high magnetic forces. Despite successful research studies and results, tissue-engineered constructs lack structural complexity. Well-defined 3D cell organization is required in the attempt to reproduce living tissue complexity and succeed in generating functional tissue constructs (Silva et al. 2012).

Diagnostic applications Nuclear Magnetic Resonance (NMR) imaging. The development of the NMR imaging procedure for medical diagnosis has impelled the need for a new class of pharmaceuticals

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Biomedical and biological applications of magnetic nanoparticles  5 called magneto-pharmaceuticals. These drugs should be administered to a patient in order to (Akbarzadeh et al. 2012) improve the image contrast between normal and diseased tissue and/or (Wu et al. 2008) represent the status of organ functions or blood flow (Akbarzadeh et  al. 2012, Rockenberger et al. 1999). Iron oxide nanoparticles of maghemite (Endorem ® and Resovit ®) have been used as contrast agents in NMR imaging for position and diagnosis of brain and cardiac infarcts, liver lesions or tumors, where the MNPs tend to accumulate at higher levels owing to the differences in tissue composition and/or endocytotic uptake procedures (Tartaj et al. 2003).

In vitro applications Diagnostic applications Magnetic resonance imaging (MRI). Magnetic resonance imaging (MRI) is a usually used non-invasive therapeutic imaging method in clinical medicine to visualize the structure and function of tissues (Weissleder 2006, Jun et al. 2008), and is based on the actions, position and contact of protons in the presence of a functional magnetic field (Xu et al. 2014). At the boundary between nanomaterials and therapeutic diagnostics, SPIO NPs are being demonstrated to be a class of novel probes useful for in vitro and in vivo molecular and cellular imaging. The face-centered cubic packing of oxygen in maghemite/magnetite, γ-Fe2O3/Fe3O4, allows electrons to move between iron ions occupying interstitial tetrahedral and octahedral locations, thus giving the molecules halfmetallic properties that are appropriate for MRI (Gupta and Gupta 2005, Faraji et al. 2010). Contrast agents are generally specified based on their relaxation and magnetic properties, and biodistribution. When explaining a contrast agent based on relaxation properties, the efficiency is defined by the longitudinal and transverse relaxivity R1 and R2, respectively. The relaxivity reflects the change in the relaxation rate as a function of the concentration of the contrast agent. The relaxivities are influenced by the composition and the size of these particles (Silva et al. 2012, Abbasi et al. 2014). The images shaped are the result of several parameters such as relaxation times (T1, T2, T2*), proton density, nuclear alignment, water diffusion, radio frequency excitation, spatial encoding, etc., supplying a digital representation of tissue characteristics (Silva et  al. 2012). MRI relies on the counterbalance between the extremely small magnetic moment on a proton, and the extremely large number of protons existing in biological tissue, which leads to a measurable consequence in the presence of large magnetic fields (Pankhurst et  al. 2003, Livingston 1996, Elster and Burdette 1994). Iron oxide NPs are the most ordinarily used super paramagnetic contrast agents. Dextran-coated iron oxides are biocompatible and are discharged via the liver after the treatment. They are taken up selectively by the reticuloendothelial system, a network of cells lining blood vessels whose function is to discharge foreign matters from the bloodstream; MRI contrast relies on the differential uptake of different tissues (Pankhurst et al. 2003, Lawaczeck et al. 1997).

Super paramagnetic contrast agents have an advantage of creating a greater proton relaxation in MRI, in comparison with paramagnetic ones. Therefore, less amounts of a SPIO agent is required to dose the human body than a paramagnetic one. A SPIO should be distributed into a biocompatible and biodegradable carrier to implement the magnetic fluids to a MRI contrast agent (Faraji et  al. 2010). Due to properties such as superparamagnetism, high saturation magnetization, biocompatibility, and low toxicity, proteins immobilized on iron oxide MNPs have been successfully implemented in MRI imaging (Wunderbaldinger et al. 2002). Human holo-transferrin conjugated to iron oxide NPs indicated that increases in receptor levels at the cell surface can cause significant changes in MRI signals. These SPIO NPs are comparatively non-toxic when managed intravenously, and similar productions are in medical application (Xu et al. 2014). However, MRIs are not appropriate for in situ monitoring, therefore a sensitive and simple method for in situ monitoring of the NPs in living cells is desirable (Faraji et al. 2010). Separation and selection. At present, significant attention is being paid to solid-phase extraction (SPE) as a way to separate and preconcentrate desired components from a sample matrix. SPE is proposed as an admirable alternative to the conventional sample concentration methods such as liquid-liquid extraction (Akbarzadeh et  al. 2012, Pourhassan-Moghaddam et  al. 2014, Gao et  al. 2004, Pellegrino et al. 2004). The separation and preconcentration of the ingredient from large volumes of solution can be highly time consuming when using the SPE standard column, and it is in this field that the use of magnetic or magnetizable adsorbents called magnetic solid-phase extraction (MSPE) have acquired importance. In this process, the magnetic adsorbent is added to a solution or suspension including the target. This is adsorbed onto the magnetic adsorbent, and then the adsorbent with the adsorbed substance is recovered from the suspension using an suitable magnetic separator (Figure 3) (Tartaj et al. 2003).

Figure 3. Schematic representation of the magnetically-assisted separation of substances. In this particular case, a magnetic nanosphere to which an antibody has been anchored is dispersed in a liquid medium containing the antigen (substance to analyze) (Tartaj et al. 2003).

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6  F. Zeinali Sehrig et al. Magnetorelaxometry. Magnetorelaxometry is the method used to evaluate immunoassays (Murthy et  al. 1999). The physical properties of MNPs allow the measurement of a magnetic relaxation signal after a quick change of an external magnetic field. The relaxation signal depends on hydrodynamic volumes and core sizes of the MNPs. Because neither the surrounding biological environment nor any remnant magnetic material in the vicinity will produce such relaxation signals, magnetorelaxometry is highly specific for MNPs (Wiekhorst et al. 2012). The phenomenon of deferred magnetic response of ferrior ferromagnetic materials to sudden changes of an external functional magnetic field has long been known, and is commonly identified as magnetic viscosity, magnetic relaxation, or magnetic after-effect (Street and Woolley 1949). Recently, it was recognized that the measurement of this effect, especially the measurement of the time-dependent response of super paramagnetic NPs to an unexpected switch-off of the magnetic field, can be utilized to achieve specific information about the NPs and their environment (Wiekhorst et al. 2012, Kotitz et al. 1995).

MNPs appear as a capable support for magnetic-based separations, since they demonstrate minimum diffusion limitations and allow rapid and easy removal of the functionalized MNPs from complex heterogeneous reaction mixtures, without requiring prior filtration or centrifugation. Moreover, these supports are easy to manipulate, which makes them a good choice for a downstream process (Figure 4) (Roque et al. 2004, 2007, Santana 2011, Birch and Racher 2006, Horak et al. 2007). Zheng and coworkers synthesized magnetic core-shell Fe3O4@SiO2@poly (styrene-alt-maleic anhydride) spheres for the separation of His-tagged proteins from cell lysates. The enrichment capacity of these particles was four times greater than that of Fe3O4@SiO2/Ni-NTA (Fang et al. 2010). Bruening and coworkers also prepared polymer-brushmodified MNPs functionalized with nitrilotriacetate-Ni2 by ATRP to entrap His-tagged proteins selectively from cell extracts (Xu et al. 2011). The polymer brushes can dramatically raise the adsorption capacity for His-tagged ubiquitin and yield high protein recoveries (Xu et al. 2014).

Bioseparation. MNPs appear as a practical choice for biotechnological industries, particularly for bioseparation procedures, since this option can overcome many problems, especially cost reduction and process integration. The request for high quality of therapeutic proteins which are at the same time low-cost associated therapies presented the need for researching different types of separation methods, in order to improve downstream processing, known to be responsible for a significant percentage of the total production cost (Roque et  al. 2004, 2007, Roque and Lowe 2006, Santana 2011). MNPs such as SPIO NPs, have been widely used for separation and purification of cells and biomolecules in bioprocesses (Akbarzadeh et al. 2012, Faraji et al. 2010, Jeong et al. 2007, Lu et al. 2007, Ebrahimi et al. 2014, Gu et al. 2006, Hultgren et al. 2003, Smith et al. 2006). Due to their small size and high surface area, MNPs have many greater characteristics for these bioseparation applications compared to those of the customary micrometer-sized resins or beads, such as good dispersibility, the fast and efficient binding of biomolecules, and reversible and controllable flocculation (Akbarzadeh et al. 2012).

Enzymes are increasingly being used in various industrial applications due to their exclusive properties, such as specificity, mild reaction conditions, and biodegradability, which translate into higher chemical precision and less side reactions. However, there are some problems associated with their use, such as short lifetimes, deactivation under rough conditions, and cost. The immobilization of enzymes, especially in MNPs, provides a lot of advantages in the field of biocatalysis. One of the major advantages is the potential for reusability and the easy recovery due to the magnetic proprieties of the solid support used (Santana 2011, Kim et al. 2006).

Biocatalytic applications

Enzyme Immobilization The challenging request for highly stable enzymes to be applied in various processes and products triggered the progress of immobilized enzymes (Kim et al. 2006, Kubitzki et al. 2009). Enzyme immobilization includes the attachment of an enzyme into or onto modified surfaces through adsorption, covalent attachment, or encapsulation. Depending on the support used, the biocatalyst can have more or less

Figure 4. Schematic representation of a bioseparation process using MNPs as adsorbent (Santana 2011).

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efficiency (Kim et al. 2006). Magnetic nanoparticles appear as a promising alternative support for enzyme immobilization. These supports indicate a lot of advantages related to their properties and have already proved to be effective for the immobilization of some enzymes, as in the case of glucose oxidase used in blood glucose sensors (Santana 2011, Rossi et  al. 2004). Through enzyme immobilization, it is possible to reutilize the enzyme, which decreases the costs associated, and permits working in a continuous mode. The environment of the enzyme is also more controlled, which increases stability (Kubitzki et al. 2009, Suh et al. 2005).

Magnetofection Another type of magnetic operation is magnetic transfection or magnetofection. It is well known that the development of an effective system for delivering genes into targeted cells is an main strategy to understand gene/protein functions and to improve therapeutics (Al-Dosari and Gao 2009). In magnetofection, MNPs are commonly coated with positively charged molecules that permit the negatively charged plasmids to be associated with them (Dobson 2006, Tabasinezhad et al. 2013). For example, MNPs for magnetofection can be prepared by coating an iron oxide core with a cationic copolymer, which consists of short chain polyethylenimine (PEI) and PEG grafted to chitosan. This system combines the biocompatibility of chitosan, the steric stabilization of PEG, and the positive charge of PEI, so that it can bind, protect, and deliver plasmids into tumor cells, both in vitro and in vivo (Kievit et al. 2009). Tanaka and coworkers mixed 29 nm maghemite MNPs with the hemagglutinating virus of the Japan envelope vector (HVJ-E) to increase the transfection efficiency. They reported that the MNPs with protamine sulfate that gives a cationic surface charge, significantly increase the transfection efficiency in vitro due to the enhanced association of HVJ-E with the cell membrane, in the presence of a magnetic force. MNPs coated with heparin increase the transfection efficiency in vivo. Therefore, the surface chemistry of the MNPs needs to be tailored to meet special demands (Morishita et al. 2005, Yi et al. 2013).

Separation and detection of bacteria Pathogen detection, such as detection of bacteria and viruses, is another promising application of MNPs. Currently, the recognition of microbial pathogens depends on the conventional clinical microbiological monitoring approaches. The standard culture and susceptibility tests allow pathogen recognition but are expensive, laborious, and time-consuming, and require labile natural products (Vora et al. 2004). One typical example is the separation and detection of Gram-positive bacteria. It is well known that an antibiotic, vancomycin (Van), binds the terminal peptide (D-Ala-D-Ala) on the cell wall of Gram-positive bacteria (Khalili et al. 2013, Xing et al. 2003). Thus, the combination of Van with MNPs permits the identification and separation of Gram-positive bacteria with magnetic separation. Moreover, core-shell MNPs are also efficient. For instance, in the case of Ag@Fe2O3 yolk-shell MNPs, the magnetic Fe2O3 shell could be functionalized with glucose molecules as anchors

for bacterial attachment. Concurrently, the porous Fe2O3 shell facilitates the release of Ag ions and/or Ag NPs, which act as broad-spectrum antibacterial agents (Yi et al. 2013).

Manipulation of cells and organs MNPs are versatile to be functionalized with biomolecules to selectively target particular cells such as tumor cells, progenitor cells, or stem cells. For instance, the particular binding of MNPs to stem cells allows the manipulation of their bio distribution (Riegler et  al. 2013). While nonspecific labeling of several types of cells with MNPs has been reported, it is more important to achieve special binding (Wilhelm et al. 2003). Perez and coworkers investigated the role of the valency of MNPs in the nondestructive magnetic-relaxation-mediated discovery and magnetic separation of cells in complex media, such as tumor cells in blood and bacteria in milk (Santra et al. 2009). They conjugated the molecules of folic acid at two different densities (low-folate and high-folate) on polyacrylic-acid-coated iron oxide MNPs for labeling cancer cells. They reported that the multivalent high-folate MNPs performed better than the low-folate MNPs with higher and faster detection kinetics, susceptibility, and more effective magnetic isolation of cancer cells. The multivalent highfolate MNPs permitted the detection of a single cancer cell in a blood sample within 15 min. Through manipulating the cellular organelles and cells, the functions of organs could be controlled. Pralle and coworkers found a novel approach using radio frequency (RF) magnetic-field heating of MNPs to remotely activate temperature-sensitive cation channels in cells, including neurons (Huang et  al. 2010). They reported that this method could be modified to remotely trigger the behavioral responses of Caenorhabditis elegans worms (Yi et al. 2013).

Conclusion Industrial and biological applications of MNPs cover a wide spectrum of magnetic recording media and biomedical applications, for example, magnetic resonance contrast media (MRI) and therapeutic agents in cancer treatment. Each potential use of the MNPs requires having special properties. Another type of magnetic operation is the deve­ lopment of an efficient system for delivering genes into targeted cells, which is a main strategy to understand gene/ protein functions and to improve therapeutics.

Authors’ contributions AA conceived of the study and participated in its design and coordination. NN, FZS, and MN participated in the sequence alignment and drafted the manuscript. All authors read and approved the final manuscript.­­

Acknowledgments The authors thank the Department of Medical Nanotechnology, Faculty of Advanced Medical Science of Tabriz University, for all support provided. This work is funded by the 2014

8  F. Zeinali Sehrig et al. Drug Applied Research Center Tabriz University of Medical Sciences Grant.

Declaration of interest The authors report no declarations of interest. The authors alone are responsible of the content and writing of the paper.

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Magnetic nanoparticles as potential candidates for biomedical and biological applications.

Magnetic iron oxide nanoparticles have become the main candidates for biomedical and biological applications, and the application of small iron oxide ...
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