Magnetic nanoparticles based nanocontainers for biomedical application

Chapter 14

Magnetic nanoparticles based nanocontainers for biomedical application Y. Slimania, E. Hannachib, H. Tombulogluc, S. G€ unerd, M.A. Almessierea,e, A. Baykalf, M.A. Aljafaryg, g f a E.A. Al-Suhaimi , M. Nawaz and I. Ercan a

Department of Biophysics, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

b

Laboratory of Physics of Materials, Structures and Properties, Department of Physics, Faculty of Sciences of Bizerte, University of Carthage, Zarzouna,

Tunisia c Department of Genetics Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia d Institute of Inorganic Chemistry, RWTH Aachen University, Aachen, Germany e Department of Physics, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia f Department of Nano-Medicine Research, Institute for Research & Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia g Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

1 Introduction to magnetic nanoparticles based nanocontainers Although the advancement of magnetic nanoparticles (MNPs) for numerous biomedical applications is currently in progress, MNPs have been broadly utilized in drug delivery, tissue engineering, hyperthermia, and theragnostics, etc. [1, 2] For this purpose magnetic nanoparticles should be functionalized with adequate groups (like polyethylene glycol (PEG), amino acids, dextrant (DEX), biopolymer, polyvinyl alcohol (PVA), poly(methyl methacrylate) (PMMA), etc.) to overcome aggregation. The surface modifications of MNPs are very important. With a proper surface modification, MNPs could circulate for a longer time and are less recognized by the biological particulate filters of the body. Although there is common consensus, it is proved that MNPs exhibiting 10–100 nm in size are most appropriate for biomedical applications [3]. The two important parameters of MNPs for the usage in biomedical applications are the magnetic moment, “m,” which establishes the strength of the signal and the nonlinearity, and the relaxation time, “τ,” which evaluates the responses to high-frequency fields. It is very important to select MNPs displaying suitable “m” and “τ” values for the desired biomedical application [4]. The nano-sized magnetic materials show prominent magnetism, which is directly proportional to the same direction of the applied magnetic field. This phenomenon is also known as ferromagnetism. For example, cobalt (Co), gadolinium (Gd), iron (Fe), and nickel (Ni) are ferromagnetic materials. Cobalt and nickel are highly ferromagnetic metals; however, they exhibit high toxicity and show high oxidation susceptibility. Notably, the magnetite (Fe3O4), maghemite (g-Fe2O3), spinel ferrites (AFe2O4 where A ¼ Mn, Zn, Co, Ni, etc.) are the abundantly used iron oxide nanoparticles (IONPs) for biotherapeutic applications. The extensive interest in IONPs has been increasing due to their biodegradability, biocompatibility, lower toxicity, simplicity of synthesis, enhanced programmed cell death, and auto-phagocytosis of the cancer cells [5, 6]. Furthermore, their superparamagnetic (SPM) properties make them the most appropriate kind of MNPs for biomedical application [7]. Moreover, due to SPM character, they do not have hysteresis, therefore, they leave behind a residual magnetization equal to zero after the suppression of the applied magnetic field. This is a very important feature of SPIONs because this property is very important to avoid coagulation, hence low possibility of agglomeration in vivo [8]. Furthermore, nanocarriers and nano-sized particles overcome the obstacles displayed by current conventional drugs such as poor bioavailability and the degradation of drug molecules before reaching their targets [9]. The multi-layer coating of the MNPs includes a magnetic core, biocompatible layer, and therapeutic layer, which have targeted ligands for cancer cell receptor-mediated endocytosis and site-specific delivery [10]. MNPs are currently utilized in many diverse fields of biomedical applications, such as magnetic cell separation [11], magneto cytolysis [12], magnetic hyperthermia [13], tracking of biological components [14], targeting and controlled release of drugs [15], contrast agents in MRI (magnetic resonance imaging) [16], increasing the growth of tissues [17], and reducing implant infection [18] (Fig. 1). MNPs could be produced via several approaches like hydrothermal synthesis, Smart Nanocontainers. https://doi.org/10.1016/B978-0-12-816770-0.00014-9 Copyright © 2020 Elsevier Inc. All rights reserved.

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FIG. 1 Biomedical applications of SPIONs. (Reproduced with permission from J. Kudr, Y. Haddad, L. Richtera, Z. Heger, M. Cernak, V. Adam, O. Zitka, Magnetic nanoparticles: from design and synthesis to real world applications, Nanomaterials 7(9) (2017) 243.)

thermal decomposition, micelle synthesis, co-precipitation, and laser pyrolysis approaches [19–22]. Although much research on biomedical applications of MNPs has been done, with many successful results, there are still a lot of questions that must be solved. To overcome some biocompatibility problems of MNPs, new synthesis methods are still needed. The other problem is the toxicity of MNPs. Toxicity is a complicated problem, since it is governed by various factors like solubility, size, chemical composition, biodistribution, pharmacokinetics, dose, biodegradability, surface chemistry, shape, and structure, etc. [23]. Hereafter, we present the physical and magnetic properties of MNPs, and review the most common and new advancements for the biomedical significance of MNPs in diagnosis and cancer therapy.

2

Magnetic properties

Magnetism in nanoparticles (NPs) is beneficial to various biomedical applications. Under magnetic field (H), diverse magnetic materials behave in a different way and consequently, some magnetic nanoparticles (MNPs) exhibit better specific features than others. It is well-known that the spin and the orbital motions of electrons in matter are responsible for the origin of magnetism. Therefore, all matter is magnetic in some sense. There exist five basic types of magnetism (Fig. 1): l l l l l

diamagnetism; paramagnetism; ferromagnetism; antiferromagnetism; and ferrimagnetism.

2.1 Diamagnetism Once an external magnetic field is applied, diamagnetic materials develop an induced magnetic field opposite to this field and thus are repelled by the field. In nature, there are a huge amount of organic substances that display diamagnetism, which is a very weak force, nonpermanent, and can be overcome by any of the other four types of magnetism. In a diamagnetic

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substance, there are no unpaired electrons and thus the magnetic susceptibility “w” (the measure of the increase in magnetic moment caused by the applied field) is below zero. For perfect diamagnets, w is equal to 1 since they expel all applied magnetic fields (excepting in a thin surface layer) owing to the Meissner effect. This is a characteristic of superconductor materials, which conduct the currents without any loss of energy [24, 25].

2.2 Paramagnetism If there are unpaired electrons in the material, it exhibits a nonzero magnetic moment causing paramagnetism. In the presence of H, the orientation of the magnetic moments is random and hence the net macroscopic magnetization is considered as zero (Fig. 2). In other words, in the absence of H, the paramagnetic material will lose its magnetic property. The susceptibilities of paramagnetic substances are in the range 103 and 105.

2.3 Ferromagnetism The ferromagnetic materials display a large magnetization even when a magnetic field is not present, due to the parallel alignments of magnetic moments (Fig. 2). The exchange interactions in ferromagnetic materials are also very strong, equivalent to a field of 103 Tesla, which is approximately 106 times higher than the Earth’s magnetic field. The susceptibility of ferromagnetic materials is much different from that of paramagnetic materials; saturated in moderate magnetic fields and at high temperatures. Above the characteristic temperature known as Curie temperature (Tc), the thermal energy becomes the dominant force compared to the strong electronic exchange forces, and a randomizing effect is generated in ferromagnetic materials. The saturation magnetization (Ms) reaches zero at Curie temperature, while it is ordered below Tc and disordered above Tc. In addition, materials that retain permanent magnetization even after the applied field is removed are known as hard magnets. The best-known examples of hard magnets are barium and strontium hexaferrites (BaFe12O19, SrFe12O19). The magnetization (M) versus magnetic field (H) plot of these materials form an area called an “hysteresis” loop (Fig. 3) defined by Ms, Mr (remanent magnetization) and Hc (coercive field). When H ¼ 0, the Mr in paramagnetic materials is also No domains

Spontaneous domain formation

Diamagnetic Ferromagnetic Paramagnetic FIG. 2 Alignments of magnetic moments in various kinds of aterials.

Antiferromagnetic

Superparamagnec

Ferromagnec or Ferrimagnec

Paramagnec Temperature increases

Ferrimagnetic

Size decreases

or

Thermal acvaon

M

M

M Mr

Ms

Hc H

FIG. 3 Different kinds of magnetic behaviors.

H

H

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equal to zero. With increasing H, the dipoles inside the matter begin to align with the applied H and the M increases. M reaches its maximum value (or saturated value; Ms) once the various dipoles are being totally aligned with the applied H. One should note that the M does not exceed the Ms value on further raising the applied H. It is well-known that ferromagnetic matter displays a magnetic “memory.” With reducing H, the M value does return to zero and it is identified as Mr. With further decreasing H in the negative direction, the M magnitude reduces also. Hence, another term is obvious, which is Hc (sometimes called the residual magnetism of a material). The latter designates the field to decrease the M values of the material to zero. The size of the material is strongly correlated with the coercivity. It is reported that an energy is dissipated as heat when a varying H is applied from H (Ms) to H (+Ms) and inversely [26]. Furthermore, when the Hc of the MNPs is high enough, the specific absorption rate (SAR) will be high also, making these products promising for hyperthermia [26].

2.4 Antiferromagnetism When the magnetic moments of a substance are aligned in an antiparallel manner but exhibit the same magnitude, hence canceling out the magnetization, this material is said to display antiferromagnetism (Fig. 2). The antiferromagnetic substances display weak magnetization regardless of applied magnetic field. Some known antiferromagnetic compounds are CoO, NiO, and FeO. The susceptibility of antiferromagnetic materials is small (105 to 103).

2.5 Ferrimagnetism Ferrimagnetism can be defined as a kind of magnetism where magnetic moments have opposing moments similar to that of antiferromagnetism; however, the antiparallel moments do not cancel each other out, and a spontaneous magnetization occurs in absence of H below a characteristic temperature called Neel temperature (TN). Just like in ferromagnetism, the susceptibility of ferrimagnetic materials is large. The presence of different atoms or ions such as Fe2+ and Fe3+ ions in the population of atoms often results in ferrimagnetism. Many ferrites display ferrimagnetic behavior, especially magnetite, which is the oldest known magnetic substance; cubic spinel ferrites also exhibit ferrimagnetism. Above TN, the material acts like a ferromagnet in the macroscopic view, since the thermal energy (kBT, where kB is Boltzmann constant) is enough to surpass the magnetic anisotropy energy (Ea ¼ KeffV, where V is the volume of particle and Keff is the effective anisotropy constant). However, as the particle size gets smaller than a critical value called “Ds,” the domains start to act like giant paramagnets, each with a certain magnetic moment (single domain) that can be aligned to the applied magnetic field (Fig. 3). Such particles are, therefore called, superparamagnetic (SPM). They have a size lower than 50 nm and do not exhibit a coercivity in the M(H) loops (Fig. 3). Once H is removed, the Hc of nanoparticles becomes zero, which makes SPIONs ideal candidates to be utilized for theranostic and other biomedical applications. The design of MNPs for various biomedical applications is not easily realized. One should note that there are important factors determining the magnetic features of MNPs, such as the shapes and sizes of nanoparticles, the intra-particle interactions, the interparticle interactions, the magnetic interactions that occur among the NPs and the matrix, and the interactions between the NPs and applied H. The majority of the biomedical and environmental applications include MNPs that are sufficiently small (less than 50 nm) that consist of a single magnetic domain and are SPM [27, 28]. The effects of these two finite sizes cause higher magnetic moments. Therefore, due to this, the magnetic force generated by an NP is proportionate to both its volume and magnetic moment, and a stronger interaction with an applied field occurs. For example, the critical Ds value, below which spherical NP is single domain, is 50 for Ni, 15 nm for Fe, and 120 nm for Fe3O4 [29]. Ferro- or ferri-MNPs are generally SPM for diameters less than 10 to 20 nm [28]. SPM behavior occurs above a critical temperature known as blocking temperature (TB). At this temperature, the kBT is adequate to exceed the Ea [30–33]. This leads the MNPs to act as giant paramagnets, where the magnetic moment is constant in each NP. This magnetic moment can be easily aligned by the application of H. Nevertheless, when H is switched off, the Mr of the NPs is equal to zero. This is very important in magnetic separation applications because, when H is effectively removed, the NPs will be re-dispersed in the solution and, therefore, could be employed for further treatment. An aggregation could be generated owing to the long-range magnetic forces between particles. Furthermore, particles with larger sizes are more susceptible to agglomeration than ones with smaller sizes, given that TB is proportional to volume. The dominant magnetic interactions that contribute to aggregation in a system of NPs come from the dipole-dipole forces and the weak direct exchange interactions among NPs. The extensive interest in magnetic nanoparticles (MNPs) has been increasing due to their biocompatibility, superparamagnetism, lower toxicity, and enhanced programmed cell death and auto-phagocytosis of the cancer cells [34, 35]. Moreover, nanocarriers and nano-sized particles overcome the obstacles displayed by current conventional drugs such as poor bioavailability and the degradation of drug molecules before reaching their targets [36]. The multilayer coating

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of the MNPs includes a magnetic core, biocompatible layer, and therapeutic layer, which have targeted ligands for cancer cell receptor-mediated endocytosis and site-specific delivery [37]. These types of surface coatings or ligand-conjugated multilayers in MNPs are getting popular in the field of personalized medicine in terms of both theranostics and therapeutic applications [38].

3 Biomedical application 3.1 Drug delivery The uses of MNPs based nanocontainers in pharmaceutical and clinical applications have shown an increasing trend until now. Magnetic nanoparticle drug delivery systems have attracted more interest as they are able to deliver the drug to the targeted site by applying H. The expectations for a safe use of these nanoparticulate systems are sufficiently enhanced permeability and retention (EPR) effect and targeted drug delivery potentials. The drug molecules are delivered inside tumor or target sites by using active or passive targeting pathways. Nowadays, great interest has been focused on the stimuli-responsive systems to, for example, pH, magnetic field, temperature, etc. for potential applications such as drug delivery. It is reported that several kinds of drug can be loaded into the MNPs based nanocontainers, such as pulmonary drugs, transdermal drugs, intracellular drugs, wound healing drugs, infectious and inflammatory diseases, Alzheimer’s disease, retroviral drugs (against AIDS), chemotherapeutic drugs, and anticancer [39]. Then, the drug included into or with MNP-based nanocontainers could be delivered to the target tissues by the application of electro-magnetic fields. Numerous approaches were recommended to produce MNPs coated with inorganic/organic materials. Generally, these strategies imply a modification of MNPs’ surface with bio-active substances that could identify the targeted receptors existing in the cancer cells [40]. Usually, drug delivery systems for theragnostic and therapeutic applications are formulated by utilizing the two routes [41–44]: (i) Therapeutic drug molecules or other bio-active materials are covalently bonded to or conjugated with the surface of the MNPs. (ii) MNPs could be encapsulated with various carriers such as hybrid magneto-plasmonic liposomes, magnetic polymeric nanoparticles, thermo-responsive magnetic hydrogels, and g-Fe2O3 MNPs with dendrimers. The major problems in the naked MNPs are the agglomeration and the risk to expose to oxidation, destroying their magnetism. Therefore, to keep their magnetism and morphology, it is essential to stabilize the MNPs chemically. The coating of the surface of MNPs by using diverse protective, nontoxic, and nondegrading agents is essential to avoid the agglomeration of NPs, to improve bio-compatibility, and to enhance the blood circulation [45]. Besides, the surface coating can include functional groups that can be altered in accordance with the anticipated application [45]. The successful surface modification of MNPs can enhance the drug release profile and achieve the effective targeted delivery. Two types of polymeric materials widely used for the MNPs coating are natural polymers that include carbohydrates (starch and dextran), proteins (albumin), RGD peptides, and lipids and synthetic polymers like PEG, PVA, and co-polymers [46–48]. Numerous studies report that the stabilization of MNPs with natural poly-electrolytes such as humic acid, starch, and basic sugars, which containing phenyl groups or carbon chains, offer steric repulsion against the agglomeration of MNPs [49, 50]. Chitosan, carboxymethyl cellulose (CMC), and poly-(acrylic acid) are other popular agents used to stabilize MNPs [51–53]. On the other hand, the functionalization enhances the control of the performance and function of MNPs and increases the efficiency in the targeted adsorption of MNPs [54]. In addition, the functionalization of MNPs is advantageous to prepare MNPs sensitive to different internal and external stimuli, like redox, light, pH, temperature, ultrasound, etc. [44] Earlier reports show that MNPs encapsulated in liposomes showed significant pharmacokinetic properties while retaining their magnetic characteristics and achieved successful targeted delivery for various applications including treatment of pulmonary arterial hypertension and hyperthermia chemo-therapeutic treatment of cancers [55, 56]. Since the SPIONs do not display any magnetization after elimination of the applied H, their aggregation could be avoided, making them useful in vivo applications. Ghorbani et al. [57] prepared core-shell Au/SPIONs@polymer MNPs for the delivery of doxorubicin (DOX). Iron oxide nanoparticles coated with SiO2 are also an interesting material for drug delivery due to several features. Yang et al. [58] investigated magnetic nanocomposites consisting of core-shell of Fe3O4@mesoporous-SiO2 for the delivery of anticancer drugs. Similarly, meso-2,3-di-mercaptosuccinic acid (DMSA) coating CoFe2O4 MNPs were produced by Oh’s group for the delivery of DOX [59]. Because of the acidic environment of cancer cells, the interaction amongst CoFe2O4@DMSA and DOX reduces, which leads to release of the drugs. Fang et al. [60] synthesized magnetic core-shell nano-capsules of Fe-oxides assembled from poly-acrylic acid polyvinyl alcohol to be employed as carriers of DOX and curcumin (CUR). Similarly, Licciardi and co-workers [61] synthesized polymeric

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nanocarriers based on MNPs for the delivery of flutamide. Shakeri-Zadeh et al. [62] reported the manufacture of nanocapsules of poly-lactic-co-glycolic acid loaded with MNPs and 5-fluorouracil to target CT26 colon tumors in BALB/c mice, exhibiting excellent antitumor activities against the colon cancer allografts. Halupka-Bryl and co-workers [63] suggested PEG-block-poly(4-vinylbenzyl-phosphonate) MNPs comprising DOX. It was noticed that doxorubicin-containing PEGylated iron oxide nanoparticles showed selectivity to the tumor area. Similarity, Kumar et al. [64] reported hollow manganese ferrite nanocarriers for sequential release of drugs in breast cancer cells and good results have been obtained.

3.2 Gene therapy Gene therapy is a method of transferring genes to the cells or tissues for the examination or prevention of diseases. In general, three principal gene delivery systems exist [65]: (i) nucleic acid transfection, (ii) nucleic acid electroporation, and (iii) viral vectors (retro-viruses and adeno-viruses). With the advances in nanotechnology, a new way of transporting the genetic material to a specific target cell or tissue has emerged using magnetic nanoparticles (MNPs); this is also called magnetofection. It has been successfully applied into living cells with low cytotoxicity and great efficiency [66–68]. One of the primary characteristics of nanocontainers or carriers for gene delivery is the size, which should be small enough to allow their passage from the cell membrane. Also, they should be free from endosome/lysosome encapsulation. In addition, their potential degradation by nucleases should be prevented. By doing so, they can be used in a broad range of metabolic and genetic diseases such as cancer, hemophilia, rheumatoid arthritis, AIDS, asthma, diabetes, etc. [5]. The procedure is based on the enhancement of transfection efficiency by applying H by a magnet to a target cell or tissue. For instance, in vitro, MNPs can be applied to adherent cells in cell culture and directed with a magnet placed at the bottom of the plate or flask. They are assumed to be internalized through endocytic pathway with high transfection efficiency. In vivo, therapeutic gene/MNP complex is injected intravenously. Then, the site of interest in the body is stimulated by a strong magnetic field that directs the MNPs to a specific target (organ or tissue), and increases the transfection efficiency. By doing so, the gene is detained abundantly only at specific target site. Ex vivo, MNPs are used to deliver therapeutic genes to the patients’ own cells in vitro and transplanted to the body, avoiding using immunosuppressive drugs. The strategy is as follows: (i) (ii) (iii) (iv)

Patient-derived cells (i.e., fibroblasts) are isolated and cultured in vitro. The cells are transfected by MNPs with desired gene complex and differentiated. Fluorescence-activated cell sorting (FACS) will be used to isolate the differentiated cells. FACS-purified differentiated cells are transplanted inside the target tissue of patient [68, 69].

MNPs could be employed to improve gene transfection of nonviral and viral vectors via coating onto their surface. For effective magnetofection, surface coating of the MNPs is key. Several modifying agents such as cationic polymer (polyethylenimine, PEI), oleic acid phospholipid, HVJ-E heparin sulfate, DOPE, etc. can be used for the generation of DNAnanocarrier interaction surface [68–70]. Upon attachment of MNPs, they are ready to deliver to the targeted cells using high-field/high-gradient magnets. Hence, the virus is maintained in contact with the tissue for a long time, increasing the efficiency of gene transfection and expression, which is difficult by using traditional methods [69, 71–74]. Nonviral vectors are less efficient for gene delivery than viral vectors; however, viral carriers can present an important threat to patients due to their possible effects on the immune system [75, 76]. IONPs conjugated nucleic acids are shown to be delivered to human embryonic kidney cells (HEK 293) [77], breast cancer cells (MDA-MB-231) [78], and corneal endothelial cells [79], in vitro. Recently, a magnetofection system has been developed to transfer pollens to the cotton plant with MNPs as gene carriers [80, 81]. In addition, miRNA inhibitor was efficiently delivered in brain regions injected into the lateral ventricles next to the striatum of a rat by using a polymeric magnetic particle, Neuromag® [82]. MNP-guided gene therapy can be a pathway not only for the treatment of human diseases, but also for improving transformation efficiency during gene transfer of other organisms, such as plants.

3.3 Imaging modalities 3.3.1 Magnetic resonance imaging (MRI) The uses of MNPs from diagnosis to therapy have been raised. MNPs are utilized as contrast agents to improve the detection of cancers and diagnosis. Bioimaging is one of the most important research topics in biomedical applications. Among the various bio-imaging systems, MRI is a familiar noninvasive image scanning technique in the clinical department. This technique gives topographical data of the healthy and diseased living system. During scanning, MRI uses radio waves,

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magnetic field, and its gradients to produce images of the specific organs. The MRI technique shows better spatial resolution images, although it suffers from lower sensitivity. The signal of MRI is generated by variations in the direction of the water hydrogen nuclei arrangements in the precession in an applied radio-frequency signal. After the application of radiofrequency pulsations, the relaxation times, T1 (longitudinal) and T2 (transverse), are useful to produce an MRI image. The relaxation time is the time taken by protons to return to their initial state. T1 and T2 reflect the spin-lattice and spin-spin relaxations, respectively. T1 and T2 depend on Ms of MNPs and their magnetic interactions with the protons of water (H2O) molecules. Various contrast agents are frequently utilized to alter the T1 and T2 and to enhance the MRI imaging [45]. At the beginning, gadolinium (Gd), manganese (Mn), and hyperpolarization are the most used contrast agents in MRI technique. Among these, the Gd causes severe side effects in the brain and diseases like nephrogenic fibrosing dermopathy (NFD) [83–85]. At first, the hyperpolarized pyruvate (1-13C) was used to monitor the heart of rodents, but some pathophysiological changes of the PDH flux were observed in vivo conditions [86]. After that, some hyperpolarized agents were developed and gave spectacular results in imaging [87]. Great efforts have been given to develop other contrast agents displaying better characteristics. Due to the higher bio-compatibility and promising MRI imaging ability, SPIONs and IONPs have been widely implemented as contrast agents in MRI techniques. By their superparamagnetic characteristics, the NPs alter the T2 of the adjacent H2O molecules and detect the tumor cells, lymph node metastases, and gene expression, etc. [88, 89]. Recently, Liu et al. [90] prepared ferromagnetic nanoflowers (FIMO-NFs) for the theranostic and therapeutic applications and applied FIMO-NFs, both as novel dual (T1-T2) model MRI agents in mice induced with glioblastoma, and as a magnetic hyperthermia agent, which displayed great magnetic induction heating properties. The FIMO-NFs potentially induced programmed cell death and complete tumor cell regression in MCF-7 breast cancer cells, devoid of side effects. Yuan and colleagues [91] recently developed irinotecan tailed with SPION derived nano drug (SPION@IR) for MRI in the biological environment. In a recent publication, Wang et al. reported a magnetically targeted triple-model nano-theranostics system consisting of NIR fluorescence, MRI, and ultrasound, for breast cancer diagnosis [92]. The nanocarrier consists of IR780/ Fe3O4 with PLGA-PEP-DOX nanoparticles and the diagnosis of the tumor with enhanced T1 (weighted) signals and by reducing the T2 (relaxation) of adjacent photons was achieved. Intravenously (IV) injected chitosan-dextran loaded SPIONs were used in a study by Shevtsov et al. [93] for the diagnosis orthotopic gliomas in a mouse model with MRI. Acceptable cytotoxicity of the NPs against the tumor cells was observed in addition to a good contrast improvement in the tumor images of the MRI. Chitosan@Fe3O4 MNPs adjusted chemically with PEG and lactobionic acid (LA) were synthesized by Song et al. [94]. The obtained results indicated that the produced MNPs are nontoxic and exhibit higher dispersion, biocompatibility, and stability. Furthermore, the produced MNPs were tested in vivo MRI of the livers in mouse, and it was found that the signal diminished after the inclusion of MNPs. This finding indicates that the produced MNPs display liver targeting function and, therefore, they can be considered as promising candidates for biomedical application. Ahmad and co-workers [95] investigated chitosan-coated NiFe2O4 NPs and the experiment results on animals indicated that they are good contrast agents in MRI. In fact, the T1 and T2 weighted images disclosed, respectively, a 25% improvement and 70% loss in signals. For example, the one pot reaction was used by Wang et al. to produce PEG/PEI-SPIONs [96]. These MNPs showed higher solubility in water, excellent colloidal stability, higher biocompatibility, great r2/r1 relaxivity ratio, and excellent contrast results for in vivo MRI imaging of the brains of mice, which indicate that the produced SPIONs could be considered as promising T2 MRI contrast agents.

3.3.2 Other imaging modalities Because of the rapid technological progressions, numerous other kinds of imaging systems like computed tomography (CT) imaging, single photon emission CT (SPECT) imaging, positron emission tomography (PET) imaging, as well as fluorescence optical (FO), and photoacoustic (PA) imaging have been established and employed for the accurate diagnosis of several difficult diseases by using Au-NPs and Fe3O4. Each of these techniques has its fundamental physical principles and, thus, possesses particular advantages and limitations regarding its specificity and sensitivity to contrast agents, tissue penetration, quantitativeness, spatial resolution, tissue contrast, etc. [97] Table 1 summarizes the characteristics of the most pertinent clinical imaging techniques. The selection of the appropriate imaging system must not be based solely on the type of existing contrast agent, but also on the intended application. For example, when whole body scans are necessary, various methods like CT, SPECT, PET, and MRI are recommended. Nevertheless, low-priced and fast diagnosis of some specific organs could perfectly well be achieved through ultrasound. Furthermore, PA and FO applications are most appropriate for examining superficial lesions,

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TABLE 1 Advantages and limitations of various kinds of imaging systems Modality

Advantages

Disadvantages

MRI imaging

Very good contrast

Limited sensitivity

High spatial resolution

Long acquisition time

Anatomical and functional information

Expensive

Nonionizing radiation Unlimited tissue depth penetration CT imaging

Anatomical imaging

Poor soft tissue

Long acquisition time

Radiation exposure

Analysis of whole body

Limited functional information

High sensitivity High spatial resolution Unlimited tissue depth penetration 3D images PET imaging

Monitoring changes in tumor metabolism

Expensive

3D images

Required radio-nucleotide equipment

High sensitivity

Limited anatomical information

Biochemical information SPECT imaging

Capable of detecting multiple probes simultaneously in contrast to PET

Lower resolution Lower sensitivity than PET

PA imaging

High ultrasonic resolution

Limited depth

High optical contrast

No three-dimensional imaging

Acoustically visualize the tissues FO imaging

Highly sensitive

Limited depth

Relatively inexpensive

Not for whole body

Real-time imaging High spatial resolution

intra-operative, and endoscopic procedures. For molecular and functional imaging, NPs as contrast agents involve liposomes, polymers, ultra-small SPIONs, and Au-NPs. Nevertheless, not every contrast agent is appropriate for clinical procedures. For example, it has been shown that computer tomography detects pulmonary embolism and vascular damages reliably, by using small molecular-weight agents [98]. Moreover, better detection of peripheral arterial diseases and atherosclerotic plaques has been established by employing small Gd-chelates [99]. Accordingly, when planning to utilize nano-diagnostic agents, their advantages over low-molecular-weight diagnostic probes, their contrast-enhancement, and their clinical needs must be carefully considered. Furthermore, possible long-term toxicity influences must be also taken into consideration. 3.3.2.1 PET and SPECT imaging systems The SPECT and PET are categorized under the nuclear imaging systems since they are based on the detection of radioisotopes that emit positrons or gamma rays. They are tremendous imaging systems because of their fast detection time, sensitivity, and specificity. Both techniques showed great performance to detect simultaneously different biological functions. Nevertheless, they lack the capacity to show pertinent spatial resolution. In the PET system, isotopes like

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68

Ga, 64Cu, 18F, 13N, 11C, 76Br, etc. are used [100]. However, heavy radioisotopes gamma rays like 133Xe, and 123I are used for SPECT [100]. Without any doubt, positron emission tomography is among the most appreciated quantitative imaging systems with an immense ability to detect anomalies at the molecular and cellular levels [101, 102]. Indeed, very small doses of radio-pharmaceuticals, having great specific activity, are employed in this imaging system in order to get highresolution images [103, 104]. SPECT displays particular characteristics that lead it to be used for the imaging of emerging biological phenomena at cellular and molecular levels. Furthermore, the development of inflammation, infections, and malignancy, as well as the delivery of radio-pharmaceuticals, have been imaged by SPECT technique [104, 105]. Various radiolabeled hybrid MNPs have been widely utilized in PET and SPECT imaging systems. In a recent study, PEGylated Mn3O4 MNPs were conjugated with 64Cu and anti-CD105 antibody [106]. The analysis proved these nanocomposites have an immense PET and MRI imaging sensitivity and specificity concerning 4T1 breast cancer detection. Additionally, safe and biocompatible PEGylated 69Ge-SPIONs are fabricated and employed to detect sentinel lymph nodes [107]. These nanocomposites are highly stable in the serum and revealed a time-dependent accumulation in tumors, suggesting that they are promising in PET imaging. Earlier, 64Cu-rGO-MNPs (where rGO is reduced graphene oxide) were established to visualize the ischemic tissues [108]. It is found that the 64Cu-rGO-MNPs localized in the ischemic tissues can be visualized by PET imaging systems, which indicate the potential of these radiolabeled hybrid MNPs for PET as well as PA imaging. In other research work, the SiO2-coated MNPs were developed and labeled with 64Cu [109]. These nanocomposites were evaluated potentially for PET imaging of cancer tissues/cells. They proved their potential capability for serving in PET and MRI imaging of cancers owing to their important stability in serum and optimum in vivo accumulation in organs. The PEGylated SiO2-coated Fe3O4 NPs functionalized with rituximab and conjugated with 188Re were examined with in vivo and in vitro models [110]. They showed their efficiency for SPECT imaging, targeted therapy, and diagnosis of cancer tissues/cells. Moreover, the radiolabeled 99mTc dextran-coated MNPs developed by Lee and coworkers [111] revealed significant results, considered as promising nano-probes in SPECT as well as MRI for the target-guided detection of the hepatic cancers. 3.3.2.2 CT imaging system Computed tomography imaging system is extensively utilized for the diagnosis of numerous diseases. This technique, based on X-rays, provides images with high spatial resolution across slices of the body area. However, it is unable to target the desired tissues/cells, particularly the detection of biological markers of cancer. The most widely used contrast agents in CT are iodine-based materials that block X-rays, thus offering contrast and improve imaging of a part of the body [112]. Earlier, Au-NPs based CT contrast agents were seen as promise candidates to replace iodine in CT imaging because they better provided contrast and X-ray attenuation, and their capability to target the tumor via the EPR effect [112]. On the other hand, recent works have been interested to develop MNPs-based CT contrast agents. In an earlier investigation, lipid-coated 67 Ga-Fe3O4 were established for the CT to follow-up the vaccine to the antigen presenting cells [113]. Some preclinical investigations have focused on the possibility of targeted lymphocyte release of radiolabeled nano-vaccines in the lymph nodes. In another study, in vitro phantom experiments indicated that the strawberry-like Fe3O4-Au NPs enhance the contrast for both CT and MRI, hence considerably improving the accurateness of disease detection [114]. 3.3.2.3

Optical imaging systems

Various kinds of optical imaging techniques have been developed to monitor biological events. They consist largely of bioluminescence, reflectance, and near-infrared fluorescence (NIRF) imaging. These systems are quickly implemented in numerous clinical and research areas. Most of the contrast agents (either inorganic or organic) used in optical imaging systems are sensitive, versatile, relatively nonexpensive, and nontoxic [115–117]. Earlier, these systems were utilized in the diagnosis of cancer by varying endogenous fluorescence of neoplastic tissue [112]. Optical contrast agents based on quantum dots are being developed and are seen as more promising than organic agents. Zhou’s group [118] have produced core/shell Fe3O4@Au hybrid MNPs. These nanocomposites are considered as promising contrast probes for PA imaging and microwave-induced thermo-acoustic imaging. Li et al. [119] synthesized Au-coated magnetite nano-roses. These nanocomposites could be used in various applications such as optical imaging, chemotherapy, photothermal therapy, etc. 3.3.2.4

Dual-mode imaging modalities

With the aim of providing images having considerably high resolution and specificity, the dual-mode imaging techniques that combine functional imaging systems with anatomically 3D modalities (e.g., MRI/PA, MRI/FO, SPECT/CT, PET/CT, SPECT/MRI, PET/MRI, etc.) are successfully used and result in improving imaging compared to the single modality

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operating techniques [120–123]. Since each imaging systems provides its own unique advantages, the combination of techniques with complementary strengths can help for the diagnosis of numerous diseases. The dual-mode imaging modalities have been utilized to enhance the medical applications, especially in diagnosis and therapy of cancers, to lower radiation exposure, to enhance the contrast of soft-tissue, and to provide more useful information [112]. For example, PET imaging provides functional and biological information about cancer with higher sensitivity. On the contrary, MRI and CT could provide images with higher resolution to collect anatomical information. Thus, the merging of these two imaging techniques could offer not only higher resolution and sensitivity at the same time, but also further detailed biological/anatomical information concerning cancer. The dual-mode imaging could also offer detailed information on the target site by targeted delivery. Fe3O4 MNPs are promising candidates for the development of dual-mode agents because of their intrinsic properties, which lead to surface modifications and tunable pharmacokinetics. Previously, dual-mode imaging systems by employing Fe3O4 MNPs were broadly used for accurate cancer diagnosis [124]. Fig. 4 shows a typical structure for merging several imaging techniques into a single NPs based on a Fe3O4 core. Furthermore, numerous Fe3O4 MNPs based contrast agents for dual-mode imaging modalities have been produced [112]. Examples and properties of some Fe3O4 MNPs based contrast agents that have been developed are listed in Table 2. In most of these material structures, Fe3O4 MNPs showed the capacity to shorten the relaxation time of water protons, which results in enhancing the contrast of images and the sensitivity. Whereas, NPs of Au are utilized as useful contrast agents for CT imaging systems because of their intensity of X-rays attenuation, which is greater than of standard iodine-based contrast agents. Therefore, the combination of the MNPs and Au with other specific additives will offer a comparatively high relaxivity and good X-rays attenuation properties. Furthermore, all these hybrid MNPs-Au composites are noncytotoxic and hemocompatible with respect to the studied concentration range. In addition, it was found that these nanocomposites could be specifically taken up by folic acid receptor over expressing cancer cells via the folate-mediated endocytosis. In some other MNPs-based nanocomposites, SiO2 and Au are used as middle layer and nano-shell, respectively. The developed fluorescent dyes showed strong near-infrared fluorescence absorption and optical absorption. Thus, they have been encapsulated/conjugated with MNPs-Au for photothermal therapy and imaging applications. These nanomaterials revealed stability enhancement and good biocompatibility. They are promising candidates for MRI/FO and MRI/PA dual-mode imaging performance. Indeed, they can accumulate efficiently at the tumor sites because of the active targeting of folic acid and convertion of near-infrared light to thermal energy, which kills the tumor cells. The different investigations revealed that the dual-functional of hybrid Fe3O4-Au based nanocomposites could be employed as proficient nano-probes for targeted dual-mode imaging systems of numerous diseases, tumors, and cancers. FIG. 4 Concept of multimodal contrast agents based on Fe3O4. (Reproduced with permission from R. Thomas, I.-K. Park, Y.Y. Jeong, Magnetic iron oxide nanoparticles for multimodal imaging and therapy of cancer, Int. J. Mol. Sci. 14 (2013) 15910–15930.)

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TABLE 2 Properties of Fe3O4 MNPs based contrast agents used for dual-mode imaging systems Dual-mode imaging MRI/CT

MRI/PA

MRI/FO

Materials

Particle size (nm)

r2 relaxivity (mM21 s21)

Field (T)

Amphiphilic polymer@Au-Fe3O4 [125]

20

245

3

PPy/Fe3O4@Au [126]

65

119

0.5

Au_NC@Fe3O4 [127]

70

28

3

Fe3O4@SiO2@Au-PEG [128]

100

41

9.4

Au-Fe3O4 (heterostructured) [129]

14

136.5

1.5

Fe3O4@Au-mPEG [130]

16.5

146

0.5

Fe3O4/Au [131]

35

124

1.5

Fe3O4/Au/Ac-FA [132]

20

92.7

0.5

Fe3O4/Au/PEI [133]

50

264

1.5

Fe3O4/Au [134]

90

208

1.5

Fe3O4/PL/PEG/Au [135]

150

–

3

Fe3O4@CS@Au [136]

336

–

3

Au/Fe3O4@SiO2 [137]

20

394

3

Fe3O4/Au/SiO2/ICG [138]

120

390

1.5

PS@CS@Au/Fe3O4-FA [139]

369

326

0.55

PPy, polypyrrole; NC, nanocage; PEG, polyethylene glycol; mPEG, methoxy polyethylene glycol; Ac, acetic anhydride; FA, folic acid; PEI, polyethylenimine; PL, phospholipid; CS, chitosan; ICG, indocyanine green; PS, polystyrene.

3.4 Magnetic hyperthermia The term magnetic hyperthermia (MH) defines a controlled amount of heat generation (40–43°C) at malignant tumors to kill the cancerous cells. The difference of MH from the traditional hyperthermia is ability to apply overheat therapy at a targeted region instead of the whole living body. The limited amount of temperature at a targeted region prevents the destroying of healthy cells that are equally sensitive to heating. MNPs can produce heat in the presence of AC magnetic field (Hac). They may also be delivered through a magnetically driving force (a magnetic field gradient) or direct injection toward targeted regions in a biological environment. The required amount of temperature at tumorous tissues can be produced at sufficient strength and frequency of Hac during relevant period of time. In most applications, transferred heat from nanoparticles to cancerous tissues causes a temperature rise to 42°C during 30 minutes or more. The idea of using magnetic nanoparticles for MH applications was initially developed by Gilchrist and co-workers (1957), whose injected nontoxic and superparamagnetic monocrystalline Fe NPs (varying sizes between 20 and 100 nm) into lymphatic channels [140, 141]. In vitro and theory-based studies were conducted by many groups during a few decades [142–145]. In 1991, Kobayashi et al. [146] reported on the first clinical trial of implant-based MH on malignant glioma tumors that occur in brain and spinal cord. In 1993, Jordan and co-workers [147] created the term magnetic fluid hyperthermia (MFH) and developed a methodology to quantify the heating efficiency (through specific absorption rate, SAR) of MNPs. Jordan and coworkers also reported the direct injection of DEX-coated Fe3O4 nanoparticles with a core size of approximately 3 nm within tumors [148]. Hilger et al. [149] injected colloidal suspensions of coated magnetite NPs having a size range of 10–200 nm inside human carcinomas implanted in mice and developed the method as “magnetic thermal ablation (MTA).” In 2005, the investigation conducted by Hergt et al. was truly a milestone; the group introduced the magnetic NPs known as Magnetosomes produced by magnetotactic bacteria as MH agents [150]. Monodisperse spinel ferrites (MFe2O4, M ¼ Co, Fe, Ni, Mn etc) NPs with sizes in the range of 5 to 100 nm are most common materials for MH applications [151]. Among them maghemite (g-Fe2O3) and magnetite (Fe3O4) are referred as MIONs and most popular ones. MIONs include Fe2+ and Fe3+ ions in parallel but opposite directions resulting a high magnetic moment and spontaneous magnetization [152]. MIONs are preferred due to high chemical stability, low toxicity, easy

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surface modification, and functionalization with respect to other highly magnetically susceptible materials like Fe, Co, Ni, or metal alloys (e.g., FePt, FeCo) [153]. In particular, long-term stability provides the ability to repeat treatments without additional injection of particles, even several weeks later. CT scans show that almost 90% of injected iron NPs are detectable. Pure iron oxide NPs in ferromagnetic or superparamagnetic phase tend to form large clusters by agglomeration even in the absence of H. This case significantly changes to their magnetic properties and biocompatibility. Therefore, NPs are coated with protective shells like PEG (polyethylene glycol), dextran, starch, CMD (carboxymethyle dextran), graphene, aminosilanes, cafeic acid, etc. to prevent agglomeration [154, 155]. The mixed ferrite spinels, mixed Ba and Sr hexaferrites, alloys like FeNi3, Fe65Co35, NiCu, NiSi, NiPd, PdCo, Fe2Ga, etc. are also important candidate nanocomposites for MH applications [30, 156]. Optimum particle size distribution in magnetic fluid for MH applications is still an important debate. Sizes under 100 nm are suitable for penetration of NPs through the tissues. The optimum size for crystal magnetic cores is around 20 nm and resultant size becomes between 30 and 40 nm after coating process of NPs. However, 5 nm is more effective for tumor penetration [157]. Size also determines the desired superparamagnetic phase of NPs. The critical dimension for superparamagnetic phase such for MIONs is 15 nm [158, 159]. Larger size is preferred for higher heat generation and magnetic response force toward the targeted region under physiological flow conditions (e.g., in blood) [160]. The efficiency of magnetic targeting increases by increasing the size of NPs. Therefore, NPs should fulfill both obligations: small enough size to be in superparamagnetic phase and as large size as possible, so as to improve targeting property. There are conducted studies to estimate the optimum particle size, especially on MIONs, following different theoretical and experimental methods. For example, Resonsweig performed a theoretical study on monodisperse colloidal magnetic particles to specify the effect of size distribution on power dissipation [161]. Ma and co-workers [162] determined the temperature curves of Fe3O4 having size in the range 7.5–416 nm at 80 kHz of frequency and 32.5 k Am1. In the study, SAR magnitudes increased for the NPs that have sizes smaller than exchange length (lexc), which specifies the scale of perturbed area when a spin is unfavorably aligned. The bigger particles exhibit the opposite behavior. The adequate amount of magnetic NPs should be transported to the tumorous region before starting the heating process. Direct injection is the preferred manner where possible, to accumulate the needed amount of NPs at targeted region, not in healthy parts of the body. For instance, antibody or intravascular magnetic targeting have disadvantages since they require overall amounts of magnetic source material to be injected into the whole body. When magnetic NPs are exposed to the AC magnetic field, there are three main mechanisms to produce heat: (i) hysteresis losses in ferro or ferrimagnetic NPs; (ii) Neel and Brown relaxation losses in superparamagnetic NPs; and (iii) frictional losses in viscous suspensions. Heat generation by small NPs due to Eddy currents are small enough to neglect [163]. The ferromagnetic or ferrimagnetic NPs have single or multidomain structure according to their dimensions. Magnetic moments align in the same direction in each domain. When nanoparticles are exposed to a cycle of increasing magnitude of magnetic field in positive and negative directions, a hysteresis loop is recorded by magnetometers. When nanoparticles are exposed to an Hac, the area of the hysteresis loops is proportional to content of heat produced per cycle (PFM) [164]: þ PFM ¼ m0 f Hac dM (1) where m0 is magnetic permeability of free space; Þf is frequency of applied Hac; and HacdM is the loop integral over the hysteresis loop. In medical applications, the common ranges for frequencies and AC field strengths are 0.005–1.2 MHz and 0–5 kA m1, respectively [157]. The hysteresis losses are the highest type of losses for single domain NPs [165]. Superparamagnetic NPs are suspended in aqueous solutions like water and form a magnetic fluid. When this magnetic fluid is exposed to high AC frequencies, magnetic moments do not follow along the DC magnetization curves because of dynamic effects. That is why AC susceptibility ( wac ) is also known as the dynamic susceptibility. At higher frequency, M can lag behind H, an effect which is identified by the magnetometer circuitry. Therefore, the wac measurements yield an in00 phase (or real) part w0 and an out-of-phase (or imaginary) part w as follows:

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FIG. 5 Main steps for bioseparation process using MNPs.

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PART III Application for drug delivery

w0 ¼ wac sin Ø;w} ¼ w}cos Ø; and wac ¼

pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ffi w0 2 + w0 0 2

(2)

As we mentioned before, power losses (or heat generations) are governed by Neel and Brown relaxation mechanisms. These two mechanisms are described in [157] in detail. The heat generation equation for superparamagnetic NPs is given with the imaginary part of AC susceptibility as shown below: Pð f , H Þ ¼ m0 pH2 f w}ð f Þ

(3)

where P is also known as power loss. It is reported that surface modifications and the possible interparticle interactions also affect values of P [30]. The unit of heat absorption rate was mentioned before as SAR; however, an equal unit, Wg1, is more commonly used. Many spinel or hexaferrite core-shell NPs and shell of different anisotropies were detected to display much higher heat generation rates compared to single-phase NPs [166]. The shape of NPs also has significant influence on heat generation capacity. Song et al. reported that quasicube shaped magnetite NPs have much higher power generation rate with respect to ordinary spherical NPs [167]. Nemati et al. also reported very similar results for superior heating performance of deformed cubes (octopods) MIONs [168].

3.5 Magnetic bioseparation Owing to the rapid grow in the biotechnology field, fast, simple, and highly productive routes are urgently needed in order to extract biomolecules from suspended solutions. Separation, along with high purification of numerous biomolecules like antigens, nucleic acids, antibodies, DNAs, and proteins is a challenging objective. Bioseparation is a prominent phenomenon for the success of numerous biological routes. Thus, potential bioseparation methods are progressively gaining importance. Numerous bioseparation methods have been suggested as innovative alternatives to the classical separation techniques: ligand fishing, chromatography, centrifugation, and precipitation. Among the various bioseparation processes, the magnetic bioseparation method (for example, by the use of MNPs) is the most favorable to overcome the numerous challenges. It is versatile, robust and simple in operation. Magnetic bioseparation techniques for specific bio-molecules are beneficial in practically different fields of biosciences and nowadays considered to be one of the most likely applications of MNPs. The special interest in biomedical applications is owing to the significant properties of MNPs, for example, large surface to volume ratios, biocompatibility, and low toxicity [169]. Furthermore, the various steps of magnetic bioseparation could occur in a single test tube [170]. The interaction among targeted molecules and MNPs with presence of an applied magnetic field allows separation of targeted molecules [171]. This is the main benefit of magnetic bioseparation. In comparison to traditional processes, the fundamental working principles of magnetic bioseparation are relatively simple. The magnetic bioseparation technique involves the following main steps (Fig. 5) [172]: l

l

l

l

l

l l

Preparation of magnetic nanoparticles: The first stage for magnetic bioseparation is the preparation of magnetic nanoparticles that include particular phases to obtain specified MNPs based on the target molecules. Numerous chemical, physical, and microbial approaches have been developed to synthesize MNPs, such as hydrothermal synthesis, coprecipitation, sol-gel synthesis, sonochemical decomposition reactions, etc. [173] These methods show the advantage of the synthesis of MNPs with noticeable control over the composition, shapes, and sizes, etc. Modification of magnetic nanoparticles: After preparation, MNPs are modified to prevent their agglomeration and reactions in the aqueous phase that is required for biomedical applications. The modifications of the surface provide magnetic nanoparticles with multifunctional properties like bio-targeting, colloidal stability, and biocompatibility. Adsorption: The modified MNPs are perfectly mixed with the targeted molecules existing in the sample solution. The admixture is incubated for some minutes. At that moment, the modified MNPs will bind with targeted molecules. Separation: The magnetic field switching maintains the modified MNPs and targeted molecules, whereas the unwanted molecules are separated. Washing: The washing buffer allows entry into the column. The admixture passes across numerous switching cycles of on/off magnetic field. The modified MNPs and targeted molecules are suspended again during the off-cycle, whereas they are re-collected from the washing buffer during the on-cycle. Elution: By adding elution buffer after washing steps, the targeted molecules are recovered. Recycling: The MNPs are incubated with a specified solution after each separation in order to include new binding sites for the next separation.

Earlier investigations of magnetic nanoparticles showed numerous successful approaches to control and probe interactions among prepared magnetic nanoparticles and biological molecules [174]. In general, two routes are usual to isolate proteins:

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conjugation of magnetic nanoparticles with antibodies and conjugation of MNPs with a specific ligands molecule. Recently, nickel-nitrilotriacetic (Ni-NTA) functionalized magnetic nanoparticles were used to separate His-tag proteins from cell lysate [175]. Mercaptoalkanoic acid was employed also to decorate magnetic nanoparticles of FePt with the Ni-NTA composite, which leads to isolate the His-tag protein from E. coli lysate with high selectivity and capacity [176]. On other hand, it was found that the targeted proteins cover the surface of MNPs quickly to reduce largely abandoned surface area that could result in a nonspecific targeting. Accordingly, numerous studies were performed to resolve this problem. For example, the NTA and dopamine are linked on the surface of iron oxide to form a strong bond of dopamine-NTA and, due to the reaction with NiCl2, a MNPs/NTA-dopamine-Ni2+ is formed [177]. This will facilitate final separation of His-tag proteins with the highest selectivity and stability. In another study, Zheng and coworkers [178] produced phenylboronic acid-Fe3O4@polydopamine (Fe3O4@PBA-PDA) to determine their binding capacity and selectivity by means of conventional glycol-proteins and nonglycol-proteins. They illustrated that adsorption capacity of standard glycol-proteins is around 3 to 8 times greater than for nonglyco-proteins, myoglobin, bovine hemoglobin, ribonuclease A, and lysozyme. Phospholipid-coated colloidal magnetic nanoparticles have been prepared by Bucak and coworkers in order to retrieve proteins from the whole mixtures with high adsorptive capacity [179]. Other types of magnetic bioseparation involve antibody attached MNPs that are particularly employed for immunoassay. For instance, antibody-protein A-bacterial attached to MNPs are found by Matsunaga and coworkers by the formation of certified automated sandwich immunoassay in order to precisely identify human insulin [180]. Furthermore, hemoglobin-functionalized magnetic nanoparticles are prepared for the aim to enhance serine peptidase inhibitor, vitamin D-binding protein, and human serum amyloid P part [181]. In addition, MNPs of Fe3O4@Au are used by C. Wang et al. for bacterial separation [182]. MNPs are used also for DNA separation, for example, for protein cases. The connection of DNA to magnetic nanoparticles depends on the surface properties of both the MNPs and DNA molecule. As an example, Neng-Biao and coauthors [183] synthesized SiO2-coated MNPs having positive surface charge at pH ¼ 7 in order to isolate the bacterial plasmid DNA from bacterial culture. They revealed that the magnetic nanoparticles respond effectively by the application of H to provide extreme separation and elevated purity of plasmid DNA. Moreover, Tang and coworkers [184] successfully provided a quick detection methodology for Pseudomonas aeruginosa on the basis of magnetic bioseparation. In addition, DNA aptamers are utilized to create a chemiluminescence aptasensor based on immunoassay and magnetic bioseparation system for better detection of hepatitis B [185]. Anti-CD3+ monoclonal antibody bio-conjugated to Fe3O4@Au core/shell MNPs are prepared for cell separation [186]. This process showed high efficiency (up to 98.5%) of cell-capture. Other kinds of magnetic bioseparation involve MNPs of Fe3O4@polymer for virus separation [187].

4 Conclusion The physical and magnetic properties of MNPs based nanocontainers, along with their greatest significant bioapplications, have been presented. In recent years, researcher has focused on the benefits of magnetic nanomaterials based nanocontainers to enhance the efficiency of their bio-applications. The researchers around the world have demonstrated some in vitro and preclinical studies of MNPs based nanocontainers. Many objections encounter the efficiency of the theranostics nanoparticles for various applications from in vitro to clinical studies. In particular, the particles’ size and biosafety of nanoparticles are the primary concerns in clinical practice. The optimal size of nanoparticles accelerates their accumulation in tumor sites by EPR effects. The perfect drug delivery systems should keep their loaded drugs when they are moving in the circulating systems. They anticipate releasing the loaded drugs only after their accumulation in the targeted tissues by the effect of internal triggers including enzymes and pH, or of external triggers including magnetic field, temperature, light, and ultrasound. Generally, the biocompatibility of magnetic nanomaterials based nanocontainers is reached by fine-tuning their shapes, sizes, and bio-physical characteristics. Numerous advantages were received from the magnetic nanomaterials based nanocontainers for targeted drug delivery like improving the stability of drugs, minimizing side effects, proficient accumulation of drugs, efficient pharmaceutical activity, and lowering dosage. Magnetic nanomaterials based nanocontainers have been investigated for an extensive range of healthcare and biomedical applications because of their higher bio-degradability, bio-compatibility, and nontoxicity, and most significantly, it is easy to maneuver them from a distance by employing an external magnetic field. The magnetic nanomaterials based nanocontainers have been explored and considered as efficient candidates for a diversity of biomedical applications, including MRI, CT, PET, SPECT, PA, FO imaging, magnetic bioseparation, magnetic hyperthermia, magnetofection, gene therapy, etc. A number of multimodality imaging techniques has been formulated by combining the advantages from the one or more imaging techniques. This might reduce the undesirable limitations and provide wide-ranging biological

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information and imaging in tumor angiogenesis. By using the magnetofection technology, the transfected intra-cellular MNPs based nanocontainers could be identified through the histological process by using the labeled cells, which show contrast in MRI. It is expected that the conjugation of MNPs based nanocontainers with proper agents and desired characteristics will provide significant enhancements in the early diagnosis and treatment of cancers, as well as promising future applications.

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Further reading [188] J. Kudr, Y. Haddad, L. Richtera, Z. Heger, M. Cernak, et al., Magnetic Nanoparticles: From Design and Synthesis to Real World Applications, Nanomaterials 7 (2017) 243.