Burgeoning tool of biomedical applications - Superparamagnetic nanoparticles

Accepted Manuscript Burgeoning tool of biomedical applications - Superparamagnetic nanoparticles Lavanya Khanna, N.K. Verma, S.K. Tripathi PII:

S0925-8388(18)31385-9

DOI:

10.1016/j.jallcom.2018.04.093

Reference:

JALCOM 45731

To appear in:

Journal of Alloys and Compounds

Received Date: 26 December 2017 Revised Date:

19 March 2018

Accepted Date: 8 April 2018

Please cite this article as: L. Khanna, N.K. Verma, S.K. Tripathi, Burgeoning tool of biomedical applications - Superparamagnetic nanoparticles, Journal of Alloys and Compounds (2018), doi: 10.1016/ j.jallcom.2018.04.093. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Burgeoning Tool of biomedical applications - Superparamagnetic nanoparticles a

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Lavanya Khanna*, N. K. Verma#, S. K. Tripathi* Department of Physics, Panjab University, Chandigarh, 160014 # Visiting Professor, Thapar University, Patiala, 147004

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Abstract This review offers a hierarchical preview of the emergence of magnetic nanoparticles (MNPs) and their composites in the biomedical field providing an insight into their essential features. The need for coating their surfaces with stabilizers such as polyethylene glycol (PEG)

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and silica has also been explained. This is required for reducing their agglomeration and appropriate functionalization for final application. A magnetic material for such an application is required to be nanosized, superparamagnetic and biocompatible; all these requisites have

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been well discussed. Various research conducted on magnetic materials as maghemite, magnetite and ferrite based nanoparticles of Ni, Co, Mn, Zn, Ca and K have been described in detail, along with their composites such as PEG and silica. Folic acid conjugation is done on the coated MNPs as folate receptors are over-expressed on the tumor cells; this makes their targeting efficiency better and precise. In addition, various challenges associated with magnetic nanoparticles/nanocomposites such as nanoparticle-biomolecule interface, drug loading, drug

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release properties, blood barrier etc., which inhibit their desired role, have also been described.

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Keywords - Magnetic nanoparticles;; PEG; Silica; Superparamagnetic; Folic acid; Cytotoxicity

Contents 1. Introduction a

Corresponding author – Dr. Lavanya Khanna Department of Physics, Panjab University, Chandigarh Email id – [email protected]

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2. Essential features 3. Need of surface coatings on magnetic nanoparticles

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3.1 Polyethylene Glycol (PEG) 3.2 Silica 4. Superparamagnetic behavior

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5. Iron oxide nanoparticles/nanocomposites for biomedical applications 5.1 Superparamagnetic iron oxide based nanomaterials

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5.2 Silica coated Iron oxide nanoparticles 5.3 PEG coated Iron oxide nanoparticles

6. Ferrite based nanoparticles/nanocomposites for biomedical applications 6.1 Cobalt Ferrite

6.3 Nickel Ferrite

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6.4 Zinc Ferrite

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6.2 Manganese Ferrite

6.5 Calcium Ferrite and Potassium Ferrite

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7. Folic Acid

7.1 Folic acid conjugated MNPs

8. Future challenges 9. Conclusions

Abbreviations used MNPs - Magnetic Nanoparticles 2

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NPs - Nanoparticles PEG – Polyethylene Glycol MRI – Magnetic Resonance Imaging RES – Reticuloendothelial System

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MTT - 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SPION – Superparamagnetic Iron Oxide Nanoparticles TEM – Transmission Electron Microscopy FT-IR – Fourier Transform Infrared Spectroscopy TEOS – Tetraethyl Orthosilicate

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ROS - Reactive Oxygen Species CCK - Cell Counting Kit PCR - Polymerase Chain Reaction DNA - Deoxyribonucleic Acid

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PVP - Polyvinylpyrrolidone

PION - Poly (4-vinyl benzyl phosphonate) iron oxide nanoparticles DOX – Doxorubicin ATPS - 3-aminopropyl triethoxysilane

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APTES - 3-aminopropyltriethoxysilane RITC - Rhodamine isothiocyanate AC – Alternating Current

PCL - Poly (ɛ-caprolactone) FA – Folic Acid

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mRNA – Messenger Ribonucleic Acid XRD – X-ray Diffraction

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PAA – Polyacrylic Acid

TC – Critical Temperature

FITC – Florescein isothiocyanate shRNA – Short Hairpin Ribonucleic acid PEI – Polyethyleneimine

FI – Fluorescein isothiocyanate AC – Acetyl CS – Chitosan FR – Folate Receptor 3

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FAR+ – Folic acid receptor positive cancer cells 1. Introduction

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It all began with the famous talk of Dr. Richard Fenyman, at Caltech, in December 1959, that “There is plenty of room at the bottom”. This talk acted as a “seed of thought” that planted the tremendous and wide-spread potential of nanomaterials in the minds of researchers worldwide. One of the most benefitted areas that have witnessed a revolutionary change due to its amalgamation with nanotechnology is biomedicine. The evolution of medicinal science, diagnostics and therapeutic treatments has seen a tremendous upsurge from the medieval medicines to the latest contemporary techniques, which involve nanotechnology. In recent times, magnetic nanoparticles have been scrutinized as a potential tool for many biomedical applications. Magnetic Nanoparticles (MNPs) as the name suggests, represent the class of materials whose dimensions fall in the nano-scale and being inherently magnetic can be controlled with an external magnetic field [1]. This helps in tracking their movement inside the body and gives clinicians flexibility as well as control while carrying out any procedure. The magnetic properties are extremely sensitive to size, composition, and local atomic environment [2]. This review summarizes different magnetic nanomaterials that have been studied for various biomedical applications. Basically, there are two types of approaches by which MNPs bind to the desired targeted tissues – passive and active. Mechanism of passive targeting includes enhanced permeation and retention (EPR). It works on the principle that in the rush to grow speedily, tumor cells produce new vessels with poor organization and leaky surface which enables the penetration of NPs into the tumor tissue. Pertaining to ineffective lymphatic drainage, NPs accumulate selectively with reduced clearance. However, passive targeting is limited to certain tumors and is challenging to effectively manage as it is dependent on many factors such as capillary conditions, blood barrier, and rate of drainage. In active targeting, surface of NPs is modified with targeting ligands which work in a lock and key manner, i.e. receptors on the ligand bind to specific cells only thereby enhancing the targeting efficiency. Folic acid conjugation is an example of such targeting. Binding capability of MNPs is dependent on density and molecular orientation of the targeting ligand, size and shape of MNPs. For targeted drug delivery applications, the basic idea is to encapsulate or attach any therapeutic drug to magnetic nanoparticles/nanocomposite. Using external magnetic field, this nanocomposite can be directed to the desired site, where by some triggering action such as pH change, the drug gets released. Apart from drug delivery applications, magnetic resonance imaging (MRI) is another area in which MNPs have been reported to be very promising. MR imaging is a non-invasive technique for obtaining anatomical, molecular, metabolic and physiological analysis with high spatial as well as temporal resolution. It is based on the principle that on applying magnetic field, nuclear magnetization of hydrogen atoms in the body gets aligned and, on its removal, nuclei relax back to its original state. The following parameters 4

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are measured from the obtained MR image - longitudinal (T1) and transverse (T2) relaxation, (T2*) relaxation, r1 (1/T1) relaxivity, r2 (1/T2) relaxivity, r2*(1/T2*) relaxivity. Image contrast is formed on variation in the rate of relaxation that enables to distinguish between tissues and malignancies. In 1970s, Widder, Senyei and colleagues introduced magnetic micro and nanoparticles for biomedical applications [3]. Iron oxide based materials are safe and currently been used. Apart from these, superparamagnetic ferrites have also been studied which have been discussed in the later section. 2. Essential features

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Following are the essential features of MNPs, which has led to their extensive use in biomedical field [4-8].

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(i) Size-matching - In human body, diseases occur at cellular level, so something to be treated at that level, also requires same size tools. Here, it can be rightly mentioned that “To treat hurt leg of an ant, the tools used should be of the same size [5]”. Likewise, for treatment at cellular level, the technology used should fall in the same scale; this is where nanotechnology is used. The controllable nanometric sizes of nanoparticles are analogous to biological entities such as virus, cell, gene, protein [6-8].The size of nanoparticles matches well with the cellular level of the human body. This makes nanoparticles to actually get close to a biological entity. The first strategic objective is to contour the properties of the MNPs for optimal magnetic response within the biological size constraints. Parameters, such as size distribution, surface charge, shape, nature of coating and magnetic properties, are significantly crucial for intravenous administration of MNPs during clinical procedures [8, 9]. The overall or hydrodynamic size of the MNPs is a major and primary parameter for being an effective drug carrier, as the magnetic properties, circulation profile in the blood vessel and its clearance depends strongly on the size [9]. It has been reported that among the various shapes and sizes, smaller sized spherical NPs exhibit higher diffusion rates. This leads to increase in the nanoparticles’ concentration in the centre of a blood vessel. This results in reduced interactions with endothelial cells and hence prolongs nanoparticles’ time of blood circulation. Oblique-shaped NPs also exhibit enhanced cell binding affinity on attaching targeting molecules [9]. Choice of size also depends on the targeted organ as NPs have to overcome many anatomical restrictions [10]. For instance, in case of brain, endothelial cells and supporting astrocyte cells limit pinocytosis due to presence of tight junctions between cells at the blood-brain interface. This result in a structural as well as metabolic barrier called blood brain barrier (BBB), where NPs of sufficiently small sizes and appropriate physiochemical properties can only pass through [9, 11]. Larger particles with diameters > 200 nm, after mechanical filtration, are separated by the spleen. These are ultimately eliminated by phagocyte cells. Also, the chances of larger particles clogging the small capillaries are significant [9, 12]. Alternatively, smaller particles, with diameters < 5 nm, get quickly eradicated by extravasations and excretion through kidney. Therefore, particles ranging from 5100 nm are best suited for intravenous injection since they display the maximum blood 5

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circulation times. 5-100 nm sized nanoparticles are small enough to escape Reticuloendothelial System (RES) (major defense system of the body) and enter the smallest capillary, ruling out the possibility of clogging the capillaries. The other significant advantages of using nanoparticles in this size range are (i) easy functionalization due to high surface/volume ratio, (ii) high stability and (iii) enhanced tissular distribution and diffusion [12]. NPs, in the size range of 25-50 nm, were found to be appropriate for multivalent binding as well as endocytosis [9].

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(ii) Non-toxicity and Bio-degradability - This requirement is primarily and obviously required since it has to be introduced in the human body, where safety is of utmost importance. MNPs considered for biomedical applications are generally Iron based compounds and these are inherently non-toxic in nature. Thus, this feature makes MNPs a safe nominee for in vivo applications. Before administering the MNPs complex into the patient, non-toxicity of MNPs as a whole and its individual components should be well-ensured. Bio-degradability is closely related to non-toxicity. As the MNPs complex is to be used against a malignant cell, it is of utmost importance that cell death should occur only because of the attached drug and not due to the MNP complex. The mechanism by which MNPs would interact with cells and how the individual components would affect the body during biodegradation and liver response are crucial aspects. Therefore, it needs to be ascertained beforehand that MNPs complex is biocompatible; this is highly dependent on the concentration/dosage, generally at higher concentration of MNPs complex cell death occurs, not due to any toxicity but shortage of the cell media. When something so complex is introduced inside the body, there is a possibility of its components to break and leach out due to incomplete removal. In that case it is highly desired that the components be biodegradable, so that there is no harmful effect on the body. MNPs serve both these purposes, being non-toxic they exhibit concentration-dependent biocompatibility and on metabolism iron ions are deposited in the body as hemoglobin, using normal biochemical pathways for Fe metabolism, making them safe for in vivo applications [13, 14]. Through pinocytosis their decomposition products can be taken up by any cell [14, 15].

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Wang et al. [16] have reported on iron oxide as the effective building material of the cardiac framework for improving post-operative recovery in patients with myocardial infract ion. This could be phagocytized by macrophages and consequently metabolized into soluble iron ions. They have reported that iron species can be stored in the form of ferritin or hemosiderin. It could alternatively be released into the circulatory system and transported back to the marrow. Owing to the critical role of iron, in sustaining the viability of red blood cells, intravenous administration of iron-containing materials could be successfully applied for treating various anemia-related diseases. Usman et al. [17] studied the metabolism of iron from iron oxide NPs using Fe-labeled ferumoxytol. Iron content was sustained where other organic components such as carbohydrate coating got driven out [17, 18]. (iii) Injectability – The aqueous and colloidal suspensions of MNPs complex can be prepared for injecting it in the human body intravenously [13]. Vlad et al. [19] reported that on adding 6

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iron oxide NPs into powdered alpha-tricalcium phosphate based cement, the initial injectability as well as maximum compressive strength of the cement significantly improved without affecting their physicochemical properties and overall biocompatibility. Campbell et al. [20] have reported on injectable, biodegradable, high strength, inert and externally triggerable superparamagnet (SPION) composite hydrogel for tissue engineering and drug delivery applications. Rufenacht et al. [21] studied injectable superparamagnetic formulation containing a liquid carrier and heat-generating SPION of ~20 nm for hyperthermia applications.

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(iv) Accrue at the targeted site – MNPs, being magnetic with high surface energy, have the tendency to agglomerate at the site where magnetic field is applied. So, by using external field the MNPs complex injected into the human body can be brought/ retained at the target site for the desired controlled action such as drug release [22].

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(v) Possibility of surface modifications – The surface of MNPs can be modified/functionalized with surface coatings (e.g. biodegradable inorganic and organic polymers, silica etc.). After surface modifications, these can be further conjugated/ attached to any biological entity or therapeutic drug, according to the desired application. Thus, it provides more specificity to the MNPs to target the desired site of medication within the body. In other words, this MNPs complex can be labeled and targeted for a specific application. Nature of coating materials, thickness, procedures of attachment and hydrophobic behaviour have a combined effect on the magnetic properties of MNPs. It has been reported that thick coatings result in decreased r2 relaxivities while coatings with less hydrophobicity resulted in higher r2 relaxivity values. This has been described in detail in section 3.

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(vi) Magnetically driven – Being magnetic, these can be guided magnetically to the target site, where they can deliver a drug or can resonantly respond to a time varying magnetic field. In hyperthermia, chemotherapy and radiotherapy an adequate degree of heat is required for destroying the tumor site effectively [7].This property gives them the power to be driven along when injected in the blood stream. It’s similar to a situation where a stone has to be controlled while moving in a water stream. So, when MNPs complex is injected into blood stream, high gradient magnetic external field focused over the target site allows it to be captured or to release the drug. This means MNPs complex can be controlled from a distance for controlled drug release. For the sites closer to the body’s surface, effect of external magnetic field can be efficiently realized but on going deeper inside the body, this falls off rapidly. Therefore, this factor needs to be taken well into consideration while planning the overall design of the MNPs complex for the desired application. The other requirement is MNPs complex must exhibit superparamagnetic behaviour which has been described in detail in section 4. 3. Need of surface coatings on magnetic nanoparticles

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The actual fate of any MNPs complex is decided when it is intravenously introduced into the body. Blood transports them to the desired region of interest. During transportation, it is highly required that the particles should not aggregate to avoid jamming their spread or distribution. Therefore, size, charge and surface chemistry of MNPs complex is very crucial as this decides its blood circulation time, internalization (this happens by endocytosis, in which cell transports a molecule inside it by engulfing them in an energy process) and bioavailability [23]. Owing to high surface energy as well as magnetic interactions, they tend to accumulate. On agglomeration, they adsorb plasma proteins due to hydrophobic interactions, by a process named opsonization. The opsonized MNPs are released out of the body by phagocyte cells and macrophages of RES [14]. So instead of working efficiently in the body, these get removed as a foreign object. This encourages their rapid removal from blood circulation. However, particles with hydrophilic surface deter opsonization. So, it is desirable that MNPs must be coated with a hydrophilic polymer in order to inhibit the opsonization process. Also, it has been reported that hydrophobic surface is more cytotoxic than hydrophilic group [24]. In any case, MNPs particle size enlargement due to aggregation leads to capillary blocking. Sometimes, surface inertness of MNPs limits possibility of biological conjugation [25, 26]. All these factors individually or jointly, become the cause for inhibition of specific property or application for which it was employed. Additionally, nature of coating and its geometric configuration determines the final size, bio-kinetics as well as distribution of MNPs inside the body. Another problem in drug releasing system is the premature leaking of the drug. A perfect coating is highly required for attaining “zero premature release” of drug. When some of the pores are not capped, leaking through the matrix might occur [27]. Various other physiological conditions as pH, chemical environment, also cause the structurally unstable soft materials loaded with drug molecule to start leaking out of the biodegradable carrier, thus leading to undesirable and uncontrollable drug release [27].

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All the above-mentioned limitations can be reduced by functionalizing/coating the surface of MNPs with appropriate functional groups or stabilizers [26]. It should be taken well into care that the functionalization of MNPs not only must facilitate their selective binding to biological entities but should also be non-toxic, hydrophilic, biocompatible and stable in aqueous suspensions [26]. The surface coatings (stabilizers) on the MNPs are required to (i) provide stabilization of MNPs against aggregation [28], (ii) increase biocompatibility [3] (iii) protect against corrosion [3] (iv) escape RES [14] (v) easily conjugate with biological entities [29]. For MNPs functionalization mainly Covalent Bonding, Electrostatic interaction, Adsorption and Hydrophobic/hydrophilic interactions are used [30]. The choice of functionalization procedure should be so chosen that the desired functionality such as targeting, imaging, diagnostic and therapeutic is not compromised [9]. Recently, there has been an escalating interest in functionalizing/coating the surface of MNPs with inorganic/organic materials. Many surface coatings have been employed comprising 8

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of natural polymers as carbohydrates and proteins, synthetic polymer coatings as polyethylene glycol, chitosan, dextran, polyethyleneimine (PEI), polyvinyl alcohol (PVA), copolymers, etc. and inorganic coatings as silica, gold [3, 29, 31]. The most widely employed stabilizers among organic polymers and inorganic material is polyethylene glycol (PEG) [9, 22, 32-41] and silica [12, 42-53], respectively. In this review, we will focus on these two types of coatings. 3.1 Polyethylene glycol (PEG)

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PEGylation refers to attachment of PEG molecules to a surface by either of the following - surface adsorption, covalent bonding and entrapment [33]. PEG coated MNPs are named as stealth nanoparticles as they escape RES system. So, these are not suitable for imaging and RES related applications [9]. Basically, it is a polymer comprising of ethylene oxide and water (H(OCH2CH2)n-OH, n ~ 4-180 ). It is water soluble, inert, non-toxic, uncharged hydrophilic surface, non-immunogenic, high surface mobility, non-antigenic and protein resistant polymer [9, 33-37]. PEGylation improves stealth properties of MNPs unmatched to other stabilizers [38]. It helps in shielding the magnetic interactions of MNPs to avoid agglomeration, protects the magnetic core from biological environment as well as corroding and enhances bio-conjugation as well as biocompatibility [9, 35]. More the PEG content, slower is the removal from the body, thus resulting in improved longetivity as well as bio-distribution of the drug carrier [54]. Following are the summarized benefits of PEGylation [33]:

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1) Better shielding of surface charge with increased hydrophilicity, resulting in diminished magnetic interaction and recognition by opsonin proteins, respectively. 2) Reduced interfacial free tension in aqueous media which further reduces protein interaction. 3) In the presence of proteins, flexible PEG chains compress and generate repulsive forces between them.

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4) The specific bonding with proteins is minimized due to high mobility of flexible PEG chains as it minimizes their interaction time.

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5) PEG chains have high affinity for dysopsonin proteins and repel opsonin proteins due to which their phagocytic uptake gets reduced and RES is avoided, owing to the minimum surface density of PEG. Also, electrostatically bonded PEG displays excellent protein rejection propensity [52]. Long term storage of PEG functionality in highly ionic suspensions and during blood circulation, is ensured by the formation of covalent bonds. 3.2 Silica Among inorganic materials, silica is the most preferred stabilizer. Silica is known to be biocompatible and chemically inert, so it does not affect the redox reaction occurring at the surface of the core (ferrite) [55-57]. It eliminates protein adsorption and also facilitates the 9

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functioning of the nanocomposite in biological environment [55]. It shields the magnetic dipolar interaction between magnetic nanoparticles, thereby reducing agglomeration and favoring dispersion in liquids. Also, it guards MNPs from leaching in an acidic atmosphere. Presence of silanol groups on the silica layer allows various functional groups for bio-conjugation to be activated on the coated surface [56]. Contrasting to polymers, silica evades microbial attack. It does not swell or change porosity with change in pH values [55]. It protects NPs from acidic erosion rendering it stable in suspensions which leads to diminished cytotoxicity [58].

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Silica coated MNPs are known to be structurally stable with defined structures, thus do not exhibit any “premature release” problem onto the targeted site [27]. Also, due to osteogenic properties (concerned with bone growth) of silica composites, it has been used in artificial implants [27]. It has been reported that silica stores and gradually releases drugs. This is favorable for controlled drug release. It is resistant to pH, heat, mechanical stress and degradation [27]. Silica particles have large affinity for head groups of various phospholipids [27, 39, 41]. This results in high affinity to be adsorbed on the cell surface eventually leading to endocytosis. Silica is “generally considered as safe” (GRAS) by the US Food and Drug Administration (FDA) [59].

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Figure 1 Magnetic nanocomposite with different bio-conjugations depending on the specific application [60] Magnetic nanocomposite comprises of a magnetic core and a protective surface coating, which can be further modified with drug molecule, antibodies, florescent entities etc., depending on the specific application, as shown in fig. 1 (based on Fang et al., 2009 [60]). In addition to all the above mentioned properties, it is very essential that magnetic nanocomposite exhibits the superparamagnetic behavior as well, for its effective functioning in biomedical applications. 4. Superparamagnetic behavior

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Superparamagnetism arises from a finite-size effect [61]. This appears in ferromagnetic or ferrimagnetic nanoparticles. In ferromagnetic materials, a quantum mechanical interaction makes the atomic magnetic moments to point parallel in a long-range order. This makes the dipoles to line up in parallel orientation. Pertaining to energetic reasons, the size range of this parallel orientation is limited. These ranges are known as magnetic domains; usually they are smaller than the grain size. Magnetic domains, within a grain are separated by Bloch walls and the direction of magnetization is changed by moving the Bloch walls. Therefore, the existence of magnetic domains and Bloch walls make it easier to change the direction of magnetization. In general, a ferromagnetic material remains magnetized to some extent on removal of the magnetic field; this effect is called remanence and magnetic field required to compensate remanence is called coercivity. The tendency of a material to memorize its magnetic history is called hysteresis.

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Large magnetic nanoparticles are subdivided by Bloch walls into magnetic domains, as their sizes are energetically controlled, so remanence and coercivity are largely independent of the particle size. On reducing particle size, no long range order exists in the material. For size smaller than the critical diameter, Dc, particles consist of a single magnetic domain, as shown in fig. 2 (based on Mody et al., 2013 [62], [63]). As the Bloch walls ease the change of magnetization, coercivity and remanence increases drastically; this is the particle size range for magnetic data storage. On further size-reduction, below superparamagnetic diameter, Dsp, coercivity and remanence rapidly approach to zero i.e. magnetization curve exhibits no hysteresis (Fig. 2(a)).

Figure 2 (a) Coercivity/Remanence as a function of nanoparticles diameter (b) Magnetization flips between parallel and anti-parallel orientations when magnetic anisotropy energy is comparable to thermal energy [62, 63] 11

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In case of single isolated MNPs, the condition leading to superparamagnetism is of typical thermal instability, given as kT ≥ Kv

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where K, v, Kv and kT represent constant of magnetic anisotropy, volume of particle, energy of magnetic anisotropy and thermal energy (k - Boltzmann constant and T - temperature), respectively. The explanation for this phenomenon is found in the magnetic anisotropy, which is an inherent property of any magnetic material and is independent of grain size. The energy required for magnetizing a ferromagnetic or ferrimagnetic crystal depends on the magnetic field direction relative to the orientation of the crystal, thus leading to “easy” and “hard” directions. These are the directions where the application of an external field easily magnetizes - “easy” direction or to a lower magnetization - “hard” direction. In superparamagnetic materials, the vector of magnetization fluctuates between the easy magnetic directions, overcoming the hard directions. Corresponding to easy axis, the magnetic moment usually has only two stable orientations, separated by an energy barrier of height ∆E = Kv. If Kv >> kT, then moment cannot switch spontaneously, as in case of a permanent magnet. However, if the energy barrier is of the order of thermal energy, Kv ~ kT or less, then spontaneous switching can occur on the timescale of the experiment, pertaining to superparamagnetism (Fig. 2(b)). The coupling between electron spins and angular momentum of the electron orbital (L-S coupling) is responsible for magnetocrystalline anisotropy. Superparamagnetic behavior is directly related to magneto-crystalline anisotropy. Considering the above, it can also be related to L-S coupling as well [64, 65]. Following formula governs it, EA = Kv sin2θ, where, EA, K, v and θ represent energy barrier to block flipping of magnetic moments, magneto-crystalline anisotropy constant, volume of NPs and angle between magnetization direction and easy axis, respectively [64-66].

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The typical time between thermally excited fluctuations, with frequency f refers to Néel relaxation time τ = (2πf)-1. When external magnetic field is absent, Néel relaxation time is much shorter that the time for measurement of magnetization of nanoparticles. At this point, average magnetization seems to be zero; pertaining to superparamagnetic state. In this state, externally applied magnetic field magnetizes the nanoparticles similar to a paramagnet but with a higher magnetic susceptibility and net magnetization. Hysteresis curve obtained is a reversible S-shaped increasing function. Generally, above Curie temperature, a ferromagnetic/ferrimagnetic material changes to a paramagnetic state. In case of superparamagnetic material, this transition takes place below Curie temperature. Absence of remanent magnetization in superparamagnetic NPs is because of the very small energy difference between two stable configurations, thus making magnetization to hop between these two states. The very less energy difference leads to cancellation of total magnetization by thermal energy. Thermal variations are strong enough to spontaneously demagnetize a formerly saturated body. Superparamagnetism is shown by less value of magnetic 12

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squareness (MR/MS ratio, where MR, MS are the remanent magnetization, saturation magnetization, respectively) [63]. In case of non-interacting superparamagnetic particles, it is 0.5 [67]. For interacting superparamagnetic particles, magnetic squareness (MR/MS ratio) and coercivity (HC) values reduce due to dipolar interactions [68]. Magnetic squareness value corresponding to interacting superparamagnetism is 0.1, i.e. more than 90% of magnetism is lost on removal of external magnetic field [69].

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The benefit of using superparamagnetic nanoparticles in biomedical applications is due to the following reason. These nanoparticles become magnetic as soon as magnetic field is applied and demagnetize when external field is removed. This behavior helps in controlling their action, activeness and triggering response by just switching magnetic field on and off. This is ideal for biomedical applications. Typically, a localized magnetic field gradient is utilized to attract and retain NPs to the desired target site for the planned time [14, 69].

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5. Iron oxide nanoparticles/nanocomposites in biomedical applications 5.1 Superparamagnetic iron oxide based nanomaterials

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Research on iron oxide nanoparticles as magnetic core for biomedical applications has rapidly accelerated in the past years. Kommareddi et al. [70] synthesized SPIONs using phenolic poly (p-ethylphenol) polymer particles. Similar iron oxide-polymer nanocomposite was prepared by Burke et al. [71] by thermal decomposition method. A novel water-soluble doxorubicin loaded oleic acid (OA) - pluronic coated iron oxide magnetic nanoparticles was developed by Jain et al. [72]. The cytotoxicity of the unconjugated nanocomposite and drug conjugated nanocomposite showed no toxicity (for concentration range of 0.1-100µg/ml) and dose dependent cytotoxic effects in cancer cell lines, respectively. Yang et al. [73] synthesized magnetic poly (ethyl-2-cynoacrylate) (PECA) nanoparticles conjugated with anti-cancer drug. Superparamagnetic behavior of magnetite and PECA coated MNPs with magnetic saturation values 45 and 6.5 emu/g was obtained by Vibrating Sample Magnetometer (VSM). MTT assay results of Poly (D, L-lactic-co-glycolic acid) (PLGA)-SPION showed minimal cytotoxicity as synthesized by Lee et al. [74], with superparamagnetic behavior and saturation magnetization of 40.2 emu/g and 8.7 emu/g, respectively, for free SPIONs and PLGA- SPIONs. Prashant et al. [75] prepared superparamagnetic iron oxide-loaded poly (lactic acid)-D-α-Tocopherol 1000 succinate (TPGS) forming PLGA-TPGS-SPIONs. Cytotoxicity tests revealed that PLGA-TPGSSPIONs had less toxicity on cancer cells at 10mmol [Fe]/L, also the saturation magnetization decreased from 84.5emu/g to 79.23emu/g (at 15% emulsifier concentration). Rahimi et al. [76] synthesized drug conjugated poly (N-isopropylacrylamide-acrylamide-allylamine) coated magnetic nanoparticles and studied their cytotoxicity tests. NPs were found to be more than 90% cell viable and as expected the drug loaded nanocomposites were more cytotoxic, less than 20% cells could only survive them. In addition to polymers, silica as well as PEG coatings have also been comprehensively employed; these have been discussed ahead. 13

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5.2 Silica coated Iron oxide nanoparticles

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Silica coated magnetic nanoparticles have been comprehensively explored for biomedical applications. Mainly the researchers investigate and compare the properties and cytotoxicity of the coated and the uncoated samples for understanding the role of coating. Campelj et al. [77] functionalized maghemite nanoparticles of average size 13.7+2.9 nm and high magnetization of 68emu/g, with a 2 nm thin homogeneous coating of 3-aminopropyl silane. Almeida et al. [78] prepared maghemite nanoparticles of 5-10 nm and functionalized them with a thin silica layer of 2-3 nm, as shown by TEM. MNPs coated with β-cyclodextrin (CD) and pluronic (F127) were studied by FT-IR spectra along with haemocompatibility by Yallapu et al. [79]. Sun et al. [25] prepared magnetite (Fe3O4) nanoparticles by partial reduction co-precipitation method using citric acid. They studied structural, magnetic and morphological properties by adding different concentrations of silica using tetra ethyl orthosilicate (TEOS) precursor. On increasing thickness of the silica shell, less aggregated formation took place, but retained its superparamagnetism even after silica coating (50 µl TEOS precursor). This can be explained by core-shell model which is described in section 6.5. Investigations on effect of reaction parameters such as type of alcohol, alcohol to water (volume ratio), amount of catalyst and precursor on synthesis of silicacoated magnetite particles were done by Deng et al. [43]. The prepared NPs possessed superparamagnetism. Similarly, He et al. [42] synthesized cubic spinel superparamagnetic Fe3O4 nano-crystals of 6–7 nm diameters by chemical co-precipitation method along with 2 nm coated silica layer. The synthesized nano-crystals exhibited superparamagnetism, and the blocking temperature TB shifted from 131K to 92K after silica coating due to reduced particle–particle magnetic dipolar interaction. Lee et al. [44] used reverse micelles as nano-reactors to synthesize silica-coated magnetic nanoparticles of uniform size. Silica coated and uncoated magnetite nanoparticles exhibited 20 emu/g and 39.6 emu/g, magnetic saturation values, respectively. Their enzyme activity and stability revealed that they were magnetically separable, highly active and exhibited stability even on severe shaking for more than 15 days. Singh et al. [48] employed sol– gel technique for applying silica layer of variable thickness ~ 1.5 - 129 nm on 12 nm sized magnetic nanoparticles’ surface. Physicochemical as well as magnetic properties were studied. On decreasing silica-layer thickness, zeta potential moved towards negative values, suggesting an enhancement in magnetic properties. Due to good dispersibility, silica coating exhibited outstanding colloidal stability as compared to uncoated MNPs. Silica-coated MNPs also exhibited much lesser cellular toxicity and decreased ROS generation in vitro in comparison to pure MNPs, thus enabling biomedical applications. Fig. 3(a) shows the intracellular localization of MNPs@Si sample (15 nm particles with 1.5 nm silica layer) within MC3T3-E1 cells, MNPs@Si accumulated in the cytoplasm (arrows), while preserving the other cellular organelles. Fig. 3(b, c) shows the cell viability as well as reactive oxygen species (ROS) generation in response to the 48 h cell-culture treatment of MNPs@Si and pure MNP, with varying concentration by CCK assay. 14

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Figure 3(a) Intracellular localization of MNPs@Si in MC3T3-E1 cells where M, Va, N, G and Er represent Mitochondria, Vacuoles, Nucleus, Golgi apparatus and endoplasmic reticulum, respectively (b) Cell viability and (c) ROS generation response on treating with MNPs@Si and pure MNPs [48]

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Rho et al. [80] described a procedure for synthesizing highly mono-dispersed silicacoated MNPs (size distribution < 2.5%). More than 95% of MNPs were separately coated with silica as shown in Fig. 4. Even no aggregation was observed upon storage of over three months.

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Figure 4 TEM images of (i) oleate-MNPs, (ii) PVP-MNPs, (iii) MNP@SiO2 NPs [80]

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Yu et al. [81] synthesized superparamagnetic silica-encapsulated maghemite using microemulsion method. These exhibited affinity towards hydroxyl groups for the immobilization of BSA (Bovine serum albumin), thus finding applications in magnetic drug delivery/administration. Quy et al. [82] prepared superparamagnetic Fe3O4/SiO2 NPs consisting of a 10–15 nm magnetic core, a silica shell of 2–5 nm thickness and magnetization of 42.5emu/g. This was prepared using polymerase chain reaction (PCR) amplification. Buffers were optimized with the synthesized nanoparticles for isolating genomic DNA of hepatitis virus type B (HBV) and Epstein-Barr virus (EBV) for detecting the viruses. The time measured for DNA isolation using Fe3O4/SiO2 NPs considerably decreased owing to particles’ attraction towards the magnet (15–20s) as compared to commercialized micro-particle (2-3 min). Digigow et al. [83] synthesized superparamagnetic silica MNPs and observed that a thicker silica shell resulted in reduction of magnetization. They also studied the effect of SPIONs/silica ratio on the morphology and number of surface amino groups. A comprehensive analysis of the particles for composition, size/morphology, surface properties and magnetic properties was done. Kralj et al. [84] investigated in detail the effect of silica coating on superparamagnetic maghemite nanoparticles by hydrolysis and poly-condensation of TEOS. Presence of non-magnetic silica layer resulted in diminished magnetic properties of the nanoparticles. The effects of various parameters of the experimental conditions on the quality of the coatings were thoroughly analyzed. Zapotoczny et al. [85] synthesized high quality ultra-small superparamagnetic iron oxides which exhibited superparamagnetism at low temperature around 2K. Tadyszak et al. studied superparamagnetism in silica coated Fe3O4 NPs [86]. Size dependent cytotoxicity and inflammatory response of PEGylated silica coated iron oxide nanoparticles were investigated by Injumpa et al. [87]. Luong et al. [88] developed a model in order to study drug delivery and payload release under magneto-thermal heating. Glycopolymer modified silica coated Fe3O4 nanoparticles exhibited enhanced intracellular uptake due to presence of glycoprotein receptor which is over-expressed on surface of liver cancer cells with high drug loading capability (11.9%) [89]. DNA separation ability of amine-functionalized magnetic mesoporous silica nanoparticles depicted higher DNA binding capability as compared to magnetic silica nanoparticles [90]. Guanidine containing co-polymers grafted on magnetic silica nanoparticles were studied as drug carriers [91]. A detailed comparison of effect of shape and aspect ratio of magnetic mesoporous silica NPs on the endocytosis, biocompatibility and bio-distribution has been very well-analyzed by Shao et al. for considerably improved efficiency and safety in the cancer theranostics [92]. 5.3 PEG coated Iron oxide nanoparticles PEG, being biocompatible has high solubility in the cell membranes. In the cytotoxicity profile of PEG-coated SPIONs even at high concentrations no cytotoxicity is observed. Mukhopadhyay et al. [93] reported a fast and easy green synthetic method for synthesizing PEG 16

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(different molecular weight) coated Fe3O4 NPs, highlighting its protective effect on NPs. The synthesized NPs were stable in water and possessed a moderately soft magnetic nature. Interaction of bare NPs with cytochrome c led to reduction of the protein, but no such reduction took place for PEG-coated magnetite NPs, thus establishing their potential applications for biomedical field.

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Gupta and Curtis [94] studied the influence of PEG coated SPIONs on human fibroblasts. They observed that PEG coated SPIONs did not affect cell adhesion behavior, as shown in fig. 5. Basically, the interaction of NPs with cell depends on their surface chemistry and more importantly it reflects on its hydrophobic/hydrophilic characteristics. On interaction with nanoparticles, cells first attach, stick and then spread on the surfaces. Cell adhesion is dependent on interaction of integrins (surface proteins) with proteins in the extracellular matrix or on nanoparticles’ surface. This is crucial for determining cellular functions such as cell growth, migration, differentiation and survival. In addition, quality of cell adhesion has impact on the organization, morphology, cycloskeleton and capacity of proliferation and differentiation. As observed, PEG coated particles showed no substantial difference in comparison to the control, this is attributed to low toxicity and high solubility of PEG in cell membranes.

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Figure 5 Graphical representation of number of cells adhered, on incubation with uncoated and PEG-coated particles [94]

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In yet another work, Gupta and Wells [22] synthesized PEG coated SPIONs and conducted their cytotoxicity tests, with average size of 40-50 nm and saturation magnetization of 45-50 emu/g. The cytotoxicity profile of PEG-coated SPION revealed no cytotoxic effect even at concentration of 1mg/ml, however, uncoated SPION exhibited considerable loss in viability ~ 25-50% at concentration of 250µg/ml. Bryl et al. [95] studied doxorubicin loaded Poly (ethylene glycol) – block – poly (4-vinyl benzyl phosphonate) iron oxide NPs (PEG-PIONs/DOX) as a possible drug nano-carrier for anti-cancer therapy. Synthesized NPs exhibited narrow size distribution, crystallinity and superparamagnetism with outstanding relaxation properties as well as ordering in the externally applied magnetic field. In the study by Cole et al. [96, 97] commercially obtained starch-coated MNPs were cross-linked, aminated, and functionalized 17

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with PEG (5 kDa (D5) and 20 kDa (D20)) for magnetic tumor targeting. It was observed that D5 and D20 exhibited 61-98 fold longer plasma half-life (hours) in rats as compared to unmodified starch MNPs. On intravenous administration, the increased plasma residence led to 100-150 greater tumor exposures to MNPs. The same group also reported on bio-distribution patterns of PEG-MNPs in organs of elimination such as liver, spleen, lung, and kidney, using 9L-glioma rat model. Long circulation lifetime of NPs resulted in enhanced magnetic brain tumor targeting. Tumor delivery ~ 1.0% injected dose Fe/g tissue was observed, indicating a 15-fold improvement in targeting efficiency as compared to the previously targeted (0.07% injected dose/g tissue). Chen et al. [98] reported a novel magnetic drug delivery system, comprising of PEG functionalized porous silica shell, doxorubicin (DOX) and Fe3O4 NPs. DOX release rate of Fe3O4-DOX/SiO2-PEG core/shell nanoparticles was slower than that of Fe3O4-DOX nanoparticles, due to porous silica shell. Typically, DOX was released from the carrier in a diffusion-controlled process. Larsen et al. [99] prepared PEG-silane coated iron oxide NPs into two distinctive size sub-populations of 20 and 40 nm mean diameters. On intravenous administration, particles in 40 nm size range exhibited enhanced phagocytic uptake in vitro and greater iron accumulation in murine tumors on MRI detection. Zhang et al. [32] successfully functionalized magnetite nanoparticles with PEG, folic acid and doxorubicin for magnetic drug delivery application. Drug release response was characterized with a rapid initial stage and a controlled second stage.

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In the study by Yu et al. [100], porcine aortic endothelial cells were exposed to 5 and 30 nm diameter PEG/dextran coated iron oxide nanoparticles. Cytotoxicity analysis, changes in cell morphology, nanoparticles uptake and ROS formation were evaluated. Nanoparticles of different sizes as well as coatings were taken up by endothelial cells in a dose dependent behavior. In both sizes, bare nanoparticles induced more than 6 fold increments in cell death at the highest concentration (0.5 mg/mL), whereas in case of coated NPs, cell viability and morphology remained invariable. It was observed that 30 nm uncoated nanoparticles induced considerable ROS formation, whereas 5 nm nanoparticles (uncoated and coated) and 30 nm coated nanoparticles did not alter ROS levels. Thus, both dextran and PEG coatings exhibited reduced cytotoxicity. Khoee and Kavand [101] connected iron oxide nanoparticles to methoxy poly (ethylene glycol) (mPEG) via a new method using ATPS (3-aminopropyl triethoxysilane), triethoxysilyl-terminated PEG and hydroxyl groups on the magnetite nanoparticles’ surface (average particle size of 20–30 nm) for potential biomedical applications. SPIONs with a phospholipids-PEG coating, loaded with Doxorubicin (DOX) were studied by Quinto et al. [102]. It showed a sustained DOX release for over 72 hours. It was observed that release kinetics was dependent on PEG length, but heating efficiency showed minimal changes. SPIONs (core size 14 nm) generated sufficient heat to increase the local temperature to 43°C, for triggering apoptosis in cancer cells. Also, the collective effect of DOX and SPION-induced hyperthermia resulted in an increase in cancer cell death in vitro. Azadbakht et al. [103] studied the therapeutic effect and targeting efficiency of Radioimmuno-conjugated (Rhenium-188 labeled Rituximab), 18

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3-aminopropyltriethoxysilane (APTES)-polyethylene glycol (PEG) coated iron oxide nanoparticles. Polydopamine, PEG and indo-cyanine (green) coated magnetite nanocluster was synthesized by Wu et al. [104]. Under near-infrared (NIR) laser irradiation, it displayed increased photo-stability, photo-thermal conversion ability as well as photo-thermal killing efficiency against cancer cells. It also exhibited excellent magnetic field targeting ability, biocompatibility and T2-weighted MR imaging. Magnetic targeting along with methotrexate macromolecular targeting was successfully employed for developing a versatile theranostics nano-platform for dual-modal fluorescence and MRI combined chemo-photodynamic cancer therapy [105]. Surface modified magnetite by comb-like PEG-acrylate-acrylic acid (PEGA-AA) was studied in comparison to carboxy-PEG (PEG-C) as well as phosphate-PEG (PEG-P). PEGAAA exhibited more efficiency owing to uniform distribution of carboxylate and PEG chains [106]. Table 1 summarizes the iron oxide based nanocomposites explored in biomedical field.

Iron oxide

5.

Iron oxide

6.

Iron oxide

7.

Iron oxide

Poly (ethyl-2-cynoacrylate) (PECA) Poly (D, L-lactic-coglycolic acid) (PLGA)

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Table 1 Iron oxide based nanocomposites used in biomedical field S. No Magnetic Coating material Application/Study core performed material 1. Iron oxide Phenolic poly (pSuperparamagnetic ethylphenol) polymer behaviour 2. Iron oxide Polyisobutylene, Superparamagnetic polyethylene based behaviour dispersants 3. Iron oxide Oleic acid (OA) – pluronic Cytotoxicity study

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Poly (lactic acid)-D-αTocopherol 1000 succinate (TPGS) Poly (Nisopropylacrylamideacrylamide-allylamine) Silica

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Maghemite

Superparamagnetic behaviour Cytotoxicity study and Superparamagnetic behaviour Cytotoxicity study

Reference

Kommareddi et al., 1996 [70] Burke et al., 2002 [71] Jain et al., 2005 [72] Yang et al., 2006 [73] Lee et al., 2010 [74]

Prashant et al., 2010 [75]

Cytotoxicity study

Rahimi et al., 2010 [76]

Functionalization with thin homogeneous coating of 3-

Campelj et al., 2009 [77]

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Magnetite

Silica

11.

Fe3O4

Silica

12.

Magnetite

Silica

13.

Magnetite

Silica

14.

Fe3O4

Silica

15.

MNPs

Silica

16.

Maghemite

17.

Fe3O4

18.

Iron oxide

Silica

19.

Maghemite

Silica

20.

Iron oxide

Silica

Structural, magnetic and morphological properties by adding different concentrations of silica Superparamagnetic behaviour Superparamagnetic behaviour Enzyme activity and stability Physicochemical and magnetic properties, Intracellular localization, Cell viability study Highly monodispersed MNPs Interaction with Bovine Serum Albumin Detection of viruses hepatitis virus type B (HBV) and EpsteinBarr virus (EBV) Effect of SPIONs/silica ratio Effect of various parameters of the procedure and experimental conditions on the quality of the coatings Superparamagnetism at low temperature 2k

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Silica

Silica

Almeida et al., 2010 [78] Sun et al., 2011 [25]

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10.

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Silica

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Maghemite

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aminopropyl silane Functionalization

He et al., 2005 [42] Deng et al., 2005 [43] Lee et al., 2008 [44] Singh et al., 2012 [48]

Rho et al., 2014 [80] Yu et al., 2007 [81] Quy et al., 2013 [82]

Digigow et al., 2014 [83] Kralj et al., 2010 [84]

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Iron oxide

PEG, Silica

23.

Fe3O4

Silica

24.

Fe3O4

Silica, Glycopolymer

25.

Fe3O4

Silica, Amine functionalized

26.

Fe3O4

Silica, Guanidine containing co-polymers

27.

Iron oxide

Silica

28.

Magnetite

29.

Iron oxide

30.

Iron oxide

Superparamagnetic behaviour Size-dependent cytotoxicity and inflammatory responses Payload release under magneto-thermal heating Drug bioavailability and anti-cancer efficacy DNA separation ability and drug delivery Drug loading properties and cumulative release Shape effect on endocytosis, biocompatibility and bio-distribution Interaction with cytochrome c

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Influence on human fibroblasts

PEG

Cytotoxicity tests on uncoated and PEG coated SPION Nano-carrier for magnetically mediated targeted anti-cancer therapy Long-circulating PEG-MNPs for magnetic tumor targeting

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PEG

31.

Iron oxide

Poly (ethylene glycol) – block – poly (4-vinyl benzyl phosphonate)

32.

Iron oxide

Starch, PEG

Tadyszak et al., 2017 [86] Injumpa et al., 2017 [87]

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Silica

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Luong et al., 2016 [88]

An et al., 2015 [89] Sheng et al., 2016 [90] Timin et al., 2016 [91] Shao et al., 2017 [92]

Mukhopadhyay et al., 2012 [93] Gupta and Curtis, 2004 [94] Gupta and Wells, 2004 [22] Bryl et al., 2015 [95]

Cole et al., 2011[96]

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Iron oxide

Starch, PEG

34.

Fe3O4

Silica, PEG

35.

Iron oxide

PEG-silane

36.

Magnetite

PEG, Folic acid

37.

Iron oxide

PEG, Dextran

38.

Iron oxide

Methoxy poly(ethylene glycol) (mPEG)

39.

Iron oxide

40.

Iron oxide

Drug (Doxorubicin) release kinetics Therapeutic effect and targeting efficacy

41.

Magnetite

Phospholipid-polyethylene glycol (PEG) Radioimmuno- (Rhenium188 labeled Rituximab), 3aminopropyltriethoxysilane (APTES), polyethylene glycol (PEG) Poly(dopamine, Polyethylene glycol (PEG), indo-cyanine green (ICG) Silica, lipid, PEG, methotrexate

MR imaging and photo-thermal therapy in vivo Multimodal imaging and multistage targeted chemophotodynamic therapy

Wu et al., 2016 [104]

Carboxylated PEG

Biomedical applications

Illés et al., 2015 [106]

Fe3O4

43.

Magnetite

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Enhanced magnetic brain tumor targeting Release rate of Doxorubicin Phagocytic uptake and greater iron accumulation in murine tumors of 40 nm NPs Drug (Doxorubicin) release response Nanoparticles uptake, cytotoxicity, reactive oxygen species (ROS) formation, and cell morphology changes were investigated New method

Cole et al., 2011 [97] Chen et al., 2010 [98] Larsen et al., 2009 [99]

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33.

Zhang et al., 2008 [32] Yu et al., 2012 [100]

Khoee and Kavand, 2014 [101] Quinto et al., 2015 [102] Azadbakht et al., 2017 [103]

Liu et al., 2017 [105]

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6. Ferrites based nanoparticles/nanocomposites for biomedical applications

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Despite much ongoing research in the area of maghemite or magnetite nanoparticles, it has been observed that their surface is relatively inert which deters formation of any strong covalent bonds for functionalizing molecules, thereby making it necessary to look for alternatives. This has given an impetus on exploring feasibility of ferrites for such applications. Following are the characteristics of ferrites that make them suitable for biomedical applications [84, 107]: (i) High chemical stability

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(v) Retain superparamagnetic properties

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(iv) Tunable magnetic moment depending on nanoparticles’ size

(vi) Easy and simple surface functionalizations

6.1 Cobalt Ferrite

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Other than iron oxide, metal doped iron oxides with composition MFe2O4 where M is a +2 cation of cobalt, manganese, nickel and zinc have been investigated for biological applications, due to their higher magnetization and ability to maintain superparamagnetic behavior at larger particle size.

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Nano-crystalline cobalt ferrites were prepared by sol-gel, reverse micelle method and co-precipitation method [108-114]. K. E. Scarberry reported about cobalt spinel ferrite nanoparticles to be used for cancer cell extraction as well as drug delivery applications [108]. Baldi et al. [114] synthesized mono-dispersed stable cobalt ferrite nanoparticles (5.4 nm) and coated them with difunctional phosphonic and hydroxamic acid, the magnetic measurements revealed their possible applications in hyperthermia. Gharibshahian et al. [115] studied structural and magnetic properties of silica coated cobalt ferrite nanoparticles. Rohilla et al. [116] synthesized silica coated cobalt ferrite nanoparticles by co-precipitation method. It was observed that at room temperature, magnetic parameters such as saturation magnetization, remanence and coercivity, initially increased with increasing annealing temperature. With further increase, the values started to decrease. Mohapatra et al. [117] synthesized folic acid conjugated superparamagnetic mesoporous CoFe2O4 particles of 35–40 nm size. They exhibited excellent water solubility, stability in physiological pH without deteriorating hydrodynamic size. HeLa cells were used to determine their internalization efficiency and cytotoxicity. Also, using simple organic coupling reactions, fluorescent molecule RITC, methotrexate and doxorubicin were 23

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successfully conjugated to amine groups for therapeutic and optical properties. Tamhankar et al. [118] synthesized cobalt ferrite nanoparticles (45 nm) using co-precipitation method and coated with sodium alginate (78 nm). Saturation magnetization reduced from 19.8emu/g to 10.2emu/g and Curie temperature was measured to be less than 100°C, indicative of superparamagnetic structure for the uncoated samples. Amiri and Shokrollahi [119] reviewed and discussed in detail cobalt ferrite nanoparticles as one of the competitive candidates for biomedical applications pertaining to their appropriate chemical, physical and magnetic properties such as high values of anisotropy constant, Curie temperature and high coercivity with moderate saturation magnetization as well as easy synthesis. Joshi et al. [120] studied varied shapes as well as sizes of cobalt ferrite nanostructures. Seed mediated growth method was used for synthesizing spherical nanostructures of varied sizes. Faceted irregular (FI) nanostructures were also synthesized by similar method but using a magnetic field. The latter displayed lesser saturation magnetization compared to the former in ordinary conditions of magnetic measurements, but exhibited higher contrast effect as well as relaxivity coefficient. This behavior reflects on the imperative role of size and shape on their magnetic properties for biomedical applications. Salunkhe et al. [121] investigated the application of cobalt ferrites in magnetic fluid hyperthermia. Sawant et al. [122] compared the anti-bacterial screening, anti-cancer, apoptotic effects and drug delivery properties of zinc ferrite and cobalt ferrite coated with PEG and chitosan. Magnetically controlled and temperature sensitive drug delivery system based on ferromagnetic cubic cobalt ferrite that releases drug selectively on heating under varying AC magnetic field has been developed [123]. Chen et al. [124] synthesized hollow mesoporous cobalt ferrite nanoparticles and studied their drug release kinetics under microwave irradiation. Asik et al. [125] studied internalization, uptake, apoptotic effects and gene expression levels of 2-amino-2-deoxy-glucose (2DG) conjugated cobalt ferrite nanoparticles. Hamid et al. [126] fabricated hydroxyapatite-Co-ferrite nanocomposite coatings on stainless steel for medical implants and hyperthermia applications.

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6.2 Manganese ferrite

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Manganese ferrite nanoparticles have been mainly studied as contrast agents in Magnetic Resonance Imaging (MRI). Liu et al. [127] synthesized superparamagnetic MnFe2O4 nanoparticles of average particle size 4 to 15 nm by reverse micelle method with blocking temperature of 150K. Size-dependent superparamagnetic properties of MnFe2O4 and their magnetization with respect to temperature and particle size were studied by Lui and Zhang [128]. Amighian et al. [129] synthesized single phase MnFe2O4 nanoparticles of crystallite size 80 nm, by co-precipitation method. Esteves et al. [130] used salt co-precipitation method to synthesize superparamagnetic Mn/Zn ferrite nanoparticles (15-17 nm), coated with bio-compatible carboxymethyl dextran (CDMx). In the cytotoxicity tests, viability more than 80% at concentration of 7.5mg/ml was observed. Similarly, morphological and magnetic properties of zinc substituted manganese ferrite nanoparticles were reported [131]. Lu et al. [132] synthesized 24

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superparamagnetic MnFe2O4 nano-crystals in organic phase. It was solubilized in water using copolymer mPEG-b-PCL, with mean diameter 80 nm. In vivo MRI study indicated that MnFe2O4 have the strongest MR contrast effect in T2-weighted images with much higher T2 relaxivity. Recently, Yang et al. [133] also synthesized MnFe2O4 nanoparticles and studied the MRI contrast agent abilities of MnFe2O4. The synthesized MnFe2O4 showed non-toxicity for concentration of 200µg/ml. Kim et al. [134] synthesized Chitosan coated MnFe2O4 nanoparticles with average size to be approximately 18 nm. Chitosan coating was studied by FT-IR also. MNPs showed superparamagnetism with a saturation magnetization, MS, of 44.1emu/g. It decreased on increasing the thickness of chitosan coating. Tromsdorf et al. [135] comparatively investigated the capability of highly crystalline and mono-disperse MnFe2O4 nanoparticles for enhancing negative contrast in MRI with respect to appropriate matrices by applying ligand exchange, amphiphilic polymer shell and lipids. They observed that transverse relaxivities, r2 and r2*, increased with increasing core size. Sahoo et al. [136] prepared silica-coated superparamagnetic MnFe2O4 NPs conjugated with fluorescent as well as targeting moieties. The shell thickness was ~20–25 nm with overall size ~200–300 nm. HeLa cells specifically took up these nanoparticles as compared to normal cells. In the drug loading studies, it was observed that the outer mesoporous silica shell encapsulated considerable amount of anticancer drug, DOX, with preferable release occurring at lysosomal pH. In vitro biological studies showed that DOXloaded folate-targeted NPs were excellently efficient for simultaneous targeting as well as for destroying cancer cells. Peng et al. [137] successfully decorated hydrophobic MnFe2O4 nanoparticles (MFNPs) on Graphene Oxide (GO) sheets with oleylamine used as an intermediate spacer. This resulted in water soluble MFNPs/GO nanocomposites with the size range ~50–60 nm, for hyperthermia applications. Shah et al. [138] synthesized superparamagnetic PEG and folic acid conjugated doxorubicin-loaded multifunctional MnFe2O4 nanoparticles for cancer therapy. The synthesized NPs had a mean diameter of ~ 22 nm with a core-shell structure comprising of 31% wt. organic shell. MnFe2O4 core of ~ 6 nm exhibited superparamagnetism owing to pseudo-single domain structure. Drug loading and releasing were efficient in the initial 8 h whereas in later hours were gradual. It was observed that temperature of the fluid increased from 25°C to 45°C in about 22 minutes. This is an effective and suitable temperature for providing localized hyperthermia and cancer treatment. Wang et al. [139] investigated cytotoxicity and drug loading capacity of manganese ferrite/Graphene oxide (MnFe2O4/GO) nanocomposites. Kamiri et al. [140] reported drug encapsulation efficiency and in-vitro release pattern of PEGylated and amphiphilic chitosan coated manganese ferrite nanoparticles. 6.3 Nickel Ferrite

Research on suitability of nickel ferrites for biomedical applications has also been studied. Albuquerque et al. [141] successfully synthesized Ni-ferrite (4 - 15 nm) by coprecipitation method followed by annealing at different temperatures. Mossbauer spectroscopy and VSM (Vibrating Sample Magnetometer) at 273ºC and -193ºC showed their 25

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superparamagnetic behaviour with high coercivity of 168 Oe, nearly twice the coercivity of bulk Ni-ferrite. Superparamagnetic nano-crystalline nickel ferrites were prepared by reverse micelle technique [69]. Rana et al. [14] investigated the use of nano-crystalline NiFe2O4 as drug carriers, functionalized and conjugated with polyvinyl alcohol, polyethylene oxide and poly-methacrylic acid (PMAA) polymers and doxorubicin, respectively. The functionalized ferrites retained superparamagnetism, enabling their drug delivery applications. Yin et al. [24] studied the effects of particle size as well as surface coating (Oleic acid) on cytotoxicity of nickel ferrites. Cytotoxicity in case of uncoated nickel ferrites was found to be particle size independent within the given mass concentration as well as surface area reachable to the cells. Oleic acid coated nickel ferrites displayed significant cytotoxicity that increased with its layers on deposition. Larger sized particles (150+50 nm) were more toxic as compared to smaller particles (10 + 3 nm). Tomitaka et al. [142] studied the biocompatibility of Fe3O4 (20-30 nm), ZnFe2O4 (15-30 nm) and NiFe2O4 (20-30 nm). Viability of HeLa cells treated with Fe3O4, ZnFe2O4 and NiFe2O4 at the concentration of 10µg/ml for 24/48 h was more than 80%. ZnFe2O4 and NiFe2O4 showed lower cell viability, at higher concentrations but at a concentration lesser than 10µg/ml, all the three ferrites exhibited non-toxicity. Different cytotoxic responses of nickel ferrite NPs in different cell lines have been explored [143-145]. Nano-toxicology is a crucial area of research which needs deep scrutiny. Ahamed et al. [143] reported about significant cytotoxicity of nickel ferrite nanoparticles on A549 cells in (25–100µg /ml). Quantitative real-time PCR analysis revealed that nickel ferrite nanoparticles altered mRNA levels of proteins involved in the apoptosis. This suggests, through ROS generation, that nickel ferrite nanoparticles induce apoptosis in A549 cells, as shown in fig. 6.

Figure 6 Nickel ferrite NPs-induced oxidative stress in A549 cells [143] Similarly, toxic effect of nickel nanoparticles (Ni NPs) on human lung epithelial A549 cells at different concentrations for 24 and 48 h were reported [144]. Ni NPs exhibited significant toxicity in human lung epithelial A549 cells probably mediated through oxidative stress, thereby 26

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warranting more cautious evaluation of Ni NPs before any industrial applications. Ahmad et al. [146] prepared chitosan-coated nickel-ferrite (NiFe2O4) nanoparticles as T1 and T2 contrast agents for imaging applications. In animal experimentation, a 25% signal enhancement in the T1weighted image and a 71% signal loss in the T2-weighted image were obtained, as shown in fig.8.

Figure 7 (a) T1-weighted image for nickel ferrite nanoparticles at different concentration depicting a dose-dependent increase in the signal intensity from left to right (b) T2weighted image of nickel-ferrite nanoparticles depicting a dose-dependent decrease in signal intensity from left to right [146]

6.4 Zinc Ferrite

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In a study done by Bano et al. [147], bovine serum albumin (BSA), chitosan (CS)/Carboxymethyl cellulose (CMC) on nickel ferrite core resulted in improved biocompatibility and relaxivity value. Excellent anti-bacterial properties as well as anti-fungal activity of NiFe2O4@Ag were investigated against Bacillus subtilis (gram positive) and Pseudomonas syringae (gram negative), as well as Alternaria solani and Fusarium oxysporum, respectively [148]. Also, the same paper reports about effective catalytic property of NiFe2O4@Mo. Nickel ferrites doped α-alumina NPs exhibited high antibacterial effect on Pseudomonas aeruginosa and S. aureus [149].

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Wan et al. [150] synthesized mono-disperse ZnFe2O4 nanoparticles using a simple and low-cost polyol process without any surfactant for MRI and cytotoxicity analyses. Chen et al. [151] synthesized zinc-doped superparamagnetic iron oxide nanocrystals (SPIONs: Zn) with lesser toxicity and improved sensitivity. Saturation magnetization was found to be Zn-dependent. Furthermore, CTAB stabilized SPIONs: Zn was studied as a MR enhanced contrast agent, a high T2 relaxivity coefficient (r2) was obtained ~ 342.09 mM−1s−1. Gahrouei et al. [152] studied the cytotoxicity effects of Cobalt-Zinc Ferrite Magnetic Nanoparticles (CZF-MNPs) and CZF-MNPs coated with Dimercaptosuccinic Acid (DMSA) on human prostate cancer cell lines, HPCs, PC3 and DU145. Yang et al. [153] successfully synthesized folic acid-functionalized magnetic ZnFe2O4 hollow microsphere core/MS shell (MZHM-MSS-NHFA) particles. It displayed drug 27

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storage capacity more than that of the reported magnetic core/MS shell system. Load amount of drug ibuprofen reached 28%, indicating its better sustained drug-release property. Nanotoxicological profile in vitro and in vivo of Zn0.8Co0.2Fe2O4 revealed reduced viability and tissue toxicities in lungs, liver and kidneys [154]. This is first report on harmful effects of such nanoparticles on human cells and mammals. Tenório et al. [155] reported drug release changes in response to an external magnetic field of Co0.50Zn0.50Fe2O4 nanoparticles.

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Successful practical utility of the above-mentioned metal ferrites for biomedical applications can be hindered by high inherent toxicity of the transition metals (Ni, Mn, Co, Zn). Biocompatible and non-permeable coatings are required for preventing leaching of these metals. Hence, it is highly needed to work towards synthesizing highly bio-favorable ferrites which exhibit superparamagnetism without any toxicity threat. Even if leaching does occur the metal used as core should not be harmful to the body rather should get metabolized by the body. For the same, calcium, potassium metals can be considered as good candidates. Exploring these areas will solve the toxicity problem faced with ferrite nanoparticles of nickel, cobalt, manganese, zinc and will provide a more biocompatible and less cytotoxic material with required magnetic properties for biomedical applications. 6.5 Calcium Ferrite and Potassium Ferrite

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Ferrites of calcium and potassium in the nano-regime have been explored for their feasibility in biomedical applications. Calcium and potassium are inherently non-toxic, rendering them safe for biomedical applications. The orthorhombic structure of CaFe2O4 NPs with spherical morphology, size (5–10 nm) and MS value - 36.4emu/g were reported [156]. Similarly, spherical formation in the size range 4-7 nm, orthorhombic structure, and MS value of 25.72emu/g of KFeO2 NPs have been reported [157]. In both cases, in vitro cytotoxicity test revealed their biocompatibility at particle concentration below 250µg/ml. The coating of PEG on CaFe2O4 NPs [158] resulted in additional peaks at 19º and 23º, characteristic of PEG with orthorhombic structure. Their spherical morphology and reduced agglomeration due to PEG coating was also observed. They exhibited superparamagnetic behavior but with reduced MS value from 36.76emu/g to 6.74emu/g, due to the formation of non-magnetic layer which reduced the magnetic diameter of the particles than its physical size. Similarly for PEG coated KFeO2 NPs [159], superparamagnetism with MS value - 5.78emu/g was observed. Dose-dependent cellular toxicity revealed toxicity below 250µg/ml but at higher concentrations, the cell viability decreased probably due to overloading of the nanoparticles. Biocompatibility and superparamagnetic behaviour in silica coated CaFe2O4 NPs have also been reported [160]. XRD pattern revealed orthorhombic structure of CaFe2O4, with a broad band near 2θ ~15–20º due to silica. Spherical morphology with no agglomeration in the narrow size distribution of 3–6 nm was observed. The nanocomposite exhibited superparamagnetism with magnetic saturation of 8.55 emu/g. Enhanced cell-viability has been ascribed to high dispersibility and insignificant agglomeration, because of silica. Similarly, coating of silica on KFeO2 NPs has been obtained 28

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by Stober process [161]. Silica coating was confirmed by FT-IR spectrum. Morphological analyses revealed their spherical formation with reduced agglomeration. Both uncoated as well as coated KFeO2 NPs exhibited superparamagnetism with magnetic saturation of 49.01emu/g and 21.17emu/g, respectively (Fig. 8 (a)). Dose-dependent cellular toxicity was observed in case of both bare and silica coated KFeO2 NPs, as depicted in fig. 8 (b). The mechanism of silica coating has been explained by aggregation model [161]. The magnetic behaviour of nanocomposite as well as magnetic dynamics have been well-explained by core–shell model, which strongly associates the competitive magnetic ordering between core and shell/surface spins to inter-particle interactions as well as surface spin configuration [161]. Magnetic ordering of the core spins dominates that of the silica shell, thus maintaining the superparamagnetic character of the ferrite core. This explains the retained superparamagnetism even on silica coating. But, it certainly has a negative effect on the overall magnetic saturation, which is reduced due to presence of magnetically dead layer of silica. Magnetization curve formation depends on the particle size as well as size distribution. This is further related to magnetic particle content. A magnetically dead surface coating increases the physical size of the nanocomposite and decreases the magnetic size, so the magnetic saturation value decreases. Also, owing to non-collinear spin structure due to pinning of surface spins and silica at the interface, total effective magnetic moment of the nanocomposite decreases. Jasso-Terán et al. [162] synthesized Zn0.50Ca0.50Fe2O4 and CaFe2O4 ferrites, which exhibited appropriate heating capability for hyperthermia applications. The release of ampicillin, biocompatibility and antibacterial activity of chitosan coated CaFe2O4 nanoparticles has been reported [163].

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Figure 8 (a) M–H curve of (a) potassium ferrite nanoparticles and (b) silica coated potassium ferrite nanoparticles (b) Cell viability of bare and silica coated potassium ferrite nanoparticles (SD error bars) [161] Table 2 summarizes the ferrite based nanocomposites explored in biomedical field.

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Table 2 Ferrite based nanocomposites used in biomedical field S. No Magnetic core Coating material Application/Study material performed 1. Cobalt ferrite Silica Influence of annealing temperature Cobalt ferrite

Foilc Acid

3.

Cobalt ferrite

Sodium alginate

Magnetization measurements

4.

Cobalt ferrite

----

Physical, chemical and magnetic properties

5.

Cobalt ferrite

----

6.

CoFe2O4

Effect of various shapes and sizes on magnetic properties Magnetic fluid hyperthermia

7.

CoFe2O4 and ZnFe2O4

8.

Cobalt ferrite

TE D ----

PEG, Chitosan

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9.

Cytotoxicity and internalization efficiency

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10.

Hollowmesoporous cobalt ferrite Cobalt ferrite

11.

Cobalt ferrite

Folic acid ----

2-amino-2-deoxyglucose (2DG) Hydroxyapatite

Anti-bacterial screening, anticancer ,apoptotic effects and drug delivery properties Temperature sensitive drug delivery system Drug release under microwave irradiation Targetable drug/gene delivery agent for cancer treatment Surface treatment for stainless steel medical implants and hyperthermia treatment of cancer.

Reference

Rohilla et al., 2011 [116] Mohapatra et al., 2011 [117] Tamhankar et al., 2011 [118] Amiri et al., 2013 [119] Joshi et al., 2009 [120] Salunkhe et al., 2016 [121] Sawant et al., 2016 [122] Dey et al., 2017 [123] Chen et al., 2017 [124] Asik et al., 2016 [125] Hamid et al., 2017 [126] 30

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Cobalt ferrite

Silica

Structural and magnetic studies

13.

MnFe2O4 nanoparticles MnFe2O4

-------

Size-dependent superparamagnetic properties Synthesis of single phase NPs

15.

Mn/Zn ferrite nanoparticles

Carboxymethyl dextran (CDMx)

16.

MnFe2O4

17.

MnFe2O4

Methoxy poly(ethylene glycol)-b-poly(ɛcaprolactone) (mPEGb-PCL) ----

18.

MnFe2O4

Chitosan

Magnetic study

19.

MnFe2O4

Amphiphilic polymer shell and lipids

MRI study

20.

MnFe2O4

21.

MnFe2O4

22.

MnFe2O4

SC

Cytotoxicity tests

MRI study

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MRI study

Silica

Drug (Doxorubicin ) loading and release studies Hyperthermia testing

MnFe2O4

24.

Manganese Ferrite

PEG, Chitosan

pH-sensitive delivery of methotrexate

25.

Ni-ferrite

----

Superparamagnetic behaviour

EP

23.

Graphene Oxide (GO), oleyamine Polyethylene glycol (PEG) & folic acid (FA) Graphene oxide

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Gharibshah ian et al., 2017 [115] Liu et al., 2000 [127] Amighian et. al., 2006 [129] Esteves et al., 2009 [130] Lu et al., 2009 [132]

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Drug loading & releasing

In vitro cytotoxicity and drug loading capacity

Yang et al., 2010 [133] Kim et al., 2010 [134] Tromsdorf et al., 2007 [135] Sahoo et al., 2014 [136] Peng et al., 2012 [137] Shah et al., 2013 [138] Wang et al., 2017 [139] Kamiri et al., 2017 [140] Albuquerq ue et al., 2001 [141] 31

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Drug (doxorubicin) carriers

Rana et al., 2007 [14]

27.

Nickel ferrites

Effects of particle size and surface coating on the cytotoxicity of nickel ferrites

Yin et al., 2005 [24]

28.

Fe3O4, ZnFe2O4, NiFe2O4

----

Cytotoxicity tests

NiFe2O4

----

Toxicity tests

30.

NiFe2O4

chitosan

31.

NiFe2O4

32.

NiFe2O4

Bovine serum albumin ,chitosan or Carboxymethyl cellulose Molybdenum, Silver

Tomitaka et al., 2009 [142] Ahamed et al. 2011 [144] Ahmad et al., 2015 [146] Bano et al., 2016 [147]

29.

33.

Nickel Ferrite

34.

ZnFe2O4

35.

36.

Zinc-doped superparamagnetic iron oxide Cobalt-Zinc Ferrite

37.

ZnFe2O4

Folic acid

Sustained drug (ibuprofen)release

38.

Zinc ferrite

Co-doped, starch

Magnetic field-responsive drug release changes

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Polyvinyl alcohol, polyethylene oxide and poly-methacrylic acid (PMAA) polymers Oleic acid

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NiFe2O4

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MRI study

Biocompatibility and MR imaging probe for breast cancer Antibacterial, antifungal activities

α-alumina

Anti-bacterial activity

----

MRI study

CTAB

MRI study

Dimercaptosuccinic Acid (DMSA)

Cytotoxicity

Golkhatmi et al., 2017 [148] Ishaq et al., 2017 [149] Wan et al., 2012 [150] Chen et al., 2011 [151] Gahrouei et al., 2013 [152] Yang et al., 2013 [153] Tenório et al., 2015 [155] 32

Zinc-cobalt ferrite nanoparticles

----

Harmful effects in human cells and mammals

40.

CaFe2O4

----

Biocompatibility and superparamagnetism

41.

CaFe2O4

PEG

Dose-dependent cytotoxicity

Khanna et al., 2013 [158 ]

42.

CaFe2O4

Silica

Dose-dependent cytotoxicity

Khanna et al., 2014 [160]

43.

KFeO2

44.

KFeO2

45.

KFeO2

46.

Zn(1−x)CaxFe2O4

CaFe2O4

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Superparamagnetic, Biocompatibility

Khanna et al., 2014 [157]

PEG

Dose-dependent cytotoxicity

Khanna et al., 2015 [159]

Silica

Dose-dependent cytotoxicity

Khanna et al., 2013 [151]

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Hyperthermia

Chitosan

Release of ampicillin

JassoTerán et al., 2017 [162] Bilas et al., 2017 [163]

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47.

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7. Folic acid Folate receptor is a glycosyl-phosphatidylinositol anchored, high affinity folatebinding protein which is over-expressed in different varieties of tumors, while its expression is limited in healthy tissues and organs [164]. Therefore, folate receptor provides preferential sites 33

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7.1 Folic acid conjugated MNPs

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that distinguish tumor cells from normal cells and impede the nourishment to the rapidly dividing tumor cells. Folate receptors are overly expressed in epithelial, breast, ovarian, cervical, lung, colorectal, kidney, brain tumors, sarcoma, lymphomas, and cancers of the testicles, pancreas, bladder and prostate glands [164-168]. In normal tissue, folate receptors are constrained to the lungs, kidneys, placenta, and choroid plexus, where they are expressed in the apical surface of polarized epithelia [164]. Folic acid is non-immunogenic, highly stable with small molecular size (441 Da) [165, 169]. Modification of the surface with a ligand as folic acid first results in attachment of the receptors located within caveolae, followed by effective internalization of nanoparticles into the cells through receptor-mediated endocytosis,. This makes them suitable for tumor selective drug delivery. Folate, also termed as pteroylglutamate, is a water-soluble B vitamin which is significant in DNA synthesis, methylation, and repair [164-166]. In addition, folic acid is stable over a wide range of temperatures and pH values. Even after conjugating with drugs/markers, it retains its binding ability of the folate receptors. Also, as the pH of endosome reaches five, folate dissociates from the receptor and drug gets released [164].

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Mohapatra et al. [165] synthesized folic acid conjugated magnetic nanoparticles to enhance the site specific intracellular uptake. The synthesized nanoparticles showed noncytotoxicity and receptor mediated internalization by HeLa and B16 melanoma F0 cancer cells. Zhou et al. [168] synthesized highly biocompatible and superparamagnetic folate-conjugated Fe3O4 nanoparticles. The synthesized nanoparticles possessed excellent physiological stability, less cytotoxicity on human skin fibroblasts and insignificant effect on Wistar rats at a high concentration of 3 mg/kg body mass. Sun et al. [47] synthesized magnetic, florescent, folic acid conjugated silica nanocomposites. The cytotoxicity of silica nanocomposite was found to be greater than 90% at the concentration of 70µg/ml. Lin et al. [170] synthesized SPIONs and functionalized them with Pluronic F127 (Triblock copolymer, PF127) and folic acid by poly acrylic acid - bound iron oxides (PAA-SPIONs) forming FA-PF127-PAA-SPIONs nanocomposite. The successful coating of MNPs was confirmed by comparing the characteristics bands obtained at each step of functionalization by FT-IR. The saturation magnetization of PAASPIONs, FA-PF127-PAA-SPIONs was 78.1emu/g, 69.8emu/g and had negligible cytotoxic effects, making them a potential tool in drug delivery. Chen et al. [46] also conjugated folic acid (FA) to magnetic iron oxide using silica and studied the effect of coating on the magnetic behavior of iron oxide. Room temperature magnetization of pure Fe3O4, Fe3O4-SiO2-FA was found to be 64.9emu/g and 41.7emu/g respectively. Recently, Rastogi et al. [38] synthesized magnetic nanocomposite comprising of polymers of N-isopropylacrylamide (NIPAAM), acrylic acid (AA) and Poly-ethylene glycol – methacrylate (PEGMA) followed by folic acid modification, for imaging and hyperthermia treatment. The magnetic saturation values of NPs and FNPs (folic acid conjugated composite) were 36emu/g and 32emu/g, respectively. The presence of thermo-responsive polymer (NIPAAM) and tuning of its Tc (44 °C) enabled 34

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controlled release of doxorubicin at the hyperthermia temperature (72.42±5.25% in 48 h). PEGMA chains increased its blood circulation time and prevented rapid clearance by RES. The nanocomposite exhibited high T1 and T2 relaxivities, thus facilitating imaging applications. Zhang et al. [37] synthesized PEG and folic acid modified superparamagnetic magnetite nanoparticles. The internalization of nanocomposite into mouse macrophage (RAW 264.7) as well as human breast cancer (BT20) cells was studied and measured by fluorescence, confocal microscopy as well as inductively coupled plasma emission spectroscopy (ICP). It was observed that the uptake of folic acid conjugated nanoparticles by breast cancer cells was significantly higher as compared to macrophage cells. Folic acid conjugation also increased target specificity and the yield of cell internalization. Andhariya et al. [171] studied the drug release kinetics of doxorubicin loaded Folic acid-PEG functionalized Fe3O4 nanoparticles. In vitro drug loading and release kinetics study revealed that the drug delivery system took 52 % of drug load and released doxorubicin over a sustained period of 7 days, making it feasible for practical utilities in chemotherapy where frequent dosing is not possible.

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Ovarian cancer is one of the most fatal diseases in gynecology. Ziu et al. [172] reported folic acid (FA) modified magnetic iron oxide nanoparticles (IO–FA nanoparticles) for effective magnetic separation and detection of ovarian cancer cells. High separation efficiency ~ 61.3% was obtained even when presence of spiked ovarian cancer SKOV3 cells was as low as 5 × 10−5%. 5 out of 10 metastatic ovarian cancer patients’ whole blood got detected, suggesting their early detection for improving overall survival rate of such patients, as shown in fig. 9.

Figure 9 Efficiency of IO–FA NPs capture of SKOV3 cells [172] 35

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Yang et al. [173] reported polyethyleneimine (PEI) and folic acid (FA) modified magnetic and fluorescent core/shell of Fe3O4@SiO2 (FITC) to deliver Notch-1 shRNA. The multifunctional nano-complex was stable and well-dispersed in aqueous solution; also it displayed negligible cytotoxicity, enhanced cellular uptake on MDA-MB-231 cell lines. Yoo et al. [174] prepared iron oxide nanoparticles modified with poly-ethylenimine (PEI) and folic acid. In vitro cytotoxicity was less in comparison to the pristine magnetic nanoparticles. Majd et al. [175] prepared tamoxifen (TMX) loaded folic acid (FA) conjugated Fe3O4 nanoparticles for targeting human breast cancer MCF-7 cells. Synthesized MNPs exhibited sustained release of TMX (90% release in 72 h).

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Saltan et al. [176] investigated the possible effects of methacrylamido-folic acid (MaFol)-magnetic nanoparticles on 5RP7 (H-ras-transformed rat embryonic fibroblasts) as well as NIH/3T3 (normal mouse embryonic fibroblasts) cells. It was observed that 4.5µg/mL of synthesized NPs caused apoptosis in 5RP7 cells. 5RP7 cells with 90% receptor expression exhibited maximum uptake while NIH/3T3 cells exhibited the minimum. Li et al. [177] developed a facile approach to synthesize multifunctional Fe3O4-PEI-Ac-FI-PEG-FA NPs. The synthesized multifunctional Fe3O4 NPs were water soluble, stable, cyto-compatible and hemocompatible in the given concentration range. High r2 relaxivity of 99.64 mM-1s-1 was observed, making it an efficient nano-probe for MR imaging of cancer cells in vitro and a xeno-grafted tumor model in vivo. Krais et al. [178] reported folic acid-conjugated iron oxide nanoparticles with two different intermediate surface coatings (PEG and Silica). Their bio-compatibility was evaluated on primary human macrophages and ovarian cancer cells. Specific internalization was observed in Fe3O4-SiO2-FA NPs in serum, but not for Fe3O4-PEG-FA nanoparticles.

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Gunduz et al. [179] synthesized idarubicin loaded polyethylene glycol (PEG) and folic acid conjugated Fe3O4 nanoparticles. Their shape, size, crystal and chemical structures, as well as magnetic properties were scrutinized. Uncoated MNPs did not exhibit any toxicity in 0–500 mg/mL on MCF-7 cells, whereas drug-conjugated nanoparticles exhibited considerable toxicity. Sanjai et al. [180] synthesized superparamagnetic iron oxide coated with chitosan and folic acid (SPION-CS-FA) NPs, which exhibited less cytotoxicity at iron concentrations 0.52 mg/L - 4.16 mg/L, and high water stability (pH = 6) at 4°C over long periods. Compared to SPION-0.5-CS NPs, due to presence of folate receptors, SPIONP-0.5-CS-FA NPs exhibited higher as well as specific cellular uptake in human cervical adenocarcinoma cells. In vivo analysis (Wistar 3 rat) revealed that only liver tissue displayed significant decrease in MR image intensity on T2 and T2* weighted images post-injection, as compared to other organs. Socaci et al. [181] established three different synthetic strategies for the synthesis of folic acid di-ester modified core-shell superparamagnetic nanoparticles. Folic acid and chitosan functionalized Fe3O4 nano-capsules were developed, which exhibited excellent magnetic responsive ability, selectivity and controlled release ability for hydrophobic drugs [182]. Vannier et al. [183] have described the interactions of fluorophores, PEG and FA coated 36

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superparamagnetic iron oxide nanoparticles with cancer cells. The synthesized nano-cluster readily entered all the cancer cell lines studied and accumulated in lysosomes, mostly via clathrin dependent endocytosis, irrespective of the FR (Folate receptor) status on the cells. Huang et al. [184] demonstrated efficient drug delivery, anti-tumor therapy and magnetic relaxivity of Doxorubicin loaded Folic acid, PEG and PEI coated superparamagnetic iron oxide nanoparticles. Fard et al. [185], have reported (for the first time) cellular cytotoxicity and release behavior of amine group, silica and folic acid functionalized doxorubicin loaded superparamagnetic iron oxide nanoparticles. Cytotoxicity of DOX loaded nanocomposite was considerably higher than free DOX. Drug release kinetics suggested the preferential release in mild acidic environments. Cellular uptake and tissue penetration of folate-targeted dendrimers on magnetic nanoparticles were measured on cell lines as well as tumor spheroids [186]. Akal et al. [187, 188] evaluated APTES, PEG, folic acid and carboxylated quercetin modified superparamagnetic iron oxide nanoparticles on various cell lines. Targeting effect of folic acid and curcumin loaded Fe3O4 nanoparticles were studied for drug delivery applications [189]. In vitro analyses (MTT assay) on HeLa, HSF 1184, MDA-MB-468 and MDA-MB-231cell lines ascertained the non-toxicity of citric acid-folic acid coated iron oxide nanoparticles, along with high level binding to FAR+ cell lines [190]. A combinatorial approach for attaining better therapeutic effects and minimizing side effects of chemotherapy using doxorubicin loaded folate conjugated multi-polymeric iron oxide nanoparticles was reported by Nehate et al. [191]. It demonstrated combined cytotoxic effect in HeLa and MDA-MB-231 cell lines, on exposing the cells to radio frequency (RF) induced hyperthermia (~43°C). In normal cells (L929), combinatorial therapy showed insignificant effect. Table 3 summarizes Folic acid conjugated nanocomposites explored in biomedical field. Table 3 Folic acid conjugated nanocomposites used in biomedical field

2.

Fe3O4

Coating material Folic acid

EP

1.

Magnetic core material Fe3O4

Silica, folic acid

4.

AC C

S. No

5.

Iron oxide

3.

Iron oxide

Iron oxide

Application/Study performed Physiological stability, and cytotoxicity tests Cytotoxicity tests

Pluronic F127 (Triblock copolymer, PF127), folic acid and poly acrylic acid Silica, folic acid

Magnetic measurements and cytotoxicity

N-isopropylacrylamide (NIPAAM), acrylic acid (AA) and polyethylene

Imaging and hyperthermia treatment

Magnetic behaviour

Reference Zhou et al., 2013 [168] Sun et al., 2010 [47] Lin et al., 2009 [170]

Chen et al., 2010 [46] Rastogi et al., 2011 [38] 37

Fe3O4

Folic acid-PEG

8.

Iron oxide

Folic acid

9.

Fe3O4

Polyethyleneimine (PEI), folic acid, silica

10.

Iron oxide

Poly-ethylenimine (PEI) and folic acid

11.

Fe3O4

12.

Iron oxide

13.

Fe3O4

14.

Iron oxide

Tamoxifen (TMX) loaded folic acid (FA) methacrylamido-folic acid Polyethyleneimine, Folic acid PEG, silica and folic acid

15.

Fe3O4

16.

Iron oxide

Chitosan folic acid

Zhang et al., 2002 [37] Andhariya et al., 2013 [171]

Early detection of ovarian cancer Minimal Cytotoxicity, gene delivery vehicle and MRI contrast agent MRI, gene delivery, and specific uptake by cancer cells Cytotoxicity analysis

Ziu et al., 2016 [172] Yang et al., 2014 [173]

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Target specificity and cell internalization Drug (Doxorubicin) release

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Magnetite

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glycol methacrylate (PEGMA) PEG and folic acid

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Polyethylene glycol (PEG) and folic acid

17.

Magnetite

Folic acid, di-ester

18.

Fe3O4

Folic acid and chitosan

19.

Iron oxide

20.

Iron oxide

Fluorophores, PEG and Folic acid PEG, PEI, folic acid

Targeting efficacy MRI Imaging

Bio-compatibility study and receptor-mediated uptake Concentration-dependent toxicity in drug (idarubicin) loaded nanoparticles Cellular uptake and MR imaging Different strategies for functionalization Magnetic responsive ability, selectivity and controlled release ability for hydrophobic drugs Clathrin dependent endocytosis Drug delivery and anti-

Yoo et al., 2013 [174] Majd et al., 2013 [175] Saltan et al., 2011 [176] Li et al., 2013 [177] Krais et al., 2014 [178] Gunduz et al., 2014 [179]

Sanjai et al., 2016 [180] Socaci et al., 2015 [181] Zhong et al., 2017 [182]

Vannier et al., 2016 [183] Huang et al., 2017 38

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Fe3O4

23.

Iron oxide

APTES, PEG, Folic acid

24.

Fe3O4

Folic acid

25.

Fe3O4

Citric acid, Folic acid

26.

γ-Fe2O3

folic acid, (PLGA-PEGPLGA-urethane-)

Drug delivery Biomedical applications on various cancer cells Drug delivery for cancer

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22.

Amine group, silica and folic acid Dendrosomes, Folic acid

In vitro evaluations on different cell lines Combinatorial therapeutic carrier in cancer therapy

SC

Fe3O4

[184] Fard et al., 2017 [185] Wang et al., 2016 [186] Akal et al., 2016 [188] Huong et al., 2016 [189] Nasiri et al., 2016 [190] Nehate et al., 2017 [191]

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tumor therapy Cellular cytotoxicity

Nanosize, superparamagnetism and biocompatibility of the magnetic nanocomposites make them a potential candidate for biomedical applications. Undoubtedly, this is a burgeoning and promising field, but some challenges need to be overcome for it to become more safe and reliable. 8. Prospects and future challenges

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This concept of using MNPs for biomedical applications is so wide that every little detail at every step needs to be addressed minutely. It is not a simple process rather a complex process with many underlying factors. Anything which has great potential also has great challenges associated with it. Right from the material specifications to its final application, every step requires deep understanding of all the pros and cons. Just qualifying the pre-requisites does not confirm a successful agent for carrying out any medicinal treatment. At the first stage, it is important that the nano-sized, superparamagnetic and bio-compatible MNPs must be stable. Mostly, over a period of time due to aging of nanoparticles, some crucial properties might be lost. Therefore, stability is a very essential factor. The next stage is the coating of the MNPs core. In addition to the aforementioned requirements, the chemistry of the nanoparticles-coating must be carefully monitored in terms of stability, bio-compatibility, retaining superparamagnetism and final intravenous injection. Similarly, after drug-conjugation also, these factors need to be monitored. There are many hurdles to overcome before a delivery system is therapeutically accepted for applying to real patients such as biocompatibility of the system, cytotoxicity at each level of coating, in vivo studies, FDA (Food and drug administration) approval, efficiency, cost effectiveness, patient’s comfort [192, 193]. Before moving to clinical treatments, the drug release kinetics has to be optimum. Delivery of drug at an optimum rate at a specified time at a specified location for a specific duration needs to be attained. Even for 39

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hyperthermia applications, the oscillatory behavior has emerged as a substantial struggle in drug design. Usually, a drug is orally administered into a body or by intravenous injections. In both these cases, there is a limited control over the drug release rate. Generally, the drug gets immediately released. But in case of drug to be released over a period of time, it is required that it be released in time specific manner i.e. initial concentration should be high and gradually it should diminish with time. This is highly required for optimum therapeutic medication in cancers which also depends on the frequency of dose and drug half-life. This is important for reducing the side-effects related to chemotherapy. As we are aware that side-effects of the medication for cancer is equally dreadful as the disease itself. Therefore, a strictly time and dose dependent treatment need to be given. It is required that the carrier must take the drug to the desired site and release it in an optimum manner, means the treatment should begin and stop in time with optimal release rate. Cell type specificity is a challenge that also requires to be addressed. Though encouraging results have been accomplished that demonstrate the effectiveness of magnetic targeting, still many challenges exist in order to effectively transform this technology into clinical treatments. To sum up, following are the challenges which need to be confronted [169, 193, 194] for improved efficacy:

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1. Chemistry of nanoparticle–biomolecule interface as magnetic carriers has to be administered systemically. NPs can enter the central nervous system and cause inflammatory responses in brain. On administration, NPs instantaneously come in contact with blood which is highly ionic heterogeneous matter. This interaction may lead to NP agglomeration, sequestration and non-specific binding leading to premature clearance. Therefore, this needs to be monitored with regards to the cellular barrier such as BBB (Blood Brain Barrier), RWM (Round Window Membrane) and endothelial luminal layer which underlines the blood vessels’ walls. An intracellular barrier hinders the desired actions of NPs resulting in failure of the system, hence this need to be engineered effectively while preparing the core material and surface modifications.

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2. Physicochemical considerations such as hydrodynamic size, morphology, charge, surface properties, shape and hydrophobicity at each stage of preparation and design significantly influence the overall magnetic, clearance from blood circulation, drug kinetics, targeting ability, internalization and cellular uptake of the MNPs complex. Reduced saturation of the core magnetic material during multi-step chemical reaction for functionalization of stabilizers, biological entities and drug conjugation. The surface coatings which are indispensable, being magnetically dead reduce the overall saturation magnetization of the composite as a whole and might also modify their magnetic property. Modification of functional group during drug conjugation might alter the chemical properties. It must also be kept in mind that nature and geometric configuration of surface coating also affect drug release kinetics.

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3. The next considerations, after optimally designing the MNPs complex, which need to be well-scrutinized, are drug loading, transport as well as release mechanisms. First, MNPs must be stable enough to carry the desired concentration of drug payload; this depends on nature of coating and loading procedure. Second, there must be option to accommodate multiple drugs in order to inhibit cellular drug resistance for enhanced efficiency, greater response sensitivity and specificity with multi-responsive potential. Lastly, rate of drug release should be controlled for maximum therapeutic efficiency. Optimum drug dosage needs to be ascertained as lower drug loading efficiency will hinder the whole process and similarly quick drug release might occur even before locating the desired tumor site. Usually, drugs get released in the endosome/lysosomes of the cells. The overall aim of drug targeting is not only to guide the therapeutic drug, but also in retaining it at the desired place. So, efficient tissue penetration of therapeutic drug loaded nano-complex is also an important aspect. For instance, while using magnetite NPs for hyperthermia treatment, the temperature needs to be controlled around 42 °C. In case it exceeds this value, the surrounding healthy tissue will get damaged.

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4. Technological improvements have enabled production of novel and superior MNPs that offer early detection of diseases with enhanced preoperative staging, tailor-made therapeutic systems designed according to the patient’s case, reduced side-effects with ease of fabrication and economically viable drug design. For reaping full advantages of these improvements, it is vital to design and plan all the relevant parameters accurately and systematically. 5. Proper interfacing and well-synchronization with the latest technologies and machines that are used for monitoring purposes need to be done for proper execution of the whole process.

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6. The Grey Goo problem - This problem is related to nanobots/nanorobots which are intelligent nano-sized machines so designed that they can automatically navigate through the blood, detect infection and treat it. If misused this technology can be used for destructive purposes. This is known as Grey Goo and was first introduced by Drexler in his well-known book [193]. Considering this, strict regulations and policies with stringent execution as well as monitoring are required. All these challenges require combined efforts of the researchers worldwide with a focus on novel smart materials. Successful translation of this technology to the clinical applications requires collective and collaborative efforts of researchers from multiple disciplinary backgrounds. Considerable improvements in areas of magnetic carriers as well as targeting magnetic systems are needed for developing magnetic targeting as a successful and practicable clinical treatment. To summarize, we believe that this technology has immense possibility in 41

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clinical applications. More scrutinized animal and clinical studies need to be done for complete realization of these magnetic nanoparticles’ systems. 9. Conclusions

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Magnetic nanoparticles (MNPs) have drawn extensive attention of the researchers worldwide for biomedical applications. The significant advantages of using nanoparticles are higher effective surface area, high stability, high bio-compatibility, injectability, easy surface modifications, and better tissular diffusion. Various combinations of MNPs with polymers, inorganic coatings have been developed for targeted drug delivery and MR imaging applications. The results have been encouraging with better targeting efficiency, early cancer detection, and better contrast in imaging. This has also resulted in reduced side-effects of the conventional drugs.

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The main focus of the researchers is to improve factors such as specificity, response sensitivity, bio-compatibility, imaging while maintaining the superparamagnetic nature of the nanocomposite. For this, iron oxide nanoparticles have been considered to be safe and are the most comprehensively researched material. In addition, ferrites of Ni, Mn, Co, Zn have also been scrutinized because of their high magnetic moment and better chemical stability. But all of them are inherently toxic, which give rise to apprehensions for their safe use in vivo. This led the research to be directed towards inherently non-toxic materials such as ferrites of Ca and K. The results obtained were encouraging to move further towards advanced investigations. For better targeting efficiency and reduced agglomeration, MNPs require surface coatings such as PEG and silica. These play a crucial role for effective bio-conjugation of biological groups/drug, better internalization and improved bio-compatibility. These have proven to render protection against RES, preventing agglomeration, thus elongating the blood circulation. Folic acid (FA) or folate receptors (FR) have been used to increase the targeting efficacy of the nano-complex. Folate receptors are over-expressed on all kinds of cancers. This provides specificity to the drug loaded nano-complex to bind with the tumor surface. Analyses of the cytotoxicity profiles in case of uncoated, coated, drug alone, drug loaded MNPs have exhibited a concentration-dependent behavior. The toxicity increased with the increased concentration and as expected in case of drug alone, more cell death occurred. Various methods, strategic pathways and synthesis techniques have been formulated and tested for improving their performance. It is worthwhile to mention here that the multi-functionality of MNPs is achieved by conjugating multiple agents. This requires deep study of their interactions and surface chemistry. As this concept is so wide and varied, therefore, the quotient of challenges associated also increases. The successful translation of this technology to clinical applications is a long journey, which needs to be scrutinized at every level. Further enhancements are probable for augmenting the catalogue of such materials for an optimum and economic treatment with high efficiency, better response sensitivity, and patient friendly approach, controlled release mechanisms, better blood circulation properties as 42

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well as precise accumulation. The research done so far being very promising and with better and sophisticated techniques, novel breakthroughs can be well-anticipated. Acknowledgement

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Dr. Lavanya Khanna gratefully acknowledges University Grants Commission, Government of India, and New Delhi, India for awarding her Dr. D. S. Kothari Postdoctoral Fellowship to carry out this research work.

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