Insights on magnetic spinel ferrites for targeted drug delivery and hyperthermia applications

Abbreviations

CPT

camptothecin drug

DNA

deoxyribonucleic acid

DOX

doxorubicin

FESEM

field emission scanning electron microscope

MRI

magnetic resonance imaging

MTT

(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay

MWCNT

multi-walled carbon nanotubes

NPs

nanoparticles

RNA

ribonucleic acid

SEM

scanning electron microscope

SAR

specific absorption rate

SF

spinel ferrite

SPM

superparamagnetic

SPMNP

superparamagnetic nanoparticle

TEM

transmission electron microscope

TUNEL

terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling

1 Introduction

Cancer is considered one of the most frightening diseases that globally kill millions of people [1]. The universal encumbrance of cancer via the GLOBOCAN 2018 assessments for the cancer incidence and mortality has been given via the International Agency for Research on Cancer, including a geographic variability in 20 world regions (Figure 1) [2]. It was reported that 18.1 million new cancer cases and the cancer mortality were 9.6 million in 2018. These cases are projected to increase to about 24 million by 2035 [3]. Many of the investigations on drug delivery procedures have been carried out in cancer treatment. This investigation has focused on overcoming the principal holdback on cancer treatment via chemotherapy, or, in other words, the damage of healthy (normal) tissue via therapeutic use. To limit the outcome of this issue (the death of the case or the dismissal of the cancerous tumor), delivery procedures that are of a specific size possessing a suit distribution of anticancer agents and a mechanism to make the therapeutic agents release (that causes the agents to assemble at the tumor sites) should be advanced [4,5]. The utilization of nanoparticles (NPs) has grown from the normal function of drug delivery to multifunctional purposes [6]. These merits are diverse such as labeling transports the drug and gene, pathogens and proteins revelation, probes of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), optical imaging reinforce, design of tissues, biomolecules, and segregation of cells and as a chemotherapeutic agent [3]. Between various types of functional NPs, magnetic spinel ferrite nanoparticles (SFNPs) have a significant focus for their possible utilization such as an opposite to agent enhancer in magnetic resonance imaging (MRI) and an energetic agent in drug delivery [7,8]. SFNPs have several essential biomedical applications [9]. They are used in hyperthermia in cancer therapy, radiosensitizer, drug delivery and release [10,11,12,13], enhancing MRI contrast [14,15,16], and for biomagnetic separation purposes [17]. NPs are of small size, <100 nm, in a minimum of one dimension. As the size diameter decreased to ≤20 nm, the paramagnetic characteristics were lost by SFNPs. In contrast, they were changed to superparamagnetic (SPM) when subjected to an externally applied magnetic field due to thermal effects [18]. The biomedical applications of SFNPs were highly dependent on the synthesis method, shape, size, and types. It is revealed that the ratio of the surface area to volume of NPs was increased as the particle size decreased [19]. Herein, this critical review conducts and evaluates the latest knowledge and exhaustive information about the anticancer activity, hyperthermia, and drug delivery of SFNPs.

Figure 1

Global cancer statistics of prevalence and death worldwide [2,20].

Ferrites can be categorized into three categories, viz., spinel, garnet, and hexa-ferrites, depending upon their crystal structures. In this review, we will focus on spinel ferrite (SF) materials. SFs are marked via the nominal formula RFe₂O₄, where R represents the divalent cations with an ionic radius ranging from 0.6 to 1 Å ; such as copper, magnesium, cobalt, nickel, zinc, etc. elements. The ferric ions (Fe³⁺) can be substituted with different trivalent cations or rare earth elements. The spinel structure is inferred from the mineral magnesium aluminate (MgAl₂O₄), which possesses a cubic structure and every cubic cell comprises eight units, as exhibited in Figure 2 [21]. This crystal structure was initially settled via Bragg and via Nishikawa [22].

Figure 2

Crystallographic representation of magnesium aluminate (MgAl₂O₄). Adapted from ref. [21] with permission from Elsevier™.

Magnetic ferrite NPs have been reported as biomedically significant agents, especially drug delivery vehicles, MRI, and hyperthermia mediators. SFs are favored over other materials due to their broader range of applications, low cost, high sensitivity, where high sensing is required, and selectivity for certain gases. Ferrites find uses in many applications in the areas such as sensors [23], transformer cores [24], chip inductor [25], electromagnetic wave absorber [26], data storage [27], heavy metals removal [28], antibacterial and antibiofilm agents [29], and water remediation [30,31]. Also, ferrites have received huge attention because of their extensive applications, such as power applications [32]. Many continuous efforts are made to control the size, shape, magnetic, and morphological properties of ferrites by different types of synthesis methods.

2 Synthesis methods of SF NPs

The synthesis techniques and conditions exercised through the synthesis route are the prime agents that manage and verify the feature nature for SF NPs [33]. Nanostructured ferrites can be fabricated via several synthesis procedures such as sol–gel [30,34,35,36,37,38,39], co-precipitation [40,41,42,43,44], hydrothermal [45,46,47], thermal decomposition [48,49,50], Polyol [51,52], solvothermal [53,54,55], spray pyrolysis deposition technique [56] and sonochemical techniques [57,58] (see Table 1). The magnetic properties are marked with interdependence on the surface morphology of magnetic NPs and the fabrication processes. These procedures provide excellent control of the crystal’s size, size diffusion, and lattice deficiencies [45].

2.1 Sol–gel method

Metal alkoxide solutions are used as preliminary precursors in the sol–gel fabrication technique, which undergo hydrolysis and condensation polymerization followed by the gel formation stage [59,60]. Besides, more heat strategies are required to exclude any volatile in the obtained gel to get the final crystalline phase [34,61]. The sol–gel technique has some merits such as cost-effectiveness and does not require particular tools; additionally, it can be performed at a moderate temperature. Furthermore, in the sol–gel method, the temperature of the reaction ranges from room temperature up to 199.85°C. This state is suitable to manufacture SF NPs with fine size distribution and manageable form and shape [34,61]. Besides the simplicity in terms of the fabrication methods of SFNPs, these merits make the sol–gel technique so unique [30,34,36,37,38,39]. Furthermore, it is one of the adopted fabrication techniques to manage structure, morphology structure, pureness, and form of SFNPs via altering several factors, such as the sol concentration, the rate of stirring, and cancellation temperature [61,62,63,64].

Abdel Maksoud et al. [30] have used the sol–gel method to synthesize Mn_0.5Zn_0.5−x Mg _x Fe₂O₄ NPs, which were synthesized in the presence of citric acid (C₆H₈O₇) solution that was added as a fuel and ethylene glycol (C₂H₆O₂) drop by drop to produce the final gel composition. The resulting Mn_0.5Zn_0.5−x Mg _x Fe₂O₄ solution was dried at 120°C and then the obtained powders were sintered (899.85°) at 1,173 K, as illustrated in Figure 3. They used Mn_0.5Zn_0.5−x Mg _x Fe₂O₄ NPs as a magnetic recyclable catalyst for outstanding photocatalytic and antimicrobial potentials.

Figure 3

Schematic diagram of the sol–gel method for the synthesis of Mn_0.5Zn_0.5−x Mg _x Fe₂O₄ NPs. Adapted with permission from ref. [30], Copyright, 2020, Elsevier.

2.2 Co-precipitation

Co-precipitation is among the commonly proficient procedures utilized to fabricate NPs with uniform distribution [65,66,67,68]. In this process related to SFNPs, aqueous solutions comprise the mix up of divalent transition cations and ferric (v/v = 1/2) [69,70]. The synthesis technique demands accurate calibration and checks of pH to obtain SFNPs with excellent features. The pH of the solution is generally maintained using NH₄OH solution or NaOH solution [43,71,72]. Then, an energetic stirring of the solution will be used with or without the drying process. Numerous research investigations, which used the co-precipitation approach to fabricate the NPs, have been performed [40,41,42,43,44]. Recently, Gul et al. [73] have reported the fabrication of Al _x ZnFe_2−x O_4, NPs via the co-precipitation technique, where the solutions of the starting chemicals were dissolved in deionized water and stirred at a stoichiometric ratio. The pH of all the solutions was kept at pH = 10 via the dropwise addition of the NH₄OH solution. Then, the solution’s color changed from orange to deep brown with coffee-colored precipitates at the ground of the beaker. The precipitates after being dried are crushed and annealed at 600°C for 8 h, as exhibited in Figure 4. The analysis of magnetic properties assumed that the prepared NPs possess excellent magnetic characteristics. Also, the optical investigations of the NPs showed that these SFs additionally possess photocatalytic applications. The photocatalytic degradation of methylene blue via spinel samples has been discussed. The ferrite particles could be separated from contaminated water easily through a magnetic field. Hence, ferrite NPs can be utilized and recycled easily for photocatalytic applications.

Figure 4

Schematic illustration of the co-precipitation method of Al _x ZnFe_2−x O₄ NPs. Adapted from ref. [73] with permission from Elsevier™.

2.3 Hydrothermal reactions

The hydrothermal technique uses an aqueous solution as a reaction system in a particular closed reaction vessel to produce a high-temperature, high-pressure reaction via heating the reaction system and pressurizing it [47,74]. In this technique, water serves as a reactant that produces a reaction hydrolysis speedup with improved solubility of related materials in the precursor. This procedure gives more significant mobility due to the lower viscosity of water and further leads to an enhancement in the crystal structure, and accelerated the ability of the NP product [47]. The hydrothermal technique is one of the popular suitable fabrication techniques for the large-scale generation of SFs. The SF synthesized has excellent features with restricted size, and excellent size distribution can be gained by choosing the proper mix of solvents and changing parameters such as temperature, pressure, and reaction time [45]. Ding et al. [75] have synthesized cobalt ferrite through an ethanol-assisted hydrothermal technique. The scanning electron microscopic (SEM) images revealed that the samples possessed a narrow size distribution (Figure 5). The water/ethanol volume ratio was chosen as 0, 5/2, 3/4, and 1/6, and the samples were labeled as sample1, sample2, sample3, and sample4, respectively. A constant increase of the ethanol ratio will appear in the particle extension restraint, and the decrease of particle size is ascribed to the surface passivation effect. It was approved via SEM and transmission electron microscopic (TEM) images of sample3 and sample4, where a speedy reduction in the particle size and crash of agglomerates can be established. It is worth remarking that, with increasing ethanol content in the ethanol–water mixed solution, apparent SPM performance of NPs was seen. The adsorption capability of ferrite NPs for Congo Red (CR) was tested. Improvement of adsorption capability for CR was shown by combining ethanol. Also, the adsorption mechanism was discussed. This examination shows that the composition of ethanol/water mixed solution possesses excellent impacts on the microstructure and magnetic properties and adsorption capacity of the CR dye of CoFe₂O₄ samples.

Figure 5

SEM and TEM images and the corresponding particle size distribution obtained from SEM images of samples 1, 2, 3, and 4 represented as (a, e, i), (b, f, j), (c, g, k) and (d, h, l), respectively. Adapted from ref. [75] with permission from Elsevier™.

2.4 Thermal decomposition

The thermal decomposition approach is among the most simplistic routes for fabricating SFs, including the thermal decomposition of organometallic sources, viz., metal acetylacetonate complexes of carbonyls. Besides, there are suitable solvents for organic and surfactants for the fabrication of SFs [61]. The size and form of SFs have been restrained via altering the temperature, the rate of heat, or the metal source concentration, and it is feasible to achieve SFs having extremely mono dispersion, consistent morphology, and close particle size distribution. Yang et al. [76] have synthesized a nonstoichiometric zinc ferrite (Zn _x Fe_3−x dO₄) NPs with Zn substituent content x = 0–0.5 by the thermal decomposition route via utilizing oleic acid as a surfactant. Alterations in the morphology of the as-synthesized samples could be examined from the SEM images. When the content of the zinc source is about 0.004 mol or smaller, octahedral particles are produced. By increasing the content of the zinc source to 0.006 and 0.008 mol, well-faceted polyhedral crystallites are formed. Meanwhile, using 0.01 mol of zinc source leads to nonuniform particles with huge cubes and some smaller ones. oleic acid acts as both a reducing agent and stabilizer in the fabrication method and the source of the zinc/surfactant ratio is essential for the morphology. Besides, an increase of the zinc precursor will give rise to insufficiency in the surfactant, which it is then challenging to stabilize all nuclei to a uniform shape. This reason for the samples appears unestablished and nonuniform. Size-dependent utilization (radar absorption and hyperthermia) was observed more. Both applications required magnetic NPs with magnetization with extraordinary saturation. In hyperthermia, Zn ferrite NPs (26 nm) coated via the P-mPEG polymer revealed higher biocompatibility and heating efficiency, indicating the possible use in in vivo cancer therapy.

Also, Sharifi et al. [77] have studied the effect of the quantity of solvent on the formation of Fe-substituted ZnFe₂O₄ NPs through thermal decomposition. Fe_0.6Zn_0.4Fe₂O₄ NPs have been synthesized via a thermal decomposition technique by utilizing metal acetylacetonate in a high-temperature boiling point solvent and oleic acid. Figure 6 displays FESEM images of the magnetic NPs. As can be noticed, the sample has approximately homogeneous spherical particles besides possessing narrow size distribution. The particle size was reduced from 39 to 14 nm.

Figure 6

FESEM micrograph of Fe-substituted ZnFe₂O₄ NPs with different sizes and three batches including 10 mL (F1), 20 mL (F2,) and 30 mL (F3) of benzyl ether. Adapted from ref. [77] with permission from Elsevier™.

2.5 The polyol method

The polyol approach has been lately considered more in the fabrication of SFs. In this process, diethylene glycol acts as both the solvent and reducing agent, viz., CoFe₂O₄ [78], Co_0.50Zn_0.50Fe₂O₄ [79], etc., were recently published. Gaudisson et al. [80] have fabricated a group of nanostructured and compact spinel CoFe₂O₄ via the polyol method by utilizing three different solvents of polyol category, viz., diethylenglycol, 1,2-dihydroxyethane, and 1,2-propanediol, including different aggregate phases. The obtained CoFe₂O₄ particles display distinct aggregate states. On utilizing diethylenglycol as a solvent, the CoFe₂O₄ particles exhibited uniform size (5 nm), were completely nonaggregated, and were in nearly isotropic form (Figure 7a). In the case of utilizing 1,2-propanediol (Figure 7d) and 1,2-ethanediol (Figure 7g) as solvents, the Co-ferrite comprises 10 and 100 nm clusters, respectively. They exhibit well-marked fringes belonging to the crystallographic planes of Co’s spinel lattice, as indicated by the indexation from the corresponding Fourier transform images. Obvious irreversibility is systematically obtained between the zero-field cooling (ZFC) and field-cooling (FC) susceptibility. The ZFC plots exhibit a distinct peak at a critical temperature defined as the blocking temperature, T _B, and decrease quickly to zero when the temperature drops below T _B, while FC slightly increases. T _B displays the threshold temperature above which the magnetic anisotropy barrier was solely defeated through the thermal activation energy, causing NPs to relax from the ferrimagnetic state to the SPM state. These drifts in ZFC and FC were characteristic of superparamagnetism in single magnetic domains.

Figure 7

TEM images of Co-ferrite obtained with separate polyols: diethylenglycol, 1,2 propanediol, and 1,2 ethanediol (as (a and b), (d and e) and (g and h)). Fourier transform images are presented in every condition ((c), (f), and (i)). Adapted from ref. [80] with permission from Elsevier™.

2.6 Solvothermal

In the solvothermal fabrication approach, aqueous or nonaqueous solvents can be utilized to fabricate NPs with accurate restrictions covering the size distribution, form, and phases of the crystals. These physical features have been adjusted via altering specific test factors, viz., the reaction temperature, contact time, type of the solvent, type of used surfactant, and purity of precursors. Numerous SFs and their related composites have been fabricated by utilizing the solvothermal fabrication approach [10,61]. Aparna et al. [81] have synthesized different SFs with nominal composition MFe₂O₄ (M = Fe, Co, Ni, Mn, Cu, Zn) via the solvothermal method using ethylene glycol as a solvent and polyethylene glycol (PEG) 600 as a co-solvent. The prepared SFs exhibit approximately spherical morphology. The average particle sizes of Fe₃O₄ (36.1 nm), CoFe₂O₄ (51.3 nm), NiFe₂O₄ (41.9 nm), MnFe₂O₄ (37.6 nm), CuFe₂O₄ (135.1 nm), and ZnFe₂O₄ (81.1 nm) are illustrated in Figure 8. The cluster configuration had larger particles produced via the accumulation of tinier particles. The results showed that the change in the solvent during the synthesis generates particles with varying morphologies, and supercapacitive performances were observed. The specific capacitances of Fe₃O₄, CoFe₂O₄, NiFe₂O₄, MnFe₂O₄, CuFe₂O₄, and ZnFe₂O₄ were estimated to be 101, 444.8, 109.26, 190, 250, and 138.95 F/g, respectively. The highest specific capacitance is observed for CoFe₂O₄ as compared to other metal ferrites. The capacitive behavior of CoFe₂O₄ was also found to vary with morphology.

Figure 8

FESEM images of (a) magnetite, (b) CoFe₂O₄, (c) NiFe₂O₄, (d) MnFe₂O₄, (e) CuFe₂O₄, and (f) ZnFe₂O₄. Adapted from ref. [81] with permission from Elsevier™.

2.7 Sonochemical technique

Through ultrasonic radiation, bubbles are generated in the solvent medium and can efficiently compile the diffuse energy of ultrasound; upon breakdown, extraordinary heating energy was discharged to the bubble’s heating treatment [82,83]. This produces a vacating localized hot spot with sufficient temperature inside the bubbles of around 5 × 10³ K and 10³ bar, respectively. These dominant conditions give rise to various chemical reactions, which are almost always not attainable [84]. Recently, Almessiere et al. [85] have investigated the effect of substitution of terbium ions on the microstructure, dielectric, and microwave properties of Ni–Cu–Zn ferrite synthesized via the sonochemical technique. The terbium-doped Ni–Cu–ZnFe₂O₄ possesses an average particle size of 21 nm. The distribution is close, which suggests a tight particle size ranging between 5 and 40 nm. The sample with the Tb content (x = 0.06) is in contrast to other samples in the appearance of bimodal size distribution performance, which is seen in Figure 9a–f. The average particle size of the Ni_0.4Cu_0.2Zn_0.4Fe_1.94Tb_0.06O₄ sample reached 57 nm. The substitution ratio revealed a substantial impact on the dielectric characteristics, while the Tb ion replacement had a small but distinguished effect on the AC/DC conductivity variation. The reflection losses as a function of frequency dependences were calculated from S-parameter data in the range of 1–4.5 GHz. The electromagnetic absorption in the frequency interval of 1.85–3.79 GHz was observed. The nonlinear performance of the amplitude-frequency characteristics was changed with Tb ions. It was observed that the microstructural parameters correlate well with the principal absorption characteristics. The decrease of the reflected electromagnetic radiation was explained along with domain-boundary resonance, which well correlates with the microstructure data. The low-dimensional magnetic oxides possessing the domain-boundary resonance have a role in the nature of absorption.

Figure 9

Particle size distribution of the Tb-doped Ni–Cu–Zn/Fe₂O₄ (x ≤ 0.1). Adapted from ref. [85] with permission from Elsevier™.

2.8 Synthesis of ferrite thin films

The significant problems the researchers face are fabricating ferrite films utilizing easy technology with low-temperature heat treatment and low vacuum. The ferrite films have been fabricated earlier using various methods, viz., RF sputtering, plasma laser deposition, etc. These methods regularly include elaborate and costly apparatus and complicated processes. Besides, the high deposition temperature limits the option of the substrate material as well as restricts various applications of ferrite thin films [56]. It should be remarked that agglomeration could be solved utilizing the synthesis techniques in which the formation and separation of particles occur. These techniques involve spray pyrolysis techniques in which liquid solutions of reagents were sprayed, and the drops of the solution were supplied to a heated reactor or flame. Heat treatment causes the evaporation of the solvent and the formation of a solid phase in the structure of nanocrystalline particles in the absence of aggregation [86]. Pratibha Rao et al. have deposited (Co, Cu, Ni, Zn) ferrite thin films onto the Si (100) and alumina substrates via the spray pyrolysis deposition technique. SEM images of CoFe₂O₄ and ZnFe₂O₄ thin films deposited on Si (100) show spherical morphology. The Ni-ferrite thin film reveals a petal-like structure while CuFe₂O₄ has a cubic morphology with spherical particles inserted in it (Figure 10) [56].

Figure 10

SEM images of spray deposited and air-annealed (Co, Cu, Ni, Zn) ferrite thin films. Adapted from ref. [56].

3 Structure and properties of SFs

3.1 Structure of SFs

The SF MFe₂O₄ possesses a cubic unit cell and comprises eight cubic cells involving 56 ions. These ions were distributed as follows: 32 oxygen (O²⁻) anions, 8 M²⁺ cations, and 16 ferric cations. The oxygen ions possess a large radius and settled an almost packed face-centered cubic structure amidst more petite metal cations filling the subsites states belonging to space group Fd3m [87]. As two separate valence cations are possible, two classes of crystallographic sites are in the spinel structure, namely, A sites enclosed via four oxygen ions (tetrahedral) and B sites circled by six oxygen ions (octahedral) [88,89]. Maksoud et al. [90] have investigated the influence of zinc ion substitution on cobalt ferrite NPs prepared using a sol–gel technique. The Rietveld refinements at room temperature for XRD patterns of Co_1−x Zn _x Fe₂O₄ NPs are illustrated in Figure 11. The detected reflection peaks correspond to the characteristic Fd3m space group SFs (JCPDS card no. 74-2082) [91,92]. All detected peaks are allowed Bragg 2 θ positions according to the space group Fd3m and are noticeable as vertical lines. The obtained data revealed successful synthesis of the cubic structure Co_1−x Zn _x Fe₂O₄ without any secondary phases [93,94].

Figure 11

Rietveld refined XRD patterns of Co_1−x Zn _x Fe₂O₄ representing the Zn content (x). Adapted from ref. [90] with permission from Elsevier™.

Generally, there are two vibrational bands characteristic for SFs, namely υ₁ and υ₂ originating from the stretching vibration of A-site groups (tetrahedral) and B-site groups (octahedral), respectively [95]. Massoudi et al. [96] have prepared Ni_0.6Zn_0.4Fe_1.5Al_0.5O₄ via the sol–gel technique following the annealing process at different temperatures. The Fourier transform infrared spectroscopy spectrum of Ni_0.6Zn_0.4Fe_1.5Al_0.5O₄ was acquired at room temperature in the range from 400 to 4,000 cm⁻¹. According to Waldron, the prominent peaks at 557–581 cm⁻¹ and 403–410 cm⁻¹ are ascribed to the cation-anion bond stretching vibration in A and B sites, respectively (Figure 12a–b). Consequently, the appearance of these two bands υ₁ and υ₂ confirmed the formation of the Ni_0.6Zn_0.4Fe_1.5Al_0.5O₄ SF structure.

Figure 12

FTIR spectra of Ni_0.6Zn_0.4Fe_1.5Al_0.5O₄ at different annealing temperatures. Adapted from ref. [96] with permission from Elsevier™.

Mössbauer spectroscopy is exceptionally sensitive to tiny alterations in electron density at Fe’s nucleus, ascribed to diverse electronic and structural situations. Isomer shift occurs due to the electrostatic interaction within the distribution of nuclear charge and S-electron density, leading to shifting the levels of nuclear energy. The isomer shift relies on the overall nuclear charge and the nuclear radius. Besides, it depends on the densities of the S-electron for both absorber and source. The isomer shift has been utilized to estimate the valence state of iron atoms. The isomer shift values are in the range of 0.1–0.5 mm/s for ferric ions and exceed 0.5 mm/s in the case of ferrous ions [97]. Poudel et al. [98] have studied the Mössbauer spectra of gadolinium-substituted nickel ferrite NiGd _x Fe_2−x O₄. The absorption results from Fe³⁺ (A Site) adapted a single hyperfine pattern. Hence, the substitution of the Fe³⁺ ion with a Gd³⁺ at the B site was not a considerable sufficient change in the whole superexchange interaction to initiate a remarkable diversity in the hyperfine field at the A site. Besides, every iron ion at the B site possessed only six A-site nearest neighbors. Therefore, for each change in the Fe³⁺ ion at the tetrahedral site via a significant ratio, an altering in the superexchange interaction is observed (Figure 13).

Figure 13

Room temperature fitted Mössbauer spectra of NiGd _x Fe_2−x O₄. Adapted from ref. [98] with permission from Elsevier™.

Also, the energy-dispersive X-ray spectroscopy mapping and scanning electron microscopy (SEM) are conducted to affirm the homogeneous distribution of spinel and their elemental mapping photographs. As presented in Figure 14, the homogeneous distribution and elemental mapping photographs of Zn, Cu, and Mn substituted CoFe₂O₄ are introduced [35].

Figure 14

Elemental mapping images of (a) CoFe₂O₄, (b) Zn–Co/Fe₂O₄, (c) Cu–CoFe₂O₄, and (d) Mn–Co/Fe₂O₄. Adapted from ref. [35] with permission from Elsevier™.

3.2 Magnetic properties of SFNPs

Magnetic NPs have exceptional magnetic and structural features in these materials and hence have wide utilization in many applications like MRI, high-density magnetic recording media, magnetically guided drug delivery, and hyperthermia [9]. Moreover, when an SF with magnetic features is exposed to a magnetic field, its magnetization (M) progresses immediately, as shown in Figure 15 [99]. As the magnetic field (H) magnitude improves, the magnetization approaches its highest value, denoted saturation magnetization (M _s). When the magnetic field is canceled, the magnetization variations exhibit distinctive performance, in which low magnetization has remained in the SF, denoted residual magnetization (M _r). By reducing the magnetic field intensity to negative states, the affected magnetization in SF continuously declines until the field intensity approaches a negative value. The material magnetization fully diminished, which is termed coercivity (H _c) [100].

Figure 15

M-H plot of SF. Adapted from ref. [99] with permission from Elsevier™.

4 SFNPs for anticancer applications

Hyperthermia treatment for different types of cancer depends on the increase of the heat from 42 to 46°C in cancer cells by SFNPs [101,102]. It is classified into the whole body, regional, and local hyperthermia upon the position of cancer cells [103,104]. Hyperthermia is considered a targeted differential therapy because cancer cells are more sensitive than normal cells to hyperthermic effects [105]. The supermagnetic SFNPs absorb energy by the alternated external magnetic field and release it as heat by magnetic relaxation mechanism or hysteresis [11]. Hyperthermia therapy is a form of medical treatment that involves raising the temperature of tissues to kill cancer cells or become dysfunctional [106]. Localized temperature increase allows the therapy to be limited to the diseased regions, which is very significant in anticancer therapies. Conventional cancer treatments are frequently linked to the harm they cause to healthy tissues and can result in long-term adverse effects. As a result, one of the primary advances in magnetic hyperthermia treatment is local cell heating. These promising techniques arise from a combination of magnetic oxides with an external oscillating magnetic field, and commonly SF has been used. The unique physiochemical characteristics of SF like low toxicity and high biocompatibility candidate them to various biomedical applications including drug delivery and magnetic hyperthermia treatment [9]. The significant advantages of SFNPs are their high surface-area-to-volume ratios, which make attaching a large number of therapeutic molecules simple, and their magnetic characteristics, which aid in MRI imaging of drug delivery.

The hyperthermia method to treat cancer tumors involved the injection of SF directly into cancer tumors with alternating magnetic fields (AMFs) to produce effective heat. The conditions should be achieved such as (1) the SF particles concentration in the tumor should be higher than that in normal tissues and (2) the SF particles should have a high specific absorption rate (SAR)

where T is the temperature increase during the time interval (t) to give substantial intratumoral doses of heat using AMFs well-tolerated by normal tissues, and c is the specific heat capacity. The SAR is maximized by four parameters to optimize heating in an AMF: (1) dielectric losses in SF has low electrical conductivity; (2) eddy current losses in SF has high electrical conductivity; (3) frictional heating is from the physical rotation of an anisotropic SF particle; and (4) hysteresis losses in an SF. Cancer cells were damaged by the generated heat, based on external field amplitude square, frequency, size, and type of SFNPs [107,108]. The SFNPs of less than 20 nm were releasing heat by Neel relaxation mechanism while Brown relaxation mechanism in case of large NPs size. The frequency and amplitude of the applied external magnetic field would be > 0 . 5 × 10¹⁰ A/ms [109], and NP sizes range from 10 to 100 nm for safe hyperthermia cancer therapy [110].

Figure 16 shows the SAR dependence on smaller NP size, whose size closer to the single domain is desirable for high SAR than the multidomain [111]. If bulk particles have multiple domains, it is limited to be used in magnetic hyperthermia treatment due to magnetization reversal taking place by the magnetic moments flipping in domains where it is antiparallel to the AMF. It also occurs by domain growth in other domains, which occurs at lower fields. If the applied magnetic fields can fully saturate the magnetization, then the energy losses in multidomain materials depend on coercivity. Jordan et al. [112] investigated at all applied magnetic fields (up to 165 Oe (13.2 kA/m) and found that the power loss in single-domain SFNPs was substantially larger than that in multidomain SFNPs. Thus, for fully saturated magnetic materials, the power loss should decrease with an increase in the domain size. As a result, to minimize the power loss, multidomain particles should be avoided.

Figure 16

The dependence of SAR on the NP size. The domain magnetic structure of the SF particle would fall into the SPM region (dis-alignment) if their diameter size is smaller than the critical size r _o; in contrast, if the size of the SF particle is bigger than r _o, the SPM states transform to a single domain (full alignment); and if the size increases to twice the critical size r _o, the magnetic structure of SF transforms to the multidomain region. As a result, particles in the r _o − 2r _o size range are predicted to be used in hyperthermia cancer therapy.

It was also highlighted that SF has the potential to be outstanding contrast agents with respect to MRI image quality contrast, sensitivity, and specificity, as well as potential drug-loaded nanocarrier targets. SF exhibits magnetic anisotropy, which is influenced by the anisotropy of the cations, the symmetry of the interstitial sites, as well as the metal type content and cationic arrangement; some toxic cations such as Sr, La, Y, Mn, Ag, or Al should be avoided. Within the close-packed arrangement of 32 oxygen ions, most SFs contain a cubic unit cell belonging to the Fd3m space group, in which 24 metal ions are arranged in 8 tetrahedral and 16 octahedral positions. The substituted cations such as Ni, Cu, Co, Mn, Mg, and Zn cause O₂ displacement due to the substitution of cations at the tetrahedral sites and have to be expanded. On the other hand, the decrease in the lattice constant in SF systems can be explained by several factors: (1) the doping cation has a smaller ionic radius than the excited cation; (2) a potential rearrangement of Fe²⁺ and Fe³⁺ ions takes place inside the tetrahedral/octahedral ionic sites, leading to significant changes in magnetic characteristics; (3) Fe³⁺ is forced to the tetrahedral sites by a proportion of Fe²⁺ ions occupying the octahedral sites against their structural preferences that affect the optical, electrical, and magnetic properties of SFs [113]. In general, the magnetic behavior of SFs is highly dependent on the cation distribution between tetrahedral and octahedral sites [114]. Because the octahedral site and tetrahedral site spins align antiparallel, one can increase the magnetization in SFs by substituting cations for ferrous and ferric ions. For example, the substitution of Zn²⁺ by Fe²⁺ cations in the tetrahedral site gives ZnFe₂O₄, which exhibits magnetic behavior than Fe₃O₄ along with high magnetic saturation due to Zn²⁺ and Fe³⁺ cations occupying tetrahedral and octahedral sites, respectively. In general, smaller positive ions prefer to occupy the lower coordination site, i.e., the tetrahedral site, due to their relative sizes. The larger positive ions tend to occupy higher-coordination sites, such as octahedral sites [115]. As the Zn fraction increases in the tetrahedral site, the magnetization increases. This approach of cation substitution must be carefully chosen to maximize magnetization in SFs [116].

Furthermore, cationic interactions, surface anisotropy, and shape anisotropy all contribute to increasing total magnetic anisotropy in a single-domain structure [117]. An increase in temperature to about 42°C causes an increase in the tumor blood flow, which may be advantageous for simultaneous administration of chemotherapeutic drugs. This suggests that there is a temperature range in which cancer cells may be killed with little damage on normal cells, which is a key issue when utilizing hyperthermia for treating cancer and increases their anti-tumor effectiveness by loaded drugs. The development of SF has increased the interest of the scientific community in magnetic hyperthermia studies during the last years. Zhang et al. optimized the Curie temperature of 45.7°C and coercivity magnetization of 174 Oe for Cr³⁺-substituted Co–Zn/Fe₂O₄ (Zn_0.54Co_0.46Cr_0.6Fe_1.4O₄) for use in magnetic hyperthermia [118]. Hanini et al. prepared cubic SF of Zn_0.9Fe_0.1Fe₂O₄ that exhibited a Curie temperature of 92.8^oC under an applied magnetic field of 50 kOe. When Zn_0.9Fe_0.1Fe₂O₄ was incubated with glioma cells (U87-MGs) for 4 h at a low dose (0.05 g/L), they exhibit a significant increase of temperature (41.5°C) in a few seconds that is enough to kill malignant cells [101].

Lee et al. [119] loaded doxorubicin (DOX) as an anticancer drug into mesoporous silica-coated magnetite nanocrystals, and their surface was modified with PEG and fluorescence. Both MIR and fluorescence imaging verified in vivo passive targeting and accumulation of NPs at tumor sites. The DOX drug was successfully delivered to the tumor region in mice (the DOX accumulation compared with a control group was analyzed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay).

Remarkably, utilizing a hybrid design of a carbon covering of SF for cancer therapy appears to be highly promising. Carbon can solve and limit the main problems resulting in biomedical uses such as the possible toxicological consequences of long-term exposure, as well as low loading capacities and poor dispersibility under physiological conditions. It is known that carbon ions increase the biocompatibility of different biomaterials used and it reduces the immunohistochemical results in the body [120,121]. Gorgizadeh et al. [122] fabricated an SF coated by the carbon ion (NiFe₂O₄/C) nanocomposite and used it successfully as an effective agent for photoabsorbing in the photothermal therapy toward the melanoma cancer mouse model of C540 (B16/F10) cell line. Because of the excellent thermal conductivities of the carbon coating as well as electrical conductivities, the efficiency of the (NiFe₂O₄/C) nanocomposite conversion of light to heat is high. Furthermore, the hybrid design of the (NiFe₂O₄/C) nanocomposite assisted in the creation of a more targeted and definite treatment procedure, resulting in fewer side effects and lower toxicity in normal tissues.

As mentioned above, ZnFe₂O₄ and CoFe₂O₄ NPs have been widely studied for electronic applications owing to their self-interaction characteristics and their ability to respond to an external magnetic field. Combining both SF (ZnFe₂O₄ and CoFe₂O₄) components through the uniform distribution of MWCNTs show high adsorption of reactive pharmaceutical and biological species because of their large surface areas, leading to their high adsorption to the promoted adsorption of SF/MWCNT nanocomposites on the surface of the target cell.

Furthermore, rather than employing a carbon coating, as can be seen, a number of publications have shown success with alternative coatings, such as hydrogel (chitosan (CS), polyethylene, and phospholipids), which indicates a high efficiency for SF tumor cell adherence [123].

Zhang and Song developed injectable and biodegradable SF-based dual thermo- and magnetic-sensitive poly(organophosphazene) hydrogels for multiple magnetic hyperthermia therapy and MRI contrast [124]. This system is intended to serve as a multipurpose theranostics system due to the following: (1) because of the fast sol–gel transition of the hydrogel after a single injection, SF is retained within the tumor for a long time; (2) a minimally invasive multiple magnetic hyperthermia treatment at a reasonable temperature significantly improves anti-cancer therapeutic results; and (3) acting as a simultaneous long-term MRI contrast to guide and monitor the treatment procedure. Combining the hydrogel with SF loaded by drugs has several advantages, including preventing aggregation, enabling secondary drug functionalization, and providing carrier protection from the body’s immune system, all of which increase circulation duration. Bisht et al. [125] synthesized SF nanocomposites poly(N-isopropyl acrylamide)-ferrite via supercritical CO₂-assisted synthesis. Drug loading and release profiles of 10 mL DOX drug were studied by varying the pH of the nanocarrier. The polymer nanocomposites exhibited enhanced drug release activity (20.98–76.54% release efficiency) and better biocompatibility in breast cancer cells (cell viability of 81–93%) as compared to spinal ferrite NPs.

Furthermore, the hydrogel-coated SF has functioned well in both covalent and noncovalent drug-loading processes, allowing access to a variety of drug release mechanisms such as external stimuli control or physiological condition-based adjustment within cancer areas. It selectively targets cancer cells and receptor engagement resulting in particle endocytosis; Figure 17 shows the coated spinal ferrite with polymer and active targeting groups.

Figure 17

The SF coating with a polymer, the control of SF particle size, shape, biocompatibility, dispersion, and quality. Because of the unique multifunctional characteristics resulting from the wide diversity of functional groups within the polymer structure, it is likely to improve the hyperthermia therapy of SF. This coating layer can also protect SF surfaces against proteins, cell adsorption, and tissue penetration, extending particle circulation duration for in vivo hyperthermia applications.

The physicochemical properties of spinal ferrite are very sensitive to the change in their crystal form and particle size. Almost cubic SF crystal structures exhibit inherent characteristics such as ferromagnetic, antibacterial, and photodegradation activities than sphere-like SF [126]. Complex surface/interface interactions and the crystallite size effects resulting from the breaking of the symmetry of exchange bonds at the particle surface’s boundary are also crucial for determining the magnetic behavior via the formation of spin canting at the particle surface, affecting their different magnetic performances. According to the literature, it seems that the cubic SF crystal structure has only been examined for biomedical applications. The obtained results are extremely impressive, showing great potential in some fields like hyperthermia, drug delivery, and MRI applications. For example, Wang et al. [127] designed hybrid nanocubes of Fe₃O₄@MoS₂ that had a superior SPM with a high surface area of 97.16 m²/g, without aggregation results or the restacking of MoS₂ layers. It also demonstrated great magnetic sensitivity and good solution dispersibility, making it suitable for a variety of biological applications; on the hybrid design, to improve blood circulation time and medication accumulation at cancer locations, as well as to make drug loading easier. Xie et al. [128] designed and modified nanocubes of Fe₃O₄@MoS₂ using PEG and 2-deoxy-d-glucose (2-DG) for targeted chemo-photothermal therapy. The obtained Fe₃O₄@MoS₂/PEG/2-DG exhibited a great chemo-photothermal effect with a relaxivity coefficient of T ₂ = 48.86/mM s and fast MRI signal detection of tumor sites with high contrast after injection.

The synthesis method can contribute to achieving the desirable properties for targeted drug delivery and hyperthermia applications. Recently, Almessiere et al. [129] have used two different techniques, citrate sol–gel combustion and sonochemical techniques, to synthesize Dy- and Y-codoped MnZn NPs. The principal aim is to compare the synthesis techniques and examine their biological applications by investigating antibacterial and anticancer activities. The different yttrium (Y) and dysprosium (Dy) ions doped Mn-Zn/Fe₂O₄ showed different magnetic behaviors attributable to the difference between the crystallite sizes of the prepared samples via the two synthesis methods. The prepared SF with a size less than 50 nm exhibited a broad SPM nature. The XRD results revealed that the synthesized samples via the sol–gel technique have a crystallite size of less than 40 nm, whereas the synthesized samples using the sonochemical method showed a crystallite size of less than 10 nm. Also, the magnetic properties at T = 10 K revealed closed hysteresis loops have nonneglected coercivity values ranging between 360 and 610 Oe for synthesized samples via the sol–gel method and from 320 to 695 Oe for the synthesized samples via ultrasonic synthesis. Further, the remanence ranged between 3.2 and 10.5 emu/g for the synthesized samples using the sol–gel method, whereas the remanence ranged between 16.2 and 26.6 emu/g in the ultrasonication route. The SEM images unveiled clusters of small cubic NPs for the samples prepared through the sol–gel method and fine spherical NPs for the samples prepared via the ultrasonication method. Besides, the DyY-MnZn NPs prepared via the ultrasonication method produced better inhibitory action on the cancerous cells as compared to those produced via the sol–gel method. The morphology of cancer cells was investigated by confocal scanning microscopy, and results showed that with the treatment of DyY-MnZn, there was an evident loss of cancer cells prepared via the ultrasonication and sol–gel methods as DAPI staining was detected to be notably reduced in the cancer cells.

Hassanzadeh-Tabrizi et al. [130] produced a cobalt ferrite/hydroxyapatite (HA) nanocomposite using a novel multistep depositional technique for the design of a homogeneous core–shell blend. Controlled drug release trials revealed that the prepared nanocomposite is capable of loading of drug and controlled drug delivery up to 50 h. Furthermore, the quantity of heat produced may be controlled using varying magnetic fields or cobalt ferrite to HA ratios, making it potential for a variety of magnetic-based hyperthermia treatments. The incorporation of hydroxyapatite on the surface of cobalt ferrite NPs greatly promotes cell compatibility while reducing magnetization saturation. The findings show that a multifunctional nanocomposite of cobalt ferrite/HA with a homogeneous structure could be useful in medical applications. Figure 18 shows SEM images. The particle size of the cobalt ferrite generated ranged between 50 and 500 nm, with random and octahedron-like morphologies. After immersing the particles in KH₂PO₄ solution, their surface shape entirely changes. On the surfaces of the particles, spherical and needle-shaped HA precipitates developed. According to Wijesinghe et al. [131], HA crystals can have a variety of morphologies depending on the process and conditions of synthesis. They found that adding 10% HA to cobalt ferrite lowers the specific surface area. The surface area of the samples was significantly enhanced when a higher amount of HA was added to the samples compared to pure HA. The surface areas of CoFe-30HA and CoFe-50HA samples were found to be quite large. As a result, these specimens were chosen to receive the ibuprofen (IBU) medication. The release of IBU from NPs was considerable in the early stages but it progressively reduced over 72 h. The extremely early release may be due to IBU dissolving rapidly on the surface of NPs. The gradual release was induced by the physical and chemical interactions between the NP surface and IBU, which led IBU to be released from the samples’ mesoporous structure. The initial release rate in this work is lower than several previously produced substances. Ansari et al. [132] studied the quick release of IBU from Cu_0.3Zn_0.2Mg_0.5Fe₂O₄ in the early hours (65%). Furthermore, the loading capacity in their study was just about 10%. The type of the material surface and its mesoporous structure are two elements that contribute to the variances in the release rate and loading capacity. Static and hydrogen interactions bind IBU molecules and NPs together. As a result, the surface of the produced NPs in the Hassanzadeh-Tabrizi et al. study [130], which comprises hydrogen groups and Ca²⁺ ions, can form active sites on the NPs’ surfaces, making it more effective to connect with IBU’s carboxylic acid groups. Wu et al. [133] demonstrated that Ca²⁺ ions might interact with the carboxylic groups of IBU molecules due to their alkalinity. Alkaline earth metals could produce basic sites, according to Khamsehashari et al. [134], leading to improved bonding with IBU’s carboxylic groups. As a consequence of the effective factors for linking IBU molecules and cobalt ferrite/HA, more bonds are created, enabling the drug molecules to bind to samples with greater loading capacity and disperse from the material at a slower pace. When comparing the two samples, it can be observed that the CoFe-50HA sample exhibited a greater drug release. Because materials with bigger pores and higher pore volumes may contain more drug molecules, drug molecules trapped in these pores can naturally be released at a quicker pace. The retention of magnetic properties and the acquisition of optimum magnetization values are critical in drug release applications. The ferromagnetic behavior of the manufactured samples may be seen in their hysteresis loops (Figure 19). CoFe₂O₄, CoFe-10HA, CoFe-30HA, and CoFe-50HA have saturation magnetization values of around 59.9, 43.4, 18.3, and 11.4 emu/g, respectively. Thus, it can be observed that as HA increased, the saturation magnetization decreased. The CoFe-30HA composite exhibits a greater heating efficiency than samples with larger HA contents, particularly in high field zone, according to magnetic hyperthermia experiments. The magnetic characteristics of ferrites are affected by a variety of parameters, including particle size, shape, composition, defects, ion distributions, and even the synthesis method. For example, increasing the calcination temperature resulted in larger particles, which led to greater saturation magnetization [135]. Because the size of CoFe₂O₄ particles and the parameters of synthesis were kept fixed throughout the investigation, these variables had no significant impact on the magnetic properties. A decrease in the saturation magnetization of HA-coated Co ferrite NPs could be linked to the spacing of nearby NPs by a diamagnetic coating of HA, resulting in a reduction in the static interaction among them. Based on prior investigations, it was stated that a 10–30 emu/g magnetization is adequate for therapeutic purposes [136]. Furthermore, when the amplitude of the field increases, the temperature increases. By regulating the time and applied AC field, the heating response of samples can be improved.

Figure 18

SEM images of cobalt ferrite NPs: (a) pure, (b) 50Ca, (c) 10HA, (d) 30HA, (e) 50HA, and (f) HA. Adapted from ref. [130] with permission from Elsevier™.

Figure 19

CoFe, CoFe-10, 30, and 50HA samples hysteresis curve. Adapted from ref. [130] with permission from Elsevier™.

Sangeetha et al. [137] developed an intelligent drug delivery system and/or a hyperthermia carrier by creating a potential magnetic nanocomposite of CoFe₂O₄/HA and loaded a chemotherapy medicine (5-fluorouracil, FU). To achieve it, a microwave-aided wet precipitation approach was used to successfully synthesize a cobalt ferrite/hydroxyapatite nanocomposite, which was then loaded with FU using an adsorption method. With 2.5–8.2 emu/g magnetic saturation, this nanocomposite exhibits ferromagnetic behavior. Using an AMF, they were able to produce hyperthermia in a short amount of time (43°C in 4.5 min) and accelerate the release of encapsulated FU from the composite. These multifunctional carriers show significant proliferative activity against healthy fibroblast cells (L929) and impede the growth of osteosarcoma cells (MG63). As a result, this multifunctional nanoplatform could be a good option for synergistic chemo-hyperthermia therapy, allowing cancer patients to receive chemotherapy and hyperthermia at the same time. TEM analysis showed the core–shell structure of the composites in the calcined sample, and PEG addition enhanced the pore radius and specific surface area of the composites. The saturation magnetization of the composites calcined at 1,100°C was 8.075 emu/g. The produced composites could release FU for 7 days at physiological temperature and could be accelerated at hyperthermia temperature, increasing the proportion of FU released. According to the findings of this study [139], this thermo-responsive nanovehicle offers possibilities as a delivery mechanism for tumor-specific treatment at hyperthermic temperatures.

Talaei et al. [138] produced a magnetic mesoporous CuFe₂O₄@SiO₂ nanocomposite with a core–shell nanostructure by sol–gel combustion and examined it for simultaneous drug release and hyperthermia biomedical applications. Around copper ferrite, TEM images revealed the formation of thin mesoporous silica covering with a thickness of 14 nm (Figure 20). After surface modification of ferrite NPs with mesoporous SiO₂ layer, the surface area of the samples increased from 2.59 to 199.2 m²/g. When compared to pure ferrites, the magnetic characteristics of core–shell samples were reduced. The drug IBU was used to test NPs’ ability to store and release the medicine. IBU loading was high and the drug release was regulated in the CuFe₂O₄@SiO₂ system. Following the synthesis of a hybrid core–shell structure, the samples’ storage capacity increased from 4 to 34%. The nanocomposite’s mesoporous structure and increased surface area resulted in these enhancements. The rate of drug release was reduced when the calcination temperature increased but the release mechanism was unaffected. The cytotoxicity of CuFe₂O₄ NPs was lowered and the drug release characteristics were improved by coating them with mesoporous silica. This coating, however, limited the potential to generate hyperthermia. Although the capacity to heat the samples was reduced when CuFe₂O₄@SiO₂ was synthesized, it increased biocompatibility and drug storage. The results suggested CuFe₂O₄@SiO₂ be a promising option for medicinal applications as a hybrid system that can release medications and create heat at the same time.

Figure 20

TEM image of the CuFe₂O₄@SiO₂ nanocomposite at 400°C. Adapted from ref. [138] with permission from Elsevier™.

Radmansouri et al. [139] combined titanium oxide NPs with cobalt ferrite NPs via microwave heating, which was subsequently electrospun into CS/cobalt ferrite/titanium oxide composite nanofibers. They tested the impact of DOX hydrochloride-loaded electrospun CS/CoFe₂O₄/TiO₂ nanofibers on melanoma cancer B16F10 cell lines to check whether heat and therapy could be combined. Cobalt ferrite NPs were made via microwave heating. Titanium oxide NPs were mixed with cobalt ferrite to control the temperature increase. The DOX loading efficiency and in vitro drug release of DOX from nanofibers were investigated using an AMF and without a magnetic field under physiological and acidic conditions. As seen in SEM images, the surface of nanofibers was smooth, and no drug crystals were visible on the nanofibers’ surface (Figure 21). As a consequence, DOX molecules were well incorporated into electrospun fibers. The fastest release of DOX from the synthesized magnetic nanofibers was observed at acidic pH by changing the magnetic field. The anticancer effects of the nanofibers generated were also tested on the melanoma cancer B16F10 cell lines. According to the results, DOX-loaded electrospun CS/cobalt ferrite/titanium oxide nanofibers may be used for localized cancer treatment. According to in vitro cell incubation tests, simultaneous loading of DOX and cobalt ferrite/titanium oxide NPs into CS nanofibers following the application of a magnetic field enhanced the cytotoxicity of the nanofibers. The generated cobalt ferrite and cobalt ferrite/titanium oxide NPs had maximum saturation magnetization (M _s) values of 90.5 and 81.2 emu/g, respectively. The reduction in M _s of cobalt ferrite/titanium oxide NPs may be explained by the addition of titanium oxide NPs. The coercivity values (H _c) of NPs composed of cobalt ferrite and cobalt ferrite/titanium oxide NPs were 830 and 640, respectively. The fact that cobalt ferrite NPs are smaller and more homogeneous than the manufactured cobalt ferrite/titanium oxide composites may explain this behavior.

Figure 21

SEM images of (a) pure CS, (b) CS/CoFe₂O₄ (10 wt%), (c) CS/CoFe₂O₄ (20 wt%), (d) CS/CoFe₂O₄/TiO₂ (20 wt%), and (e) CS/CoFe₂O₄/TiO₂/DOX nanofibers. Adapted from ref. [139] with permission from Elsevier™.

Wang et al. [140] created SPM cobalt ferrite/graphene oxide (CoFe₂O₄/GO) nanocomposites with MRI and controlled drug delivery through sonochemistry. The method is simple and effective, and GO nanosheets are uniformly coated with CoFe₂O₄ NPs ranging in size from 5 to 13 nm. The CoFe₂O₄/GO nanocomposites created have SPM properties, are hydrophilic, and have a low degree of cytotoxicity, indicating that they have a lot of potential in biomedical applications. On CoFe₂O₄/GO, DOX hydrochloride was loaded as an antitumor model drug. The nanocomposites were shown to be effective in transferring DOX into cancer cells and caused cell death. This nanocarrier had a drug loading capacity of 1.08 mg/mg, and the drug release behavior was delayed and pH-responsive, which is useful for preventing rapid drug release in the neutral circulatory system while promoting drug release at acidic tumor sites or inside cells. Suárez et al. [141] created a composite of CS and polyvinylpyrrolidone (PVP) with CoFe₂O₄ NPs for use in drug delivery systems and hyperthermia (see Figure 22 for a schematic depiction of the manufacturing process). They examined how the structural, magnetic, and SAR characteristics of Co _x Fe_3−x O₄ (x = 0.25, 0.50, 0.75, and 1.00) as a hyperthermia heat nanomediator were influenced by CS and PVP. At a frequency of 454 kHz and a magnetic field amplitude of 5.5 mT, hyperthermia tests were conducted. At x = 1.00, CS–PVP-coated NPs had a maximum SAR of 386 W/g, compared to 270 W/g for untreated NPs. The coated NPs exhibit higher SAR values than the untreated NPs due to the presence of CS and PVP. The variable mixing of CS and PVP for heating cobalt ferrite NPs improves the biocompatibility and stability of the samples. The impact of changing the Co²⁺ concentration on the nanocomposite structure may alter magnetic characteristics, increasing hyperthermia SAR, and NPs coated with hydrophilic polymers enhance biocompatibility and SAR efficiency.

Figure 22

A schematic depiction of the synthesis mechanism of the composite of CS and PVP with CoFe₂O₄ NPs. Adapted from ref. [141] with permission from Elsevier™.

Daboin et al. [142] used the thermal decomposition technique to prepare magnetic mixed manganese–cobalt ferrite NPs (Mn_1−x Co _x Fe₂O₄); then, they were coated with SiO₂ using the Stöber process and adorned with Au@Fe₃O₄ NPs. TEM images of the undecorated and decorated nanocomposites are shown in Figure 23a–f. These images show that the nanostructured material has a spherical shape and that Au@Fe₃O₄ NPs were successfully deposited on the silica nanocomposites’ surfaces. They investigated the generated composite as magnetic fluid hyperthermia heat mediators using a hydrogel as a tissue equivalent. The SAR of the nanocomposites increased when they were decorated with Au@Fe₃O₄ in water. By integrating magnetic NPs, SiO₂, and Au@Fe₃O₄, the magnetic properties of the synthesized nanocomposite system may be fine-tuned to optimize SAR.

Figure 23

TEM images of the decorated (left) and undecorated (right) nanocomposites with varying Mn²⁺ contents. Adapted from ref. [142] with permission from Elsevier™.

Mondal et al. [143] developed a MnFe₂O₄/ZnS magneto-fluorescent nanocomposite using a simple co-precipitation method. The NPs are near SPM at room temperature, with a small coercivity of 66 G, and saturation magnetization increases significantly after coating ZnS on the MnFe₂O₄ core surface. MnFe₂O₄/ZnS core–shell NPs have a magnetic saturation of 1.15 emu/g, which is higher than MnFe₂O₄ NPs. The Zn²⁺ ions induce cation rearrangement in the nanocomposites’ interstitial regions, resulting in an increase in saturation magnetization. The heating efficiency of the MnFe₂O₄/ZnS core–shell nanocomposite is determined using the SAR and intrinsic loss property, which decreases with increasing sample concentration. Hatamie et al. [144] utilized GO/cobalt ferrite NPs to heat-treat the MCF7 breast cancer cell line. The ferrimagnetic NPs were 5 nm in diameter. The NPs were likewise uniformly distributed on the GO nanosheets. The cell survival rate was 58% after 72 h of NP treatment, suggesting that the IC₅₀ had been reached. The vitality of the cells, on the other hand, was decreased by 30% following heat therapy. In addition, BALB/c mice were used in in vivo testing; the findings showed a reduction in tumor growth after 27 days with dosages of 0.001 and 0.002 g/mL and corresponding magnetic frequencies of 400 and 250 kHz for 10 min. The MRI studies revealed the presence of NPs not only inside the tumor but also in adjacent tissues. The MRI validated dark spots as a representation of the presence of NPs and tumor disruption as a consequence of the hyperthermia procedure in contrast to the control group (see Figure 24). The molecular gene expression of the treated tumor showed a higher expression of apoptotic genes. Hematoxylin and eosin (H&E) staining, on the other hand, revealed that NP concentrations of 0.002 g/mL at frequencies of 250 and 350 kHz disrupted the tumor cytoskeleton.

Figure 24

MRI scans of mice with (a) NPs and hyperthermia; and (b) NPs without hyperthermia treatment. Adapted from ref. [144] with permission from Elsevier™.

5 Selected doped SFNPs and their composites

Cobalt ferrite CoFe₂O₄ has a hyperthermic effect on cancer therapy and drug delivery [145]. Balakrishnan et al. [146] used the cubic-shaped cobalt ferrite NPs (Co–Fe NCs) as magnetic hyperthermia agents and as a cytotoxic agent ascribing to the distinguished cobalt ion toxicity, supporting both heat and cytotoxic impacts from a single platform (Figure 25a). The polymer-coated CoFe₂O₄ was injected intratumorally (i.t.). NPs were injected when the tumors were ≈80–100 mm³ (day 0), followed by 30 min HT cycles on days 0, 1, and 2, totaling 3× HT cycles on three consecutive days (HT1, HT2, and HT3). The iron oxide cubic-shaped nanoparticles (IONCs) were injected into rats i.t. within the 3× HT (TEM; Figure 25b) or CoFe₂O₄ (TEM; Figure 25c); the tumor temperature (T _Tumor) and the skin tail temperature (T _Skin) were detected with an infra-red camera (Figure 25d). They found that ΔT = T _Tumor − T _Skin were about 6, 3.5, and 3.5°C for IONCs on HT1, HT2, and HT3, respectively; while, CoFe₂O₄ presented only ΔT of 3°C on HT1, HT2, and HT3. The detected reduction in the temperature for CoFe₂O₄ and CoFe₂O₄ in water was because the immobilized nanocubes in the tumor cells’ viscous medium [147,148] caused a decrease in the release of heat from high anisotropy particles [149]. Also, they revealed that monitoring the temperature and cancer growth for 12 days post CoFe₂O₄ injection showed that the decrease of the growth of the tumor by Co–Fe NCs + hyperthermia, compared to Co–Fe NCs or the ions and the IONCs + hyperthermia, respectively, was nonsignificant (Figure 25f). Further, they compared the obtained IONCs + HT results with those of the previously revealed in vivo study [150]. Kolosnjaj-Tabi et al. [150] found that 18 nm IONCs-based hyperthermia monotherapy did not significantly decrease tumor growth [150]; while Mai et al. revealed that the combination therapy, IONCs hyperthermia + Doxo intravenous injection, enhanced the ions possessing cubic shape-based hyperthermia efficiency [151].

Figure 25

The efficiency of the ions possessing cubic shape-based hyperthermia and Co–Fe NCs during in vivo study. (a) Plan of the treatment. Particle injection is symbolized by a black arrow (0.7 mg Co–Fe NCs or 0.7 mg IONCs) and the days of HT therapy (3 × hyperthermia) are symbolized by red arrows, using AMF conditions. (b and c) TEM images of the ions possessing the cubic shape of particles (18 nm) (b) and sizes of poly(maleic anhydride-alt-1-octadecene‐coated CoFe₂O₄ was (17 nm) (c) In vivo studies. Scale bar: 50 nm. (d) Mouse IR images post the ions possessing cubic shape and CoFe₂O₄ injection during hyperthermia therapy (HT1, HT2, and HT3). Cancer temperature is represented by white arrows, while skin temperature is shown by black arrows, to estimate ΔT values. (e) ΔT graph (ΔT = T _Tumor − T _Skin) plotted for HT1 at day 1, HT2 at day 2, and HT3 at day 3 for (orange bars) the IONCs (in vivo) or (red bars) Co–Fe NCs. (f) Tumor or cancer growth curve represented the marginal decrease in cancer growth for Co–Fe NCs and exposed to 3× hyperthermia (Co–Fe NCs + hyperthermia) compared to Control, the ions possessing cubic shape alone; Co–Fe NCs alone, and the ions possessing cubic shape + hyperthermia; N = 6. Adapted from ref. [146] with permission from John Wiley and Sons.

Figure 26a shows that the Co–Fe NC chains and prolonged cobalt toxicity were present, as confirmed by long‐term in vivo study, resulting in decreased tumor growth and longer survival. It was focused only on Co–Fe NCs with or without hyperthermia efficiency. Also, Balakrishnan et al. [146] monitored the tumor size by digital photographs and showed that the tumor size was significantly reduced in the Co–Fe NCs + HT group than that in the Co–Fe NCs group compared to the control animals group on day 15 (Figure 26b). They revealed that the tumor was completely eradicated on day 30 after injecting Co–Fe NCs + HT i.t. without recurrence up to a post-treatment period of 200 days (Figure 26c). Furthermore, the survival rate was significantly higher in the Co–Fe NCs + hyperthermia group (about 200 days) than in the control group (22 days) and Co–Fe NCs group (30 days) (Figure 26d). As revealed in Figure 26e and f, the long-chain formation was confirmed by transmission electron microscopic images at day 30 for tumor tissues, indicating that strong interactions persisted for a long time. It was also shown that Co–Fe NCs were presented within the tumor at day 30, as indicated by histological Prussian blue staining (Figure 26g and h). The Co–Fe NCs + hyperthermia group showed a whirling movement of nanocubes from the tumor injected point to its peripheral surface, post exposed to an AMF (Figure 26h) [150]. The HT increased the chain length of injected Co–Fe NCs, resulting in mechanical damage to the cancer cells during the whirling movement of Co–Fe NCs. Marangon et al. [152] concluded that one of the important reasons for the tumor drug resistance was the tumor’s outer collagenous peripheral layer. Even the damage or necrosis was induced centrally in the tumor post-treatment; the outer layer was rich in angiogenesis, and viable cells resulted in the uncontrolled growth of cancer cells. Balakrishnan group [146] presented that CoFe₂O₄ NCs were injected i.t. in rats to avoid nonspecific cobalt toxicity. Chu et al. [153] revealed that the i.t. injection in the case of cancer patients was accepted. The outer layer of the Co–Fe NCs + HT group was rich in collagen (darker pink) (Figure 26h) and cells (pink) in the outer layer had more toxicity at the peripheral region, which led to the destruction of stroma; while in the CoFe₂O₄ NCs alone group, cancer cells were still viable (Figure 26g). Finally, they found that CoFe₂O₄ NCs + HT destroyed the outer tumor membrane completely, which led to the prevention of the recurrence or relapse of the tumor (Figure 26c) [146].

Figure 26

The efficacy of Co–Fe NCs during in vivo HT examination. (a) Diagram of plan therapy. (b) Images of a control animal (at 0 and 15 days) and Co–Fe NCs injected alone, and Co–Fe NCs injected + hyperthermia display the decrease and whole eradication of cancer 30 days after treatment, respectively. The treated cancer is represented by an enlarged image in boxes. (c) The complete eradication of cancer represented in tumor or cancer growth curve and no relapse up to 200 days in case of Co–Fe NCs + hyperthermia (in vivo). (d) A Kaplan–Meier survival graph indicating Co–Fe NCs + hyperthermia enhanced the survival rate up to 200 days after therapy, while in other groups for only one month. (e and f) TEM images proved that cancer cells have a chain shape even at one month after therapy for both Co–Fe NCs alone (e) and Co–Fe NCs + hyperthermia (f). (g and h) Light microscopy images of cancer slices of Co–Fe NCs alone (g) and Co–Fe NCs + hyperthermia (h) display the incidence of NPs and absence of stroma. Blue color representsNPs due to Prussian blue staining; dark-pink stained the collagen and light-pink stained the cells in the case of Fast Red staining. Scale bars in (g) and (h) are 0.5 cm. Adapted from ref. [146], with permission from John Wiley and Sons.

It is known that conservative drug delivery suffered from unstable metabolic tissue distribution and was nontargeted to cancer cells, which leads to a decrease in cancer therapy efficiency and increases whole-body toxicity [154]. On the other hand, cytotoxic drugs were efficiently delivered by encapsulating within polymer-SFNPs composite [155,156]. Ponce et al. [157] revealed that antibody-based drugs are bound to specific targets in cancer tissues. However, once the molecular targeted drugs were administered, their target did not change; while the magnetic drug delivery system was guided by a magnet by magnetic field exposure [157,158]. Namiki et al. [159] reported that cytotoxic anticancer drugs were combined with SPM particles [159,160] by micelle emulsification or ionic bond [161]. Gupta and Gupta [162] found that a targeted magnetic drug delivery system was widely used in tissue repair, enhancing contrast for magnetic resonance (MR) imaging, hyperthermic therapy, and cytotoxic anticancer therapy [116].

Especially in hyperthermia therapy, Fe₃O₄ and γ-Fe₂O₃ were preferred to Fe₃O₄ or γ-Fe₂O₃ NPs due to slower magnetic moment relaxation of CoFe₂O₄ than that with similar size [163,164]. The hyperthermic efficiency of CoFe₂O₄ NPs was improved by adding a trace amount of Zn²⁺ (5–15%) relative to cobalt (Co), while further addition of Zn²⁺, more than 15% relative to Co, resulted in a reverse effect [165]. Likewise, the anticancer activity of CoFe₂O₄ NPs against human colon cancer has been enhanced by trace Ce–Nd addition [166].

Besides, the cations of rare earth elements (REs) doped CoFe₂O₄ were found to be suitable for tumor hyperthermia therapy, specifically NPs of Co_0.9Gd_0.1Fe₂O₄ due to their high ability to lose energy [71]. Almessiere et al. [166] reported the anticancer properties of Nd³⁺ and Ce³⁺-substituted cubic CoFe₂O₄ against human colon cancer cells (HCT-116) via MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. After 48 h of treatment with Nd³⁺ and Ce³⁺, the substituted CoFe₂O₄ samples displayed apoptosis of HCT-116 cells. These results showed that Ce–Nd-substituted nano Co-ferrite had anticancer efficiency against colon cancer.

Zhang et al. [167] used leucine-coated cobalt ferrite (CoFe₂O₄) NPs in drug delivery with a DOX loading capacity of 0.32 mg/mg; the loaded DOX displayed a progressive and sustained release. The MTT assay was used to determine the cytotoxicity on HeLa cells, and the results showed that the Leu-coated CoFe₂O₄ NPs demonstrated comparatively minimum cytotoxicity compared with that of CoFe₂O₄ NPs, and the DOX-loaded Leu-coated CoFe₂O₄ NPs showed an observable cell death for HeLa cells. Iqbal et al. [168] have reported that cobalt ferrite doped with zinc (Zn_0.5Co_0.5Fe₂O₄) NPs produced by a novel, simple sol–gel method, resulted in good magnetic amorphous NPs. Neutral red assay (NRA) was used to test the anticancer activity on HepG2 cell lines. The results revealed that 250 μg/mL Zn_0.5Co_0.5Fe₂O₄ incubated with HepG2 cell lines at 80 J/cm² laser fluence resulted in the cell viability loss of about 60−65%. The incubation time increased with increasing the absorbance for Zn_0.5Co_0.5Fe₂O₄ NPs (250 μg/mL), which was examined at incubation times 3, 24, and 49 h; the absorbance reached 0.40, 0.51, and 0.65 a.u., respectively. Different studies reported that ferrites have an anticancer cytotoxic effect against malignant cell models in the absence of light/laser [169,170]. Also, they revealed that the cell viability loss significantly differed pre and post laser irradiation, even after post cells exposure to 400 μg of Zn_0.5Co_0.5Fe₂O₄ NPs. The cell inhibition was significantly higher (44%) at a laser fluence of 80 J/cm² than in dark cell inhibition (18%).

McBain et al. [171] reported that CoFe₂O₄ NPs were promising as drug delivery nanocarriers. Cai et al. [172] reported three potential properties: high effective drug loading; surface area; and varied multifunctional nanocomposites due to feasibility and magnetically targeted controlled through an external magnetic field. The DOX delivery and release were controlled by magnetically driven dandelion pollen-like CoFe₂O₄ nanostructures. They also revealed a loading capacity of 88.6% of the nanostructure, a loading content of 118 mg of DOX/g of CoFe₂O₄ microspheres, and drug release of ∼55% under an AMF field at 8 h [173].

Liu et al. [174] reported magnetic affinity and designed mesoporous silica nanotube worm-like with settled CoFe₂O₄ NPs over the surface that triggered the nanotubes magnetically in biological fluids. They also studied the release-uptake process by using 6-carboxyfluorescein as a drug delivery model in vitro using HeLa cells. The cargo was released within 1 h into HeLa cells, after AMF (0.5 mT, 100 Hz) of the nanotubes.

Iatridi et al. [175] prepared a mixture of MnFe₂O₄ and CoFe₂O₄ coated with poly(sodium methacrylate)-co-(dodecyl-methacrylate-co-2,4-diphenyl)-6-(4-vinyl-phenyl quinoline)-g-poly(N,N-dimethylacrylamide-co-N-isopropylacrylamide)(P(MANa-co-DMA-co-SDPQ))-g-(P-(DMAM-co-NIPAM)). It was applied in hyperthermia cancer therapy. Also, Iatridi’s group evaluated the hyperthermic activity of colloidal NPs by exposure to a field of kHz and 250 Oe, which was heated to 44°C within 10 min. It was found that NPs were suitable for luminescence and MR imaging and pH and temperature-controlled drug release along with hyperthermia cancer therapy.

Yang et al. [176] revealed that the CoFe₂O₄ core and polydopamine and zeolitic imidazolate framework shell (CoFe₂O₄@PDA@ZIF-8) were used to encapsulate CPT in the ZIF-8 shell and DOX in the CoFe₂O₄ core where the photothermal NP activity was stimulated by both ZIF-8 and polydopamine. Also, they found that the loading capacities of NPs were 98 and 46% for DOX and CPT, respectively, which were released at pH 5 during 7 h by 75 and 45%, respectively, post 5 min laser irradiation. It was shown that the nanocarrier was heated to 65°C after 10 min exposure to 808 nm laser. Therefore, CoFe₂O₄ NPs have shown potential results in hyperthermia, diagnosis, and cancer therapy [177].

Magnetite Fe₃O₄ is one of the oldest and yet one of the most commonly used SFNPs with a unique inverse spinel structure [178]. Fe₃O₄ NPs were used as therapeutic hyperthermia cancer agents and magnetic-guided drug delivery [178,179] agents. Fe₃O₄ NPs reached the highest and the lowest hyperthermia by doped Mn²⁺ and Zn²⁺, respectively [180,181]. Two types of anticancer drugs, curcumin (Cur) loaded and synthesized SF nanocomposites (SFNCs), were synthesized by using Fe₃O₄ NPs as the core; one of them (Fe₃O₄/OCMCS/Cur) was Cur, burdened, and encapsulated with O-carboxy methylchitosan (OCMCS), and another one, (Fe₃O₄/OCMCS/Cur/Fol) was folate attached to Fe₃O₄/OCMCS/Cur [182].

The bio-distribution and the effectiveness of SFNCs were investigated by injecting at a dose of 20 μg/kg SFNCs into mice bearing solid tumor Sarcoma-180. The results have shown that Fe₃O₄/OCMCS/Cur/Fol was distributed uniformly after 5 h than Fe₃O₄/OCMCS/Cur. It was proved that SFNC was a good curcumin loader in, as well as, cancer-targeted drug delivery; SNFC also showed a synergic action of hyperthermia and chemotherapeutic [183]. It was revealed that CS-based magnetic hybrid NCs with folate-conjugated tetrapeptide composite (CS, CdTe quantum dots QDs (a fluorescent dye), and SPM Fe₃O₄, camptothecin CPT cytotoxic drug, folate and tetrapeptides) [184].

Manganese ferrite (MnFe₂O₄) is used for drug delivery and as an enhancer for hyperthermia to increase anticancer efficiency [185]. Five SFNPs were synthesized with a combination of core–shell components or exchanging the order of coating for power loss as follows CoFe₂O₄@Fe₃O₄ < CoFe₂O₄@MnFe₂O₄ < Fe₃O₄@CoFe₂O₄ < MnFe₂O₄@CoFe₂O₄ < (Zn_0.4Co_0.6) Fe₂O₄@Zn_0.4Mn_0.6Fe₂O₄. Lee et al. [185] revealed that the heat efficacy of hyperthermia cancer therapy was enhanced by coupling exchange between a soft shell and a magnetically hard core.

The supermagnetic DOX poly(lactic-co-glycolic acid) (PLGA)@CS-stabilized (CS)@Mn_0.9Zn_0.1Fe₂O₄ NPs was synthesized with low M _s = 13.2 emu/g as compared to Mn_0.9Zn_0.1Fe₂O₄NPs (M _s = 56.1) that led to efficient magnetic response during the drug release, which was adjusted by the pH of cancer cells. The DOX-PLGA@CS@Mn_0.9Zn_0.1Fe₂O₄NPs revealed drug loading, delivery, and hyperthermic cancer therapeutic effect [186].

Wang et al. [187] synthesized MnFe₂O₄@GO NC via the sonochemical method within high DOX loading capacity due to π–π interactions and hydrogen bonding between DOX and GO. Hence, the MnFe₂O₄@GO delivered targeted drug delivery for DOX to cancer cells, and DOX was released due to the acidic tumor microenvironment. Slimani et al. [188] found that HCT-116 growth was significantly inhibited by lanthanide/dysprosium (Ce³⁺/Dy³⁺) co-activated co-doped manganese-zinc nanospinel ferrites (CDMZNSFs) (with IC50 values ranging from 0.74 to 2.35 mg/mL for 48 h), whereas the healthy HEK-293 cell growth was not damaged.

Hekmat and Saboury [189] revealed that the antiproliferative and anticancer effects of Co_0.3Mn_0.2Zn_0.5Fe₂O₄ NPs were determined by MTT assay after the T47D cell line was treated with 6–300 nM Co_0.3Mn_0.2Zn_0.5Fe₂O₄ NPs 48 h. Also, Hekmat and Saboury found that the IC50 of Co_0.3Mn_0.2Zn_0.5Fe₂O₄ NPs on the T47D cell line was equal to 70 nM. It was found that Co_0.3Mn_0.2Zn_0.5Fe₂O₄ NPs were a potential anticancer–antiproliferative agent. Further, Hekmat and Saboury studied the morphological of cancer cells by treating T47D (1 × 10⁵ cells per well) with 70 nM Co_0.3Mn_0.2Zn_0.5Fe₂O₄ NPs and 1 mg/mL DAPI solution. It is known that DPAI binds to DNA resulting in increased fluorescence by 20-fold based on the displacement of H₂O from the minor groove of DNA and DAPI. Furthermore, Hekmat and Saboury showed that the living cells showed regular blue, while the dead cells that were treated with Co_0.3Mn_0.2Zn_0.5Fe₂O₄ NPs (70 nM) were bright blue doted nuclei, which indicated DNA fragmentation of nuclei and confirmed the previous MTT results [190].

Hekmat et al. found out that flow cytometry was a sensitive and fast apoptotic assay, and could easily differentiate between apoptotic and necrotic cells [98]. Hekmat and Saboury [189] studied the apoptosis after exposure of T47D (1 × 10⁶ cells/well) at 70 nM Co_0.3Mn_0.2Zn_0.5Fe₂O₄ NPs (24 h) by Annexin V and then evaluated by flow cytometry. It was revealed that the NPs reduced the viable cells and increased the apoptotic cells.

Nickel ferrite NiFe₂O₄ NPs were found to be a potent differentiated hyperthermia agent for cancer therapy [191]. The new nanoformulation β-cyclodextrin-dextran layered on NF NPs (Ni_1.04Fe_1.96O₄) was synthesized in about 6 nm. It was found that camptothecin CPT was loaded by 88% in the polymer-coated NPs. Moreover, the nanocarrier sustained the CPT release profile; on the other hand, a decrease in pH by 1.4 leads to faster release of CPT. The CPT-loaded β-cyclodextrin-dextran coated on magnetic nickel ferrite nanocomposite displays cell growth inhibition of HeLa human cervical, breast MDA-MB-231, and lung A549 cancer cell lines with cytotoxicity IC50 values of 1.49, 1.35, and 1.41 µg/mL, respectively. It was found that the anticancer efficacy of CPT-loaded CD-Dx MNP nanoformulation was greater than 5-fluorouracil and cisplatin against different cancer cell lines [191].

Alahmari et al. [192] synthesized Ni_0.5Co_0.5−x Cd _x Fe_1.78Nd_0.02O₄ (x ≤ 0.25) nanofibers (NFs). They evaluated the cytotoxic anticancer effect of NFs by MTT assay on HEK-293 and HCT-116 cells [193,194]. The cells were treated with a range of dosages from 2 to 25 μg/mL for 48 h. They found that NFs profound a significant cell growth inhibition in HCT-116 cancer cells but not in HEK-293. Finally, they concluded that NFs were highly specific and targeted to colon cancer cells.

Tombuloglu et al. [195] revealed that synthesized nanocomposites showed promising results for drug delivery and cancer therapy. They synthesized Co_0.5Ni_0.5Nb _x Fe_2−x O₄ by the hydrothermal combination of Co, Ni, Nb, and Fe₂O₄. They examined the effect of the prepared nanocomposite by incubating different concentrations (0.3, 1.5, 3.8, 6.1, and 12.2 mg/mL) at 48 h with HCT-116 and HEK-293 using MTT assay and stained with DAPI (microscopic). The prepared nanocomposites led to a dose-dependent decrease in the proliferation and viability of cancer cells. The 0.3 mg/mL dose of the nanocomposite resulted in 98.2, 95.2, 93.2, 92.2, 91.2, and 90.2% cell viability versus Nb(x) of 0.00, 0.02, 0.04, 0.06, 0.08, and 0.1, respectively; while 1.52 mg/mL MNP led to decreased 68.0, 59.9, 59.1, 56.9, 57.6, and 56.5% cell viability. The 3.85 mg/mL dose of the nanocomposite repressed cell viability to 66.2, 59.1 58.5, 55.9, 57.9, and 55.9%, respectively. Increasing the nanocomposites concentration to 6.1 and 12.2 mg/mL led to decrease in cell viability (65.3, 58.1, 57.7, 54.7, 55.7, and 54.7%;and 64.3, 57.9, 57.0, 54.0, 54.0, and 54.0%), respectively. It was found that the use of Co_0.5Ni_0.5Nb _x Fe_2−x O₄ did not cause cytotoxicity on HEK-293 cells [195].

Zinc ferrite (ZnFe₂O₄) has been used as an essential radiosensitizer in human prostate tumor radiotherapy (RT) [164]. It was reported that 100 μg/mL ZnFe₂O₄ enhanced the γ-irradiation efficiency 17 times greater than only γ-irradiation via 53% cancer cell growth inhibition. Gamma irradiation induces a dose-dependent alteration of structural integrity [196,197,198,199,200]. Also, gamma irradiation offers advantages in economy and convenience over autoclaving and has been used in sterilization and preparation of different materials [201,202,203,204,205]. The SPM NPs synthesized should possess high Ms and small particle size to be suitable and safe for cancer patients during hyperthermia [101,102,108] and RT [33]. The enhancement of hyperthermia cancer therapy by manganese-doped zinc SFNP (Zn_0.4Mn_0.6) Fe₂O₄ was due to their high values of M _s (175 emu/g) and specific loss power [206]. Almessiere et al. [129] synthesized DyY-MnZn NSFs by ultrasonic irradiation and citrate sol–gel combustion methods; a chain of Mn_0.5Zn_0.5Fe_2−2x (Dy _x Y _x )O₄ (0.0 ≤ x ≤ 0.05) was formed. They found out that the pure phase of SF was produced by ultrasonic irradiation, while a mixture of hematite and SFs was produced by the citrate sol–gel method. It was also shown that both the mixture or pure DyY-MnZn NSFs inhibited cell growth of the colon cancer cell line (HCT-116), but did not inhibit the healthy cell line growth (HEK-293). The ultrasonicated DyY-MnZn NSFs were better than the sol–gel DyY-MnZn NSFs in inhibition of HCT-116 cell growth.

Al-Qubaisi et al. [207] studied the cytotoxicity of NiZn ferrite NPs against HT29 (human colon cancer), MCF7 (Michigan Cancer Foundation7; breast cancer), and HepG2 (liver cancer) cells by MTT assay. The NiZn ferrite NPs were used in different concentrations (15.6–1,000 μg/mL; 72 h) and the cancer cell growth inhibition showed a dose-dependent behavior. The DNA fragmentation and caspase-3 and -9 activities were assayed to confirm the apoptotic effect of NiZn ferrite NPs on different cancer cell lines. The cytotoxic effects of HT29 or MCF7 cells were less sensitive than that of HepG2 to NiZn ferrite NPs (72 h). Also, Al-Qubaisi et al. reported considerable morphological variations in MCF7, HT29 and HepG2 cells after incubation with NiZn ferrite NPs (72 h). More apparent morphological changes (membrane blebbing, cytoplasmic shrinking, cells dispersion, and cell shrinking) were found in HepG2 than the other cell lines. Besides, Al-Qubaisi et al. revealed that NiZn ferrite NPs selectively killed HepG2 cells via induction of apoptosis and suppression of proliferation. The apoptotic effect of NiZn ferrite NPs in cancer cells was due to to the significant activation of caspase-3 and caspase-9, which was responsible for the induction of DNA fragmentation in HT29, MCF7, and HepG2 cell lines.

Lartigue et al. [208] presented that cells treated with NiZn ferrite NPs induced apoptosis and were associated with morphological changes. The magnetic NiZn ferrite NPs were speedily dispersed in epithelial tissues that were firmly bound to albumin. Mitamura et al. [209] revealed that the potential candidate in apoptosis was the activated endogenous nuclease enzymes, which led to DNA fragmentation and was mediated by caspase-3 as a nuclease activator. Al-Qubaisi et al. [207] found that NiZn ferrite NPs induced apoptosis in cancer cells with the highest effective dose of ∼100 μg/mL in HepG2 cells and 1,000 μg/mL for HT29 and MCF7 cells after 12 h. Ahamed et al. [210] reported that nickel ferrite NPs induced apoptosis in the human alveolar adenocarcinoma A549 cell line at 100 μg/mL. Hathaway et al. [211] found that the magnetic NPs had two essential characteristics as an effective anticancer drug, cancer specificity, and minimum cytotoxicity to normal cells. In conclusion, Ni–Zn ferrite had potential apoptotic anticancer activity against cancer cells.

Sarala et al. [212] revealed that ZnFe₂O₄ NPs were synthesized with Lawsonia inermis leaf extract as a surfactant by the green method. The MTT method was used to detect mitochondria’s cell activity and that reflected the viable cells [213]. The ferrite NPs induced cytotoxicity by the generation of ROS. ROS such as superoxide anions, hydroxyl radicals, hydrogen peroxide, and alkoxy radicals denatured biological macromolecules (DNA, carbohydrates, proteins, lipids, etc.). MTT assay was used to determine the anticancer effect of ZnFe₂O₄ NPs; MCF-7 cells were incubated with 25, 50, 100, 250, and 300 μg per well ZnFe₂O₄ NPs for 24 h. The cell viability decreased by 60, 53, 44, 32, and 24%, respectively.

The cytotoxicity mechanism of ZnFe₂O₄ NPs based on ROS generation due to intracellular Zn²⁺ resulted in cellular redox machinery failure [214]. ROS enhanced mitochondrial respiration and apoptosis in mitochondria, cellular redox disequilibrium, and lipid peroxidation in the cell membranes [215]. The direct interaction of ZnFe₂O₄ NPs with cell walls led to the damage and denaturation of the membrane. ROS generated on the surface of the ZnFe₂O₄ NPs and particle disbanding and free Zn²⁺ ions release resulted in the ROS production within the cells [212].

Magnesium ferrite MgFe₂O₄ NPs were selected due to their easy breakdown in the human body and their application in biomedical fields, such as biocompatibility, magnetic hyperthermia therapy, as a contrasting agent in MRI, and drug delivery [216,217,218]. Selvam et al. [219] revealed the cytotoxicity on the healthy human embryonic kidney cell line (HEK293) for poly(vinyl alcohol) cross-linked β-cyclodextrin polymer coating of magnesium ferrite NPs (PVA-CD-MNPs) and camptothecin-loaded PVA-CD-MNP nanocomposite (PVA-CDMNPs@ CPT), where IC₅₀ values were found to be 18.96 and 5.104 μg/mL, respectively. The anticancer efficacy was studied on colorectal cancer HCT-15 cell lines, and the IC50 values were 28.89 and 66.17 μg/mL for PVA-CD-MNPs@CPT and the PVA-CD-MNPs, respectively. The HEK 293 cells are more sensitive to PVA-CDMNPs@ CPT. Together with the host polymer, the magnetic NPs combined with an excellent antineoplastic nanocomposite when loaded with the topoisomerase inhibitor (camptothecin), a promising drug delivery vehicle for cancer therapy. The nanocomposite vehicle accommodated any drug of suitable size that fits into the cyclodextrin cavity. It does not rely upon the open-on covalent linking of the drug to the polymer through complex methods of synthesis and the requirement to cleave the drug-polymer bond at the target site for drug release. Therefore, the nanoformulation vehicle can be loaded and released by any anticancer drug.

RT was considered to be one of the effective cancer therapy methods [220]. Furthermore, the efficacy of the RT therapeutic effect can be enhanced by NPs [216]. The anticancer therapeutic effect of magnesium ferrite NPs MgFe₂O₄ on the human breast cancer cell line MCF-7 [216,217,218] was investigated. Meidanchi and Motamed [221] revealed that MgFe₂O₄ was successfully synthesized in a single-step reaction hydrothermally with an average particle size of 10.5 nm and sample crystallite size of 9 nm. The SPM MgFe₂O₄ behavior was revealed at room temperature. Additionally, the MgFe₂O₄ as X-ray irradiation radiosensitizers was applied in MCF-7 RT. It was found that (a) the concentration of MgFe₂O₄ up to 10 μg/mL had no significant cytotoxicity on MCF-7 and cytotoxicity was evident only at 100 μg/mL; and (b) significant cell damage was found in the presence of 10 μg/mL MgFe₂O₄ concentration under 2 and 4 Gy X-ray irradiation. Therefore, no significant cytotoxicity and significant cell damage were observed at 10 μg/mL MgFe₂O_4, indicating that MgFe₂O₄ could be used as a radiosensitizer for cancer cell therapy in comparison with RT alone. MgFe₂O₄ was considered as a radiosensitizer due to the production of Auger low-energy electrons due to its photoelectric effect under X-ray irradiation.

Copper ferrite CuFe₂O₄ NPs and their composites are also used in cancer therapy. Jermy et al. [3] investigated the anticancer cytotoxic effect of CS enclosed CuFe₂O₄/HYPS. Cell inhibition was detected by MTT assay. They studied CS over spherical hydrophilic silica (HYPS) NPs at two concentrations (0.06 and 0.6) wt% and varied pH values (5, 6, and 6.5). Also, they used the impregnation method for the synthesis of four nanocomposites of SF/silica. It was found out that their magnetization order was CoFe₂O₄/HYPS (14.15 emu/g) > NiFe₂O₄/HYPS (7.73 emu/g) ∼ CuFe₂O₄/HYPS (7.65 emu/g) > MnFe₂O₄/HYPS (1.49 emu/g).

The SPM effect was observed in MnFe₂O₄/HYPS, whereas the ferromagnetic effect was observed in CoFe₂O₄/HYPS. Both Cu Fe₂O₄/HYPS and Ni Fe₂O₄/HYPS presented similar paramagnetic effects. Jermy et al. revealed a physicochemical method (method I) for 6–12 nm CuFe₂O₄, CS, and cis-Pt over HYPS. It was verified that CS was essential for the restricted release of cisplatin (cis-Pt) over CuFe₂O₄/HYPS by pH adjustment of CS (method I). In the same context, they proved that nanoformulation of cis-Pt/CuFe₂O₄/HYPS/CS (method I) had an insignificant cell viability effect. However, the CS/CuFe₂O₄/HYPS/cis-Pt nanocomposite synthesized via the impregnation method (method II) by CS prewrapping and preloading cis-pt(0.15 mmol/g cis-pt). Also, they showed that 64% cis-pt was released during 72 h from the nanocomposite and had a significant cytotoxic effect. Jermy et al. studied the cell viability of CS/CuFe₂O₄/HYPS/cis-Pt on the healthy human embryonic kidney (HEK293) and MCF-7 cells. Besides, they found that CuFe₂O₄/HYPS was noncytotoxic, and cis-Pt, cis-Pt/CuFe₂O₄/HYPS, and CS/CuFe₂O₄/HYPS/cis-Pt significantly induced cell inhibition in both HEK293 and MCF7 dose-dependently. The MCF7 cell viability at the lowest concentration was as follows: cis-Pt, 58.17%; cis-Pt/CuFe₂O₄/HYPS, 63.36%; and CS/CuFe₂O₄/HYPS/cis-Pt, 70.73%. However HEK293 cell viability was 73.47% for cis-Pt, 80.24% for cis-Pt/CuFe₂O₄/HYPS, and 95.07% for CS/CuFe₂O₄/HYPS/cis-Pt. Finally, Jermy et al. showed that CS/CuFe₂O₄/HYPS/cis-Pt method II was the best nanoformulation due to the biocompatibility advantage of CS, avoiding the premature cis-pt release during the pH adsorption of CS (Figure 27) and effectively targeted tumor cells with a similar pure cis-pt efficiency; thus making it a novel magnetically targeted drug delivery system.

Figure 27

The CS/CuFe2O4/HYPS/cis-Pt nanocomposite optimized route. Adapted from ref. [3] with permission from Elsevier™.

Meidanchi [222] used the hydrothermal process in the synthesis of Mg_(1−x)Cu _x Fe₂O₄ SPMNPs (0.2 ≤ x ≤ 0.8). Meidanchi studied the anticancer effect (MTT assay) of Mg_1−x Cu _x Fe₂O₄ SPMNPs at various concentrations (0.1, 1, 10, and 100 μg/mL) on the MCF-7 cell line before and after 2 Gy X-ray RT. Also, Meidanchi showed that X-ray irradiation at a high concentration of Cu and Mg_(1−x)Cu _x Fe₂O₄ SPMNPs resulted in significant inhibition of the growth of MCF-7 cells. However, nonsignificant cell growth inhibition of Mg_(1−x)Cu _x Fe₂O₄ SPMNPs was observed at lower concentrations (0.1–10 μg/mL). Further, Meidanchi concluded that Mg_(1−x)Cu _x Fe₂O₄ SPMNPs (x = 0.2 (10 μg/mL) and x = 0.6 (1 μg/mL)) was considered as a nano-radiosensitizer due to synergistic therapeutic effect without cytotoxicity on the MCF-7 cells.

6 Challenges and perspectives

Diverse properties of SFNPs, such as the shape, size, charge of the surface, and surface adjustment, should be identified when composites-incorporated SFNPs were formed to reduce the elimination of SFNPs from circulation and maximize their influence on the targeted tissues. The size of the composites-incorporatedSFNPs is significant for controlling the rate of their internalization through target cells and magnetic properties. The suitable size range was reported to be in the range of 10-100 nm to allow them to pass through tiny capillaries and restrict SFNPs’ elimination from circulation. The decrease in the size is of importance due to the tendency to aggregate. The second significant factor was the surface charge or zeta potential of SFNPs incorporated with composites. The best zeta potential was found between 10 and 30 mV or between −10 and −30 mV to obtain a stable suspension of SFNPs with minimum aggregation. The surface charge of the SFNPs was influenced by surface modification. The incorporation of composites on the SFNP surface led to a decrease in their magnetization, resulting in weak magnetic targeting. So, thickness and type of material incorporated significantly impact variations in the magnetic characteristics of SFNPs. Consequently, the beneficial characteristics of magnetic composites for drug delivery would be traded off with the increase in the particle size and the decreased magnetic properties. In contrast to hyperthermic applications where heat damage was initiated via exposing diseased tissues to high temperatures for a period of time, controlled heating (4–10°C) in short periods of time is in demand in drug delivery purposes via the heat-responsive polymer-incorporated SFNPs. This is a challenging problem because if the polymer is subjected to any excessive heating, its structure can be degraded, and hence, its reversible phase transition may be destroyed. Overall, complex synthesis methods are usually needed for the successful configuration and purpose of nanomaterials [82,83,205,223,224,225], and remarkable unclear aspects concerning their magnetic response are still lingering.

7 Bibliometric mapping analysis

Search methodology for bibliometric mapping: (anticancer SF OR drug delivery SF or cancer therapy SF) OR TOPIC: (anticancer Manganese ferrite) OR TOPIC: (anticancer Nickel ferrite) OR TOPIC: (anticancer Zinc ferrite) OR TOPIC: (anticancer Magnesium ferrite) OR TOPIC: (anticancer Copper ferrite) OR TOPIC: (anticancer Lithium ferrite) OR TOPIC: (“anticancer NPs”) OR TOPIC: (drug delivery Manganese ferrite) OR TOPIC: (drug delivery Nickel ferrite) OR TOPIC: (drug delivery Zinc ferrite) AND TOPIC: (drug delivery Magnesium ferrite) AND TOPIC: (drug delivery Copper ferrite) AND TOPIC: (drug delivery Lithium ferrite) OR TOPIC: (hyperthermia SF)

Timespan: All years. Indexes: SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI.

The bibliometric mapping analysis is shown in with the network visualization and density visualization, respectively. The bibliometric mapping analysis showed 402 results using the search methodology mentioned above from the Web of Science (WOS). There is a strong relationship in the literature between hyperthermia and iron oxide NPs and different types of SF NPs, as shown in Figure 28. Many investigation studies in the literature on parameters are linked to the hyperthermia phenomenon such as the temperature, particle size, cation distribution, and facile synthesis methods. The hyperthermia phenomenon also showed large co-occurrence with anticancer NPs and drug delivery for magnetic materials and SF. On the other hand, Figure 28 shows a significant gap in the literature regarding in vivo, photothermal therapy, heating efficiency, toxicity, theranostics, and controlled release. Figure 29 shows prominent keywords in this field as shown from the density visualization map such as magnetic properties, hyperthermia, NP size, and drug delivery.

Figure 28

The bibliometric network mapping of SF NPs as anticancer and drug delivery research field in all years in WOS.

Figure 29

The bibliometric density visualization mapping of SF NPs as anticancer and drug delivery research field in all years in WOS.

8 Conclusion

One of the essential applications of SF NP SFNPs is cancer therapy, hyperthermia, drug targeted delivery, and release. In this review, the synthesis methods used to prepare SFNPs are presented in detail. Also, the structural and magnetic properties of SFNPs are discussed. Further, the relation between the surface morphology and different properties of SFNPs is revealed. The unique physicochemical characteristics of SF include low toxicity and high biocompatibility for use in various biomedical applications, including drug delivery and magnetic hyperthermia treatment. The frequency and amplitude of the applied external magnetic field, and NP sizes are the main factors for safe hyperthermia cancer therapy. The anticancer efficiency of SFNPs depends upon their synthesis and cytotoxicity methodology, which was evaluated by MTT assay on normal cell lines and different cancer cell lines. The results showed acceptable cell viability on normal cell lines and cytotoxicity and cancer cell growth inhibition. Generally, the surface of SFNPs coated with nontoxic chemicals enhanced cell viability and biocompatibility with normal cells. The hyperthermia effect of SFNPs is considered a targeted differential therapy due to cancer cells being more sensitive to the hyperthermia effect than normal cells. Cancer cells were damaged by the heat generated based on the external field amplitude square, frequency, size, and type of SFNPs. It is known that the conservative drug delivery suffered from unstable metabolic tissue distribution and was nontargeted to cancer cells, which leads to a decrease in cancer therapy efficiency and increased whole-body toxicity. On the other hand, cytotoxic drugs were efficiently delivered by encapsulating within polymer-SFNPs composite.