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

: Magnetic spinel ferrite nanoparticles ( SFNPs ) attract high scienti ﬁ c attention from researchers due to their broad area for biomedicine applications, comprising cancer magnetic hyperthermia and targeted drug delivery. Uniquely, its excellent performance, namely, tuning size and surface morphology, excellent magnetism, extraor dinary magnetically heat induction, promising biocompat ibility, and speci ﬁ c targeting capacity, is essential for their e ﬀ ective utilization in clinical diagnosis and therapeutics of diseases. This review emphasizes the anticancer properties of nanoparticles of spinel ferrites with extra focus on the most recent literature. A critical review is provided on the latest applications of SFNPs in cancer therapy. Based on the results obtained from this review, SFNPs have the inde ﬁ nite ability in cancer therapy through two mechanisms: ( 1 ) hyperthermia, where SFNPs, used as a hyperthermia medi -ator, elevated the tumor cells heat post - exposure to an external magnetic ﬁ eld and radiosensitizer during cancer radiotherapy;and ( 2 ) targeteddrugdeliveryofcytotoxicdrugs intumortreatment.SFNPsinducedapoptosisandcelldeathof cancer cells and prevented cancer cell proliferation.


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. 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 RFe 2 O 4 , 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 (Fe 3+ ) can be substituted with different trivalent cations or rare earth elements. The spinel structure is inferred from the mineral magnesium aluminate (MgAl 2 O 4 ), 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].
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.

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  . Adapted from ref. [21] with permission from Elsevier™. 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 0.5 Zn 0.5−x Mg x Fe 2 O 4 NPs, which were synthesized in the presence of citric acid (C 6 H 8 O 7 ) solution that was added as a fuel and ethylene glycol (C 2 H 6 O 2 ) drop by drop to produce the final gel composition. The resulting Mn 0.5 Zn 0.5−x Mg x Fe 2 O 4 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 0.5 Zn 0.5−x Mg x Fe 2 O 4 NPs as a magnetic recyclable catalyst for outstanding photocatalytic and antimicrobial potentials.

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 NH 4 OH 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 NH 4 OH 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.

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  [97] 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 CoFe 2 O 4 samples.

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 dO 4 ) 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, wellfaceted polyhedral crystallites are formed. Meanwhile, 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™.
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 ZnFe 2 O 4 NPs through thermal decomposition. Fe 0.6 Zn 0.4 Fe 2 O 4 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.

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., CoFe 2 O 4 [78], Co 0.50 Zn 0.50 Fe 2 O 4 [79], etc., were recently published. Gaudisson et al. [80] have fabricated a group of nanostructured and compact spinel CoFe 2 O 4 via the polyol method by utilizing three different solvents of polyol category, viz., diethylenglycol, 1,2-dihydroxyethane, and 1,2propanediol, including different aggregate phases. The obtained CoFe 2 O 4 particles display distinct aggregate states. On utilizing diethylenglycol as a solvent, the CoFe 2 O 4 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.

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 MFe 2 O 4 (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 Fe 3   other metal ferrites. The capacitive behavior of CoFe 2 O 4 was also found to vary with morphology.

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 × 10 3 K and 10 3 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-ZnFe 2 O 4 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   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.

Synthesis of ferrite thin films
The significant problems the researchers face are fabricating ferrite films utilizing easy technology with lowtemperature 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 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 Fe 2 O 4 NPs are illustrated in Figure 11. The detected reflection peaks correspond to the characteristic Fd3m space group SFs (JCPDS card no.   [91,92]. All detected peaks are allowed Bragg 2θ 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 Fe 2 O 4 without any secondary phases [93,94]. Generally, there are two vibrational bands characteristic for SFs, namely υ 1 and υ 2 originating from the stretching vibration of A-site groups (tetrahedral) and B-site groups (octahedral), respectively [95]. Massoudi et al. [96] have prepared Ni 0.6 Zn 0.4 Fe 1.5 Al 0.5 O 4 via the sol-gel technique following the annealing process at different temperatures. The Fourier transform infrared spectroscopy spectrum of Ni 0.6 Zn 0.4 Fe 1.5 Al 0.5 O 4 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 υ 1 and υ 2 confirmed the formation of the Ni 0.6 Zn 0.4 Fe 1.5 Al 0.5 O 4 SF structure. 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 O 4 . The absorption results from Fe 3+ (A Site) adapted a single hyperfine pattern. Hence, the substitution of the Fe 3+ ion with a Gd 3+ 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 Fe 3+ ion at the tetrahedral site via a significant ratio, an altering in the superexchange interaction is observed ( Figure 13).
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 CoFe 2 O 4 are introduced [35].

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

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 × 10 10 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.
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 O 2 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 Fe 2+ and Fe 3+ ions takes place inside the tetrahedral/octahedral ionic sites, leading to significant changes in magnetic characteristics; (3) Fe 3+ is forced to the tetrahedral sites by a proportion of Fe 2+ 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 Zn 2+ by Fe 2+ cations in the tetrahedral site gives ZnFe 2 O 4 , which exhibits magnetic behavior than Fe 3 O 4 along with high magnetic saturation due to Zn 2+ and Fe 3+ 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 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.
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

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 (NiFe 2 O 4 /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 (NiFe 2 O 4 /C) nanocomposite conversion of light to heat is high. Furthermore, the hybrid design of the (NiFe 2 O 4 /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, ZnFe 2 O 4 and CoFe 2 O 4 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 (ZnFe 2 O 4 and CoFe 2 O 4 ) 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 CO 2 -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.
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 Fe 3 O 4 @MoS 2 that had a superior SPM with a high surface area of 97.16 m 2 /g, without aggregation results or the restacking of MoS 2 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 Fe 3 O 4 @MoS 2 using PEG and 2-deoxy-D-glucose (2-DG) for targeted chemo-photothermal therapy. The obtained Fe 3 O 4 @MoS 2 /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/Fe 2 O 4 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 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 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 magneticbased 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 KH 2 PO 4 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 0.3 Zn 0.2 Mg 0.5 Fe 2 O 4 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 Ca 2+ 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 Ca 2+ 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). CoFe 2 O 4 , 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 CoFe 2 O 4 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 HAcoated 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.
Sangeetha et al. [137] developed an intelligent drug delivery system and/or a hyperthermia carrier by creating a potential magnetic nanocomposite of CoFe 2 O 4 /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 CuFe 2 O 4 @SiO 2 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 SiO 2 layer, the surface area of the samples increased from 2.59 to 199.2 m 2 /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 CuFe 2 O 4 @SiO 2 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 CuFe 2 O 4 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 CuFe 2 O 4 @SiO 2 was synthesized, it increased biocompatibility and drug storage. The results suggested CuFe 2 O 4 @SiO 2 be a promising option for medicinal applications as a hybrid system that can release medications and create heat at the same time.
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/CoFe 2 O 4 / TiO 2 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.
Wang et al. [140] created SPM cobalt ferrite/graphene oxide (CoFe 2 O 4 /GO) nanocomposites with MRI and controlled drug delivery through sonochemistry. The method is simple and effective, and GO nanosheets are uniformly coated with CoFe 2 O 4 NPs ranging in size from 5 to 13 nm. The CoFe 2 O 4 /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 CoFe 2 O 4 /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 CoFe 2 O 4 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 O 4 (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 Co 2+ concentration on the nanocomposite structure may alter magnetic characteristics, increasing hyperthermia SAR, and NPs coated with hydrophilic polymers enhance biocompatibility and SAR efficiency.
Daboin et al. [142] used the thermal decomposition technique to prepare magnetic mixed manganese-cobalt ferrite NPs (Mn 1−x Co x Fe 2 O 4 ); then, they were coated with SiO 2 using the Stöber process and adorned with Au@Fe 3 O 4 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@Fe 3 O 4 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@Fe 3 O 4 in water. By integrating magnetic NPs, SiO 2 , and Au@Fe 3 O 4 , the magnetic properties of the synthesized nanocomposite system may be fine-tuned to optimize SAR.
Mondal et al. [143] developed a MnFe 2 O 4 /ZnS magnetofluorescent 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 MnFe 2 O 4 core surface. MnFe 2 O 4 /ZnS core-shell NPs have a magnetic saturation of 1.15 emu/g, which is higher than MnFe 2 O 4 NPs. The Zn 2+ ions induce cation rearrangement in the nanocomposites' interstitial regions, resulting in an increase in saturation magnetization. The heating efficiency of the MnFe 2 O 4 /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 IC 50 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

Selected doped SFNPs and their composites
Cobalt ferrite CoFe 2 O 4 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 CoFe 2 O 4 was injected intratumorally (i.t.). NPs were injected when the tumors were ≈80-100 mm 3 (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 cubicshaped nanoparticles (IONCs) were injected into rats i.t. within the 3× HT (TEM; Figure 25b) or CoFe 2 O 4 (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, CoFe 2 O 4 presented only ΔT of 3°C on HT1, HT2, and HT3. The detected reduction in the temperature for CoFe 2 O 4 and CoFe 2 O 4 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 CoFe 2 O 4 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 26a shows that the Co-Fe NC chains and prolonged cobalt toxicity were present, as confirmed by longterm 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 CoFe 2 O 4 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 CoFe 2 O 4 NCs alone group, cancer cells were still viable (Figure 26g). Finally, they found that CoFe 2 O 4 NCs + HT destroyed the outer tumor membrane completely, which led to the prevention of the recurrence or relapse of the tumor (Figure 26c) [146].
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  (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.
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, Fe 3 O 4 and γ-Fe 2 O 3 were preferred to Fe 3 O 4 or γ-Fe 2 O 3 NPs due to slower magnetic moment relaxation of CoFe 2 O 4 than that with similar size [163,164]. The hyperthermic efficiency of CoFe 2 O 4 NPs was improved by adding a trace amount of Zn 2+ (5-15%) relative to cobalt (Co), while further addition of Zn 2+ , more than 15% relative to Co, resulted in a reverse effect [165]. Likewise, the anticancer activity of CoFe 2 O 4 NPs against (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.
human colon cancer has been enhanced by trace Ce-Nd addition [166].
Zhang et al. [167] used leucine-coated cobalt ferrite (CoFe 2 O 4 ) 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 CoFe 2 O 4 NPs demonstrated comparatively minimum cytotoxicity compared with that of CoFe 2 O 4 NPs, and the DOX-loaded Leu-coated CoFe 2 O 4 NPs showed an observable cell death for HeLa cells. Iqbal et al. [168] have reported that cobalt ferrite doped with zinc (Zn 0.5 Co 0.5 Fe 2 O 4 ) 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 0.5 Co 0.5 Fe 2 O 4 incubated with HepG2 cell lines at 80 J/cm 2 laser fluence resulted in the cell viability loss of about 60−65%. The incubation time increased with increasing the absorbance for Zn 0.5 Co 0.5 Fe 2 O 4 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 0.5 Co 0.5 Fe 2 O 4 NPs. The cell inhibition was significantly higher (44%) at a laser fluence of 80 J/cm 2 than in dark cell inhibition (18%).
McBain et al. [171] reported that CoFe 2 O 4 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 CoFe 2 O 4 nanostructures. They also revealed a loading capacity of 88.6% of the nanostructure, a loading content of 118 mg of DOX/g of CoFe 2 O 4 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 CoFe 2 O 4 NPs over the surface that triggered the nanotubes magnetically in biological fluids. They also studied the releaseuptake 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.
Yang et al. [176] revealed that the CoFe 2 O 4 core and polydopamine and zeolitic imidazolate framework shell (CoFe 2 O 4 @PDA@ZIF-8) were used to encapsulate CPT in the ZIF-8 shell and DOX in the CoFe 2 O 4 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, CoFe 2 O 4 NPs have shown potential results in hyperthermia, diagnosis, and cancer therapy [177].
Magnetite Fe 3 O 4 is one of the oldest and yet one of the most commonly used SFNPs with a unique inverse spinel structure [178]. Fe 3 O 4 NPs were used as therapeutic hyperthermia cancer agents and magnetic-guided drug delivery [178,179] agents. Fe 3 O 4 NPs reached the highest and the lowest hyperthermia by doped Mn 2+ and Zn 2+ , respectively [180,181]. Two types of anticancer drugs, curcumin (Cur) loaded and synthesized SF nanocomposites (SFNCs), were synthesized by using Fe 3 O 4 NPs as the core; one of them (Fe 3 O 4 /OCMCS/Cur) was Cur, burdened, and encapsulated with O-carboxy methylchitosan (OCMCS), and another one, (Fe 3 O 4 /OCMCS/Cur/Fol) was folate attached to Fe 3 O 4 /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 Fe 3 O 4 /OCMCS/Cur/Fol was distributed uniformly after 5 h than Fe 3 O 4 /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 Fe 3 O 4 , camptothecin CPT cytotoxic drug, folate and tetrapeptides) [184].
Manganese ferrite (MnFe 2 O 4 ) 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  [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 0.9 Zn 0.1 Fe 2 O 4 NPs was synthesized with low M s = 13.2 emu/g as compared to Mn 0.9 Zn 0.1 Fe 2 O 4 NPs (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 0.9 Zn 0.1 Fe 2 O 4 NPs revealed drug loading, delivery, and hyperthermic cancer therapeutic effect [186].
Wang et al. [187] synthesized MnFe 2 O 4 @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 MnFe 2 O 4 @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 (Ce 3+ /Dy 3+ ) 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 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 × 10 6 cells/well) at 70 nM Co 0.3 Mn 0.2 Zn 0.5 Fe 2 O 4 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 NiFe 2 O 4 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 1.04 Fe 1.96 O 4 ) 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 0.5 Co 0.5−x Cd x-Fe 1.78 Nd 0.02 O 4 (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.
Zinc ferrite (ZnFe 2 O 4 ) has been used as an essential radiosensitizer in human prostate tumor radiotherapy (RT) [164]. It was reported that 100 μg/mL ZnFe 2 O 4 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 0.4 Mn 0.6 ) Fe 2 O 4 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 0.5 Zn 0.5 Fe 2−2x (Dy x Y x )O 4 (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 ZnFe 2 O 4 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 ZnFe 2 O 4 NPs; MCF-7 cells were incubated with 25, 50, 100, 250, and 300 μg per well ZnFe 2 O 4 NPs for 24 h. The cell viability decreased by 60, 53, 44, 32, and 24%, respectively.
The cytotoxicity mechanism of ZnFe 2 O 4 NPs based on ROS generation due to intracellular Zn 2+ 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 ZnFe 2 O 4 NPs with cell walls led to the damage and denaturation of the membrane. ROS generated on the surface of the ZnFe 2 O 4 NPs and particle disbanding and free Zn 2+ ions release resulted in the ROS production within the cells [212].
Magnesium ferrite MgFe 2 O 4 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) crosslinked β-cyclodextrin polymer coating of magnesium ferrite NPs (PVA-CD-MNPs) and camptothecin-loaded PVA-CD-MNP nanocomposite (PVA-CDMNPs@ CPT), where IC 50 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 MgFe 2 O 4 on the human breast cancer cell line MCF-7 [216][217][218] was investigated. Meidanchi and Motamed [221] revealed that MgFe 2 O 4 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 MgFe 2 O 4 behavior was revealed at room temperature. Additionally, the MgFe 2 O 4 as X-ray irradiation radiosensitizers was applied in MCF-7 RT. It was found that (a) the concentration of MgFe 2 O 4 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 MgFe 2 O 4 concentration under 2 and 4 Gy X-ray irradiation. Therefore, no significant cytotoxicity and significant cell damage were observed at 10 μg/mL MgFe 2 O 4, indicating that MgFe 2 O 4 could be used as a radiosensitizer for cancer cell therapy in comparison with RT alone. MgFe 2 O 4 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 CuFe 2 O 4 NPs and their composites are also used in cancer therapy. Jermy et al. [3] investigated the anticancer cytotoxic effect of CS enclosed CuFe 2 O 4 / 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 /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.

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 heatresponsive 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. 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.

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.
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Conflict of interest:
The authors state no conflict of interest.