Potential of Ferrite-Based Nanoparticles for Improved Cancer Therapy: Recent Progress and Challenges Ahead

Abstract

Recently, ferrite nanomaterials have emerged as a potent entrant in the biomedical field, especially in diagnosing and treating cancer in various organs because of their low toxicity, favorable magnetic properties, and biocompatibility. The conventional chemotherapy used for cancer treatment suffers from a deep setback because of the associated severe side effects produced in cancer patients during the treatment, such as bone marrow depression, hair fall, kidney damage, heart problems, neurological disorders, and others. Hence, in this context, ferrite nanomaterials provide the benefits of targeted delivery of a cytotoxic anticancer drug(s) to the specific tumor site using an external magnetic field, causing minimal side effects on healthy tissues. Another important benefit of using these nanomaterials lies in their ability to enhance the water solubility of hydrophobic drugs in order to extend the prolonged circulation of drugs in the blood and also to prevent fast renal excretion. Therefore, in this chapter, we will address the recent status and progress of ferrite-based nanomaterials in cancer therapy and will also cover the major challenges that hinder their translation from research to clinic.

1. Introduction

The interdisciplinary approach of nanomaterials brings researchers from physics, chemistry, and biology to put equal effort into synthesizing, understanding, and proceeding for various applications, from electronics, health, and environment to energy and information technology [1, 2, 3, 4, 5]. In this context, advancement in nanotechnology boosts human society with improved attributes of nanotechnological products. Nanomaterials are ultrafine particles of nanometer dimension (at least one dimension within 1–100 nm) with altered physico-chemical properties than macromaterials [6]. The magnificent properties of these nanomaterials provide a better future for their use in different diverse fields when compared to their bulk counterpart of the same composition because of the modified surface-to-volume ratio and tunable surface features [7, 8]. Among these, magnetic nanostructured materials (MNMs) have appeared as a robust entrant in the field of material synthesis and engineering because of their stupendous applications in the biomedical field, data storage, electronic devices (microwave, radiofrequency, and optoelectronics devices) [9, 10, 11], environmental remediation (catalysts, hydrogen storage), and others [12, 13] as summarized in Figure 1.

Figure 1.

Schematic representation of few technological applications of magnetic nanostructured materials.

Furthermore, in the biomedical field, especially in the diagnosis and treatment of cancer, MNMs have gained proficient attention because of their excellent magnetic property and biocompatibility [14, 15]. The biomedical applications of MNMs rely on their ferromagnetic or superparamagnetic nature. This is because of the fact that in using an external magnetic field, these MNMs can be used for targeted delivery and release of anticancer drugs at the specific disease site. MNMs can be used for hyperthermia therapy, and they can also be used as a magnetic contrast agent in MRI diagnostic. For effective in vivo applications, such MNMs should be stable in an aqueous medium at physiological pH (7.4) and should be biocompatible [16, 17, 18]. In general, MNMs intended for in vivo must be conjugated or coated with a biocompatible polymer-like dextran, polyethylene glycol (PEG), polyvinyl alcohol (PVA), Poly D, L-lactic-co-glycolic acid (PLGA), and others during or after the synthesis process. Such type of surface-coated polymers on the MNMs helps to overcome the formation of large aggregates and also facilitates biodegradation when exposed to a biological system [19].

In a study from the International Agency for Research on Cancer (IARC), nearly 10 million cancer deaths were reported alone in 2020. Among all cancer cases, breast cancer tops the position with 684, 996 deaths in 2020 [20]. In recent times, similar to breast cancer, other types of cancer, such as lung, colon, and prostate cancer, have also been identified as one of the most fatal diseases with an alarming mortality rate across the globe. To date, the major prevention of cancer relies on early diagnosis, surgery, radiation, and drug therapy; however, once the cancer cells start metastasizing, drug therapy (chemotherapy) remains to be the only available option. However, chemotherapy seriously fails to meet the expected outcome in cancer patients, owing to its severe healthy tissue toxic effects. Many cancer patients even fail to complete chemotherapy regimens because of unbearable side effects, including immune suppression, risk of heart attack, hair fall, kidney problems, and others. It would not exaggerate to claim that the toxicity of conventional drug therapy is directly attributed to the off-target distribution of anticancer drugs to healthy tissues [21]. Hence, the main difficulties of cancer treatment lie in the cancer cell-specific delivery of cytotoxic drugs with diminished side effects. Consequently, in recent years, major efforts have been devoted to develop and design novel drug carriers that will overcome the downsides of conventional chemotherapy.

Many novel drug carriers, such as nanoliposomes [22], polymeric nanoparticles [23], carbon-based systems [24], gold nanoparticles [25], and others, have been reported over the past few years to enhance treatment outcomes in cancer patients. Despite the development of numerous types of nanocarrier for cancer therapy, magnetite (Fe₃O₄), manganese ferrite (MnFe₂O₄), and cobalt ferrite (CoFe₂O₄)-based MNMs because of their biocompatibility, favorable magnetic properties, higher chemical stability, ease of surface modification, and others are deliberated preferable over other nano drug carriers for tumor cell-specific delivery of cytotoxic anticancer drugs [19, 21]. MNMs provide the benefits of targeted delivery of anticancer drug(s) to the specific tumor site by applying an external magnetic field, causing minimal side effects on healthy tissues [19, 25]. Another important benefit of using such MNMs lies in their ability to enhance the water solubility of hydrophobic anticancer drugs, extend the prolonged circulation of drugs in the blood, and also prevent fast renal excretion [26, 27]. The nanoscale dimensions of the MNMs allow them not only to pass through the narrowest blood vessels but also to cross through cell membranes (paracellular transport) [21]. The present chapter deals with recent developments in the ferrite-based nano drug carriers investigated over the past years for cancer therapy. Along with some light has also been thrown on the challenges associated with MNMs for their clinical feasibility and large-scale technology transfer.

2. Anticancer drug delivery through magnetic nanocarriers/magnetic drug targeting

The drug-targeting concept for the cell-specific treatment of cancer has been a widely expanding field in medical science research. The idea of “magnetic drug delivery” by employing MNMs as drug carriers was proposed at the end of the 1970s by Widder and Senyei et al. [28, 29]. Despite the development of various nanocarriers, magnetic-mediated drug nanocarriers are becoming increasingly popular for the targeted delivery of cytotoxic anticancer drugs. Here, the therapeutic agents are encapsulated or attached to MNMs using a polymeric layer, which are then guided to the target site using an external magnetic field. The advantages of using these polymers include helping in the conjugation with the biological ligands for better tumor specificity and also enhancing the circulation time of MNMs in the blood (increased half-life) [19, 25]. A variety of anticancer drugs, such as cisplatin, methotrexate, danorubicin, doxorubicin, and paclitaxel, have been loaded into the organic/inorganic scaffold of surface-modified MNMs for drug delivery application. MNMs have the ability to carry a large dose of anticancer drug to attain high, local concentration, and avoid other inimical side effects resulting from high drug doses in other healthy tissues of the body. The low-cost factor and the simple synthesis technique further add value for their future large-scale production. After entering the body, MNMs can be directed to a specific solid tumor site under the influence of an external magnetic field. For use in the biomedical field, MNMs of homogeneous size and uniform shape are required [30, 31]. At the same time, good crystallinity and phase control of MNMs are also desired. MNMs must also have biocompatibility, good thermal stability, and suitable magnetic moment. MNMs can be coated with biomolecules or biodegradable polymers to increment the residence time in the blood circulation systems or to make them interact with a cell or a biological entity [19]. Drug-loaded MNMs are injected into laboratory animals (rats/mice) via an intravenous (IV) route. Around the tumor location, an external magnetic field is then applied where the maximum amount of the administered drug is supposed to be localized under the influence of the applied magnetic field. The drug from MNMs is then released by the enzymatic activity or changes in temperature/pH or other physiological conditions [32]. Furthermore, the smaller size of MNMs possesses many additional benefits, such as increased internalization across fenestrated tumor vessels, smart escape from RES uptake, improved blood circulation, and others [15]. The size and surface charge of MNMs have robust effects on the pharmacokinetics and the bioavailability of the loaded cargo within the body. The first phase clinical trial of magnetic targeting was performed in cancer patients using epirubicin-loaded MNMs [33]. The mechanism of drug targeting by ferrite-based nanocarriers at tumor locations has been represented in Figure 2.

Figure 2.

Schematic representation of magnetic drug targeting under the influence of an external magnetic field.

3. Design of MNMs for biomedical applications

For drug delivery applications, the used MNMs consist of several including magnetic core, outer coating, and surface functional groups. A proper selection of magnetic core is essential, which defines the capabilities of the system, for example, heating; sensing, and others. The core portion of the MNMs should have a homogeneous size and uniform shape with a superparamagnetic or ferromagnetic nature [25, 34]. The superparamagnetic behavior ensures that the MNMs exhibit zero remanent magnetization when there is no applied field and a high magnetization under an externally applied magnetic field. Proper surface modification of MNMs is crucial to retain their colloidal stability and biocompatibility in any biological environment [35]. In selecting a magnetic core, a few key features such as particle size, functionality, stability, biocompatibility, and superparamagnetic nature are usually taken into consideration. The size distribution of the MNMs must be as small as possible (about 10–200 nm) having a monodisperse pattern. This is because all the physicochemical and magnetic properties strongly depend on the size and morphology of the MNMs. The hydrodynamic size of MNMs (which includes the total diameter of MNMs and the protective coating thickness) is also crucial for improved blood circulation time. Various kinds of inorganic materials, such as pure metal, metal alloys, iron oxide, and core-shell structures, have been explored for biomedical applications. Among MNMs, transition metals such as Fe, Co, Ni, and Mn are good options because of their high magnetization values, which is one of the key parameters for high performance hyperthermia and MRI applications. However, they are unstable and easily oxidized during synthesis time [7, 8]. These unavoidable problems make them unsuitable for biomedical applications. However, iron oxide-based magnetic nanoparticles such as magnetite (Fe₃O₄) [36, 37], cobalt ferrite [38, 39], manganese ferrite [40, 41], and zinc ferrite [42, 43] have received substantial attention for their promising application in biomedical fields. This is because of their biocompatibility and biodegradability along with their optimum magnetic property. Iron oxide nanoparticles (IONP) are stable and have good magnetization. It has an outstanding chemical stability, superb electrical insulation, moderate saturation magnetization, and a high Curie temperature. The similarity in magnetic behavior and other properties of both magnetite and maghemite make them difficult to distinguish. Fe₃O₄ has an inverse spinel structure where Fe⁺² ions are occupied by octahedral sites, and Fe⁺³ ions are equally distributed between octahedral and tetrahedral sites and can be represented by [Fe³⁺] A [Fe³⁺, Fe²⁺]BO₄. In Fe₃O₄, there is an equal number of Fe⁺³ ions in the octahedral and tetrahedral sites, which compensate for each other, and the resulting magnetization arises only from the uncompensated Fe⁺² ions in octahedral sites. However, maghemite (which has the same spinel structure as magnetite) forms as a result of the oxidation of magnetite and contains only Fe⁺² ions distributed randomly over the octahedral and tetrahedral sites. The magnetization of maghemite arises from uncompensated Fe⁺³ ions [44, 45]. The cation distribution in the tetrahedral and octahedral sites strongly depends upon the methodology adopted for the synthesis. The other alternative ferrites, namely, cobalt ferrite, manganese ferrite, and zinc ferrite are also investigated for various types of biomedical applications. Here, Fe⁺² ions are fully or partially altered by transition metals such as (M = Co, Mn, and Zn) in spinel structure, then they are represented by the general formula MFe₂O₄. Currently, more than 20,000 studies on IONPs have been reported, wherein the number of papers and biological effects of other MNMs, such as CoFe₂O₄, MnFe₂O₄, and ZnFe₂O₄, were less.

4. Synthesis of nanostructured magnetic materials

Over the past few years, considerable efforts have been devoted to the preparation of MNMs and understanding their properties for utilizing them in different areas of application. It is well-established that for a nanoparticle system, the physicochemical properties along with its biological fate strongly depend on the chemical composition and morphology of the particles, which are very sensitive to the synthesis route and surface engineering strategy of the given nanoparticle. Therefore, it is very crucial for controlling the synthesis conditions and surface engineering of MNMs, which governs their physicochemical properties, colloidal stability, and biocompatibility. Although numerous techniques have been reported for the synthesis of a wide variety of magnetic nanoparticles, some of the techniques are single-step, whereas others are multi-step techniques. All these techniques have both advantages and disadvantages, and none of these shows an authentic solution for all types of MNMs. Thus, one has to consider whether the chosen route is suitable for synthesizing the specific MNMs in a given environment using the available instrumental and synthesis facilities. Most of the synthesis techniques involve simple, basic inorganic chemistry methods. Instead of discussing all synthesis routes, here, we only discuss the synthetic procedure and its corresponding formation mechanism of co-precipitation and hydrothermal techniques. These chemical routes can be used to prepare steady and size-controlled MNMs when compared with other physical methods, such as gas-phase deposition.

4.1 Co-precipitation method

This method is one of the simplest techniques for synthesizing MNMs. The IONPs can be prepared using the method of precipitation from aqueous solution containing ferric and ferrous salts (in a 2:1 stoichiometric ratio) at a temperature (70–90°C) under an inert atmosphere by the addition of a base. The size and morphology of MNMs strongly depend on the type of salts, such as chlorides, sulphates, nitrates, and others, Fe²⁺ to Fe³⁺ concentration ratio, reaction temperature, and pH of the solution [46, 47]. The pH of the solution during formulation development usually remains between 9 to 14 [48, 49]. The chemical reaction for this process can be expressed as Fe²⁺ + 2Fe³⁺ + 8OH⁻ = Fe₃O₄ + 4H₂O.

Magnetite is not stable enough and easily converted into maghemite in the presence of oxygen. The chemical reaction is written as Fe₃O₄ + 2H⁺ = Fe₂O₃ + Fe²⁺ + H₂O. The surfaces of MNMs are coated with organic polymers during the precipitation process to prevent the oxidation caused by air, as well as the formation of aggregates. MNMs with broad particle sizes having irregular morphology are prepared by this technique. However, the preparation of mixed oxide via this technique is less straightforward because the different metals precipitate at different pH values. In this synthesis technique, only kinetic factors control the growth of the crystal. However, getting a narrow size distribution with a homogenous shape is a challenging task using this synthesis route. In terms of simplicity, the co-precipitation method is considered a preferred route for IONP synthesis.

4.2 Hydrothermal method

Like the co-precipitation technique, hydrothermal method is relatively less explored for the synthesis of MNMs, although it allows the synthesis of high-quality particles. Polar solvents, such as water, methanol, or isopropanol as well as organic solvents, are used in this technique. The MNMs are formed by the dissolution and crystallization mechanism. In this technique, mixture consisting of FeCl₃, ethylene glycol, sodium acetate, and polyethylene glycol is stirred vigorously to form a clear solution, then sealed in a Teflon-lined stainless steel autoclave, and heated to and maintained at (130–250°C) temperature for 8 to 72 hours [8]. The precursor solution is poured into the Teflon chamber in such a way that 80% of it is filled. Finally, the temperature of the autoclave is allowed to cool down to room temperature and the resultant supernatant solution is washed to remove unused surfactants, impurities, and unreacted precursors. Here, ethylene glycol is used as a high-boiling point reducing agent, sodium acetate as an electrostatic stabilizer to prevent particle agglomeration, and polyethylene glycol as a surfactant against particle agglomeration [8]. The parameters, such as heating temperatures, reaction timings, and the ratio of the precursor to surface coatings, are tailored to obtain biocompatible MNMs with various sizes and shapes. In this way, different types of MNMs can be fabricated with tunable sizes with a high degree of crystallinity [50, 51]. Other metal oxide nanoparticles can be also prepared using this technique.

5. Stabilization of nanostructured magnetic materials

Stability is a pivotal requirement for almost any technological application of MNMs. Bare MNMs tend to agglomerate and form clusters in order to reduce their large-surface area-to-volume ratio. Therefore, the protective coating of MNMs is a mandatory requirement to achieve good colloidal stability with non-agglomerated particles. This is usually done by developing a core-shell structure, wherein the bare MNMs can be coated with a material forming a shell, hence, isolating the magnetic core from the outside environment. MNMs can be coated using an organic or inorganic material. For organic coating, organic materials including polymers, oleic acid, oleylamine, dodecyl amine, and others are used. For coating with inorganic components (viz. silica, carbon, and Au), and others are used. For polymer coating of MNMs, natural polymers, such as chitosan, starch, dextran, albumin, and others, and synthetic polymers such as PEG, PVA, PLGA, and others can be employed. To avoid agglomeration, the surfaces of MNMs are passivated by polymer coatings. Here, the polymers are adsorbed on the surface of MNMs by forming a single or double layer. This layer causes steric repulsion to balance the magnetic and the van der Waals forces acting on the particles. MNMs stabilized by polymers are not stable in air and can be easily separated by acidic solution, affecting their magnetization value. At higher temperature, polymer-coated MNMs exhibit low intrinsic stability, which can even be enhanced by a possible catalytic action of the metallic cores. Therefore, non-polymeric coated materials are sometimes a better choice instead of polymer-coated materials to provide better colloidal stability and prevent agglomeration of MNMs.

6. Recent research findings on MNMs in drug delivery system

The idea of “magnetic drug targeting” by employing MNMs as drug carriers to specific tumor sites was proposed by Widder and Senyi in late 1970 [28, 29]. Following their early investigations, the anticancer efficacy of this approach was proved in several minor animal tests against various types of malignancies, such as lung, breast, prostate, and brain cancer and even resulted in a limited number of animal studies [52]. Despite these efforts, however, this technique has yet to be standardized at the pre-clinical level. One of the primary reasons is that present MNMs have limited payload capacity because payload can either be affixed to the surface or incorporated in the double-layer covering that surrounds MNMs. Lubbe et al. conducted the first animal MNM investigation, in which tiny volumes of ferrofluid were utilized as delivery systems to concentrate epirubicin in tumors [33]. The study found that there were no significant anomalies caused by the ferrofluid. Therefore, it was determined that the magnetic fluid was safe and could be utilized to treat cancer. According to the findings, the same study team conducted Phase I and Phase II clinical studies between 1996 and 2001 [33, 53]. The outcomes showed that patients tolerated magnetic drug targeting with epirubicin well; and that in around 50% of patients, the nanoparticles were successfully targeted to the tumors. Methotrexate-conjugated IONPs were created by Kohler et al. [53] and have the potential to serve as drug carriers in controlled drug release as well as contrast-enhancing agents [54].

Superparamagnetic CoFe₂O₄ NPs coated with folic acid were created by Mohapatra et al. [54], and their anticancer effectiveness was tested on HeLa cells. They noticed that CoFe₂O₄ NPs did not significantly alter the proliferation at concentrations up to 20 mg/mL in comparison with the control, indicating the nontoxicity of CoFe₂O₄ NPs [55]. According to Georgiadou et al. [55], CoFe₂O₄ NPs with oleylamine dramatically lowered their toxicity in normal cells when compared to malignant cells [56].

RBCs and polymorphonuclear (PMN) leukocytes from human blood, as well as an 8-week-old Swiss male mice, did not exhibit any in vivo or in vitro toxicity when exposed to spherical CoFe₂O₄ NPs with a size of 20 to 100 nm, according to L.F. Cotica et al. [56]. No discernible toxicity was seen in studies of in vitro toxicity on RBCs and PMN leukocytes for periods of 24 and 6 hours at concentrations of 0.02, 0.01, 0.005, and 0.0025 mg/mL [57].

Because of the increased hyperthermia and coercivity created by mixing the magnetic component (Co) with Fe₃O₄ in Matsuda et al.’s [57] study, spermine-coated CoFe₂O₄ nanoparticles exhibit more potent anticancer activity against the MCF-7 cell line than the Fe₃O₄ NPs [38].

CoFe₂O₄ NPs were developed hydrothermally by Ansari et al. [38], and their anticancer activity against MCF-7 cells and healthy cells was studied. According to their research, CoFe₂O₄ nanoparticles were harmless for normal cells and only weakly anti-proliferative against MCF-7 cells [58]. The L-cysteine coating improves the colloid stability and biocompatibility of CoFe₂O₄ NPs according to Wang et al. [58]. They claimed that CoFe₂O₄ NPs coated with L-cysteine could transport doxorubicin at a concentration of 0.62 mg/mg in the form of a nanocarrier. They also demonstrated that medication release is almost twice as great under acidic circumstances as it is in neutral ones. Additionally, their findings showed that even at concentrations as high as 150 g/mL, HeLa cells only exhibited around 10% of the expected rate of apoptosis after 24 hours of incubation [59].

Similar to this, Fan et al. [59] suggested using silica-coated CoFe₂O₄NPs as a targeted nanocarrier for DOX delivery to the HeLa cell line. They demonstrated the pH dependence of the nanodrug delivery system’s drug release performance and its rise with a lowering pH value [60]. Docetaxel-loaded PLGA-PEG-based CoFe₂O₄ nanodrug delivery system was created by Panda et al. [15] who also tested the in vitro cytotoxicity against the MCF-7 and MDA-MB-231 breast cancer cell lines. Drug-loaded NPs were reported to have respective IC₅₀ values of 15.58 g/ml and 14.05 g/ml against MDA-MB 231 and MCF-7 cell lines [15]. To test the system’s potential for magnetic drug targeting, Gaihre et al. [60] synthesized doxorubicin-loaded IONPs in gelatine [61]. In a research on drug release under various pH conditions, an acidic medium showed a persistent pattern of drug release compared with a neutral media.

In the transport of docetaxel to prostate cancer cells, Ling et al. [61] established PLGA-based IONPs functionalized by PEG [62]. Their research showed that the formulation had improved drug release characteristics and increased drug loading effectiveness (6.08%). They concluded by saying that these nano-drug formulations would be appealing for future nanomedicine development of multifunctional vesicles for simultaneous targeted imaging and drug delivery vehicles for prostate cancer treatment.

Because of the considerable cellular absorption of nanoparticles on CT-26 (Colon) cell line and their magnetic characteristics, Schleich et al. [62] demonstrated that paclitaxel-loaded PLGA-based Fe₃O₄ NPs might be employed as tumor-targeting MRI contrast agents [63]. Future nanomedicine applications might combine molecular imaging, drug delivery, and real-time treatment response monitoring because of the NPs’ multifunctionality. Maghemite NPs with a silica coating were made by Rudzka et al. [63], and then they were functionalized with gold [64]. Using a magnetic drug delivery device, they saw a maximum loading of 80 mol/g for doxorubicin. The cytotoxicity investigation also showed that a medication delivery method based on maghemite is more effective against colon cancer than against liver cancer. By developing iron oxide-based PLGA NPs, Zhou et al. [64] hypothesized that these microspheres may be employed as contrast agents for dual imaging and to improve the effects of high-intensity focused ultrasound ablation on liver tissue [65].

Curcumin-loaded chitosan-modified Fe₃O₄ NPs were generated by Pham et al. [65], and their anticancer effectiveness against the A549 cell was examined. The IC₅₀ value for the A549 cell was 73.03 g/ml. The findings demonstrated that the altered Fe₃O₄ NPs might be utilized as a nanodrug carrier for the treatment of cancer [66]. Cui et al. [66] generated magnetic PLGA NPs modified with transferrin receptor-binding peptides by co-encapsulating MNPs with a dual medicine (paclitaxel and curcumin). Comparing the dual-targeting effects with the non-targeting NPs, they found that cellular uptake studies showed a > 10-fold increase, and brain delivery showed a > 5-fold improvement [67].

A hydrophobic surface on a magnetic nanocarrier of Fe₃O₄ was created by Pourjavadi et al. to enable the adsorption of significant quantities of anticancer medicines [68]. To increase the colloidal stability and biocompatibility, the drug-loaded magnetic nanocarriers were coated with an alginate polymer shell. Additionally, they noted that alginate shells are removed from nanocarrier surfaces in acidic media, resulting in a higher rate of drug release than in neutral media wherein alginate shells are stable. To improve the delivery of docetaxel to breast cancer cells, Panda et al. (2018) created a PLGA-PEG-based Fe₃O₄ nanodrug delivery system [19]. Drug-loaded NPs were found to have an IC50 value of 18.4 g/ml. The proposed nanodrug formulation displayed acceptable cytotoxicity against MCF-7 cells and a predominate uptake by MCF-7 cells throughout a 0.5-hour incubation period. Additionally, the team investigated the in vivo pharmacokinetics of docetaxel-loaded Fe₃O₄ in comparison with the drug’s free form. The cytotoxic efficiency of curcumin-loaded PLGA-Fe₃O₄ microspheres against HeLa (cervical cancer) cells was enhanced in comparison with the bare curcumin and magnetic microspheres according to Ayyanaar et al. [68]. They suggest using magnetically tailored medicine delivery devices using their magnetic nanocomposite [68].

Doxorubicin-loaded PLGA-Fe₃O₄ core-shell nanocomposite was created by Zhu et al. [69] and was employed as a dual drug delivery method and an MPI quantification tracer. Using the nanocomposite injection, observing the drug release, and evaluating the resulting tumor cell mortality, they also carried out in vivo drug release monitoring in a cancer treatment context using a mouse breast cancer model. Compared with existing monitoring techniques, this study offers a better method for in vivo drug release monitoring. A pancreatic cancer cell line and an orthotopic xenograft mouse model were used by Khan et al. (2019) to examine the effectiveness of the curcumin-loaded Fe₃O₄ NPs to overcome gemcitabine resistance and enhance its therapeutic potential [70]. Their findings showed that gemcitabine and curcumin-loaded Fe₃O₄ NPs had powerful synergistic effects in suppressing human pancreatic cancer cells as well as cancer stem cells. One significant advancement is the development of targeted drug delivery systems using ferrite-based nanoparticles. These nanoparticles can be functionalized with specific ligands or antibodies that selectively bind to cancer cells, allowing for targeted delivery of therapeutic agents directly to the tumor site. This approach minimizes off-target effects and improves the efficacy of treatment while reducing systemic toxicity [71]. Ferrite NPs can generate heat when exposed to an alternating magnetic field. This property has been utilized in hyperthermia therapy, wherein the nanoparticles are selectively delivered to the tumor site and then heated to induce localized tumor cell death. Recent studies have demonstrated enhanced therapeutic outcomes by using ferrite nanoparticles with improved heating capabilities and biocompatibility [72]. Recent progress has focused on developing ferrite-based nanoparticles with enhanced imaging capabilities, such as improved signal intensity and prolonged circulation time. These advancements allow for better visualization of tumors and monitoring of treatment response [73].

7. Challenges of magnetic drug targeting

• Biocompatibility and toxicity: Ferrite nanoparticles need to be biocompatible to ensure minimal adverse effects on healthy tissues. Their potential toxicity, particularly when used at high concentrations or for long durations, requires careful evaluation and optimization.

• Pharmacokinetics and biodistribution: Understanding the behavior of ferrite nanoparticles in vivo, including their pharmacokinetics, biodistribution, and clearance pathways, is crucial for safe and effective therapeutic applications. Addressing concerns related to long-term stability and potential accumulation in organs is essential.

• Scalability and manufacturing: Developing scalable synthesis methods for ferrite nanoparticles with consistent size, shape, and surface properties is essential for clinical translation. The cost-effectiveness of large-scale production should also be considered.

• Clinical translation: Although preclinical studies have demonstrated promising results, clinical trials are necessary to assess the safety, efficacy, and long-term outcomes of ferrite-based nanoparticle therapies. Regulatory and approval processes need to be navigated to bring these therapies to the clinic.

• Combination therapies: Integrating ferrite-based nanoparticles with other treatment modalities, such as chemotherapy, immunotherapy, or radiation therapy, requires careful optimization and understanding of synergistic effects, dosing regimens, and potential drug interactions.

• Tumor heterogeneity: Cancer is a highly heterogeneous disease, and the efficacy of ferrite-based nanoparticle therapies may vary across different tumor types and subtypes. Tailoring treatments to individual patient characteristics and addressing interpatient variability pose significant challenges.

• Stability and controlled release: Ensuring the stability of ferrite nanoparticles during storage and transportation, as well as achieving controlled release of therapeutic payloads, remains a technical challenge that needs to be overcome.

Addressing these challenges will pave the way for the successful implementation of ferrite-based nanoparticles in cancer therapy. Continued research, interdisciplinary collaborations, and advancements in nanotechnology will be crucial to overcome these obstacles and fully realize the potential of ferrite-based nanoparticles for improved cancer treatment.

8. Conclusion

Although substantial progress has been achieved in the case of in vivo applications, to date, confirmed clinical studies are still complicated. Various basic issues such as the size, controlled synthesis, stability, biocompatibility, drug release capacity in physiological conditions, drug-MNMs binding, and others need to be solved. In conclusion, the potential of ferrite-based nanoparticles for improved cancer therapy has shown promising progress in recent years, but several challenges lie ahead for their practical application. The use of ferrite nanoparticles in cancer therapy offers several advantages. These nanoparticles possess unique magnetic properties, such as high magnetic saturation and superparamagnetism, which allow them to be easily manipulated using external magnetic fields. This characteristic enables targeted drug delivery and localized hyperthermia, leading to enhanced therapeutic outcomes while minimizing side effects. Additionally, the surface of ferrite nanoparticles can be modified to attach targeting ligands, antibodies, or drugs, enabling specific targeting of cancer cells and reducing off-target effects. Recent research has demonstrated the efficacy of ferrite-based nanoparticles in various cancer treatment strategies. Magnetic hyperthermia, for instance, utilizes the heating effect generated by ferrite nanoparticles under an alternating magnetic field to selectively kill cancer cells. Moreover, the ability to load and deliver chemotherapeutic drugs directly to tumors through magnetic targeting has shown improved drug efficacy and reduced systemic toxicity. However, several challenges need to be addressed before ferrite-based nanoparticles can be widely implemented in cancer therapy. One significant obstacle is the limited understanding of the complex interactions between nanoparticles and biological systems. The nanoparticles’ behavior in vivo, including their biodistribution, clearance, and potential long-term toxicity, requires comprehensive investigation. Further studies are necessary to assess the safety and biocompatibility of these nanoparticles. Ferrite-based nanoparticles hold immense potential for improved cancer therapy. Their unique magnetic properties, coupled with targeted drug delivery and hyperthermia capabilities, offer new avenues for personalized and effective treatment. However, addressing the remaining challenges, such as biocompatibility, synthesis scalability, and regulatory considerations, is crucial for realizing the full clinical potential of these nanoparticles in cancer therapy. Continued research and collaborative efforts are needed to overcome these obstacles and pave the way for the successful implementation of ferrite-based nanoparticles in cancer treatment.