2.1. Superparamagnetic iron oxide nanoparticles-based materials for cancer therapy

Superparamagnetic iron oxide NPs (SPIONs) are auspicious drug carrier platforms due to their high biocompatibility, T₁ and T₂ contrast effects for MRI, flexible surface functionalities, and stable colloidal suspensions in vivo [37], [38], [39]. Moreover, SPIONs may be metabolized and biodegraded while not accumulating in the body [34]. The US Food and Drug Administration (FDA) provided several types of SPIONs for clinical utilization [40]. Recent examples of SPIONs based materials for cancer therapy are reviewed below.

Zuvin et al. [41] demonstrated the anti-cancer effects of polyacrylic acid-coated SPIONs on breast tumor cells at the low magnetic field strength of 0.8 kAm^-1 by attachment of anti-HER2 antibody to NPs. The modified NPs were successfully internalized by MDA-MB-453 and HER2-positive SKBR3 cell lines. The HER2 overexpressing cancer cells were targeted and then killed by an anti-HER2 antibody conjugated SPIONs by hyperthermia made through induction under lower magnitudes and magnetic field strengths. The modified NPs also showed low toxicity to the cell lines resulted in a noticeable reduction in survival in MDA-MB-453 cells and cell proliferation exposing them to hyperthermia [41]. Compared with other therapeutic methods, this method has increased specificity, consequently, it can also provide a more effective treatment. Furthermore, several features such as high stability, ultra-small size, and resistance to aggregation, make it more appropriate for further in vivo studies.

Magnetically-guided NPs are promising candidates in targeted drug delivery systems. To transport bare MNPs or loaded with drugs to a targeted area, a constant external magnetic field is needed [42]. SPIONs are one of the best options which have acquired increasing attention for their applications in cancer therapy owing to their outstanding stability, good biodegradability, low toxicity, and superparamagnetism [43], [44]. Magnetically-guided drug delivery system is mainly simplified with the developing multifunctional NPs by encapsulation of SPIONs and the chemotherapeutic agents inside the desired polymeric systems. These multifunctional NPs can deliver the agents in a targeted manner within the tumors. To date, the studies reported on the multifunctional MNPs have not fully investigated their physicochemical properties, including cytotoxicity, solubility, magnetic properties, etc. A new multifunctional magnetic-polymeric NPs (MF-MPNs) was explained by Kandasamy et al. [45] based on ferrofluids by individual encapsulation of oleylamine-coated hydrophobic SPIONs into the poly(lactic-co-glycolic acid) (PLGA) NPs, as well as two drugs, curcumin (Cur) or verapamil (Ver). They investigated the magnetic properties, dispersibility, biocompatibility, and heating efficacies of the selected MF-MPNs. Ultimately, the therapeutic efficiency of the MF-MPNs was validated in the treatment of HepG2 liver cancer through two different mechanisms, thermotherapy via using SPIONs and chemotherapy via Cur or Ver. All results revealed that dual-drugs and SPIONs-PLGA NPs improved therapeutic efficiency in HepG2 tumor cells through integrated treatment (chemotherapy and thermotherapy) in comparison to the individual treatment. Hence, the MF-MPNs-based ferrofluids (SPIONs/dual-drugs co-loaded PLGA NPs) showed possible therapeutic options for in vitro multimodal cancer therapy. It has also been shown that PLGA encapsulation could improve the stability of SPIONs without altering or affecting the photothermal potency which can minimize the toxicity and maximize the treatment efficiency of the formulation [46], [47].

Magnetic hyperthermia cancer therapy is another conventional treatment option like chemotherapy and radiotherapy [48]. Interestingly, it has targeting capacity and low systemic toxicity. Nevertheless, this approach has major problems in clinical translation such as agglomeration susceptibility of the nano heating agents in aqueous media, uncontrolled heat generation and dissipation at the target region, and eschewed clearance by reticuloendothelial systems. In this regard, SPION as a potential targeted nano heating agent stabilized by a micellar conformation was fabricated for novel therapeutic applications. It was covered with a thin layer of polycaprolactone (PCL) to obtain higher thermo-sensitivity and cytocompatibility. Based on the in vitro findings, the human liver tumor cells’ viability at the greatest concentration of SPIONs (100 μg/mL) was considerably diminished to 40.1 ± 0.9% in the secure hyperthermia temperature range. This range was obtained with the heating effects of polymer-coated SPIONs in the existence of alternating magnetic field (AMF), representing them on or off cytotoxicity occurrence of polymer-covered SPIONs while exposing them to AMF [49]. The advantages of PCL-coated SPION include structural stability, better dispersity, cytocompatibility, and controlled heating under hyperthermia conditions that introduce it as a promising strategy for active targeting of the carcinoma cells in the future [49].

The synthesis process of iron oxie NPs (IONs) has been assessed in various studies utilizing iron (II) precursors. Nonetheless, the synthesis procedures include the use of different alkaline reagents or bicarbonate solutions, which are not desirable for bio-medical aims [50], [51]. The impacts of different oxidative circumstances were assessed on the magnetic and physicochemical features and cytocompatibility of synthesized SPIONs utilizing a single alkaline reagent and iron (II) precursor. For the first time, they assessed the synthesis of SPIONs through a sole precursor. The synthesis conditions were optimized where the N₂:O₂ flow ratio playing a critical role in targeting practical uses for cancer therapy. Various dose-response features of the synthesized SPIONs on several alternating magnetic fields (AMF) strengths were also investigated. Then, the induction heating efficacy of the optimum SPIONs was assessed under different AMF exposure. The cell viability was reduced to 49 ± 0.3% by the cytotoxic activity of the synthesized SPIONs on the human liver cancer cells under hyperthermia conditions. The findings revealed that such magnetic nano heating agents are effective candidates for cancer therapy objectives.

Antibody-conjugated NPs could maintain the chemical structure of the drugs and deliver them in a controlled way with low toxicity. Since some breast cancer indications have restricted therapeutic options, this field offers hope for the future treatment of breast cancer patients. Nevertheless, cross-linking of antibodies is not selective and causes the major drawback of lacking control on antibody orientation onto the surface of NPs [52]. In a recently published study, the theranostic ability of SPIONs was assessed to diagnose and treat cancer by establishing a single integrated nanoprobe. Oleylamin-coated SPIONs (SPION-Ol) were synthesized and modified with trastuzumab (TZ) and protoporphyrin (PP). The photothermal ablation and the relaxivity r₂ values were determined along with in vitro laser irradiation and MRI. There was no cytotoxicity after incubation of MCF-7 cells under different concentrations of theranostic agents and SPION-Ol. The results showed that water-soluble SPION-PP-TZ is an auspicious bimodal agent for diagnosing and treating human epidermal growth factor receptor (EGFR) 2-positive breast cancer cells utilizing photothermal therapy and a T₂ MRI contrast agent [53].

A formulation of SPIONs with polyaspartamide (PA) biopolymers was developed for the treatment of tumor cells through the hyperthermia method. PA is a biodegradable and biocompatible polymer with a polysuccinimide backbone that has a critical role in the encapsulation of SPIONs. Multifunctional drug carriers might be conjugated with further groups like biotin to increase the uptake ability of SPIONs to tumor-cell receptors. The findings revealed that great biocompatible performance is obtained by encapsulation of SPIONs nano heaters with PA biopolymer in terms of cell viability and represented useful cancer-killing activities in both in vivo and in vitro hyperthermia tests. PA-encapsulated SPIONs exhibited good heating ability via hyperthermia experiment in room-condition, increased cancer cellular uptake capability, and high cytotoxicity against cancer cells. These results will open the further potential for cancer treatment in the future [54].

Previous studies have shown that a particular bioactive moiety should be installed on SPIONs for treating breast cancer bone metastasis and targeting bone tissues. It was revealed that short-sized acidic peptides comprising repetitive sequences of aspartic acid [55] preferentially bind to hydroxyapatite, as the main element in the organic composition of bone. Pang et al. [56] reported examples of SPIONs-based material for cancer treatment. They utilized bone targeting SPIONs for inhibiting furin to alleviate breast cancer bone metastasis. In both osteoclast function and tumor cell invasion, proprotein convertase furin plays a vital role. The furin inhibitor, a peptide comprising a repetitive sequence of lysine-aspartic acid-glutamic acid, was delivered via the bone targeting SPIONs for enhancing the circulation of NPs within the bloodstream [56]. Besides, a matrix metallopeptidases (MMPs) 2/9-responsive linker has further attached to furin inhibitory peptide for enhancing the specificity of NPs [57], [58]. The MMP2/9 is an enzyme-responsive stimulus activated with metastatic/invasive phenotypes, which is a crucial element of tumor progression. Simultaneously, MMPs, particularly MMP9, also are critical enzymes in the process of bone resorption. Therefore, a multi-responsive and multifunctional SPIONs system was established. It specifically targets the bone metastatic sites, releases the Furin inhibitory peptide via MMP2/9 prompted cleavage, and generates contrast for the MRI imaging leading to the anti-osteoclastic and theranostic anti-cancer impacts (Fig. 1). The in vivo and in vitro data revealed that such a system can prevent breast cancer invasion and osteoclastic bone resorption resulting in alleviated osteolysis [56].

The peptide–conjugated NPs have shown increased selectivity, greater binding affinity, and more therapeutic efficacy. But, the behaviors of peptide–conjugated NPs in physiological conditions, e. g. intracellular space and bloodstream, have not been understood. Also, the vulnerability of peptides to enzymatic degradation [59], and possible immunogenicity of the engineered peptide–conjugated NPs, and the loss of biological function of the peptides that covalently combined with NPs are some common drawbacks for in vivo and clinical use [60], [61]. From this section, it is concluded that different types of SPIONs-based materials were applied for cancer therapy. An overview of the reported studies that utilized SPIONs-based materials for cancer therapy revealed that combining hyperthermia-targeted SPION approach with dye-labeled anti-HER2 antibody was the efficient approach that effectively achieves tumor specific, local, very effective therapeutic method against breast cancer. Also, the installation of a special bioactive moiety on SPIONs can efficiently be used for targeting breast cancer bone metastasis due to the difficulty of delivering anticancer drugs to the bone. However, inadequate tissue selectivity, poor drug-loading capability, uncontrolled biodistribution of SPIONs are the main drawbacks that limit their clinical translation.

2.2. Silica-based magnetic materials for cancer therapy

Silica-based materials are biocompatible materials with high chemical and physical stability [62], [63]. Recently, several studies have been performed to produce hollow mesoporous silica materials for increasing the efficiency of drug loading [64]. For the production of hollow silica spheres with mesoporous structures, the interior hard and soft templates were eliminated to create the nanocomposite’s hollow structure [65]. Nonetheless, the present synthesis approaches have limitations like time-consuming procedures and complicated experimental setup due to the removing template’s complexity [62], [63], [66]. Hence, it is significant to develop a facile technique for hollow mesoporous silica-based nanocomposite [67]. Here, recent examples of silica-based magnetic materials for cancer therapy are given.

A novel theranostic platform was constructed by Hsiao et al. [68], comprising a drug and a carrier which folic acid-Europium-gadolinium-mesoporous silica was grafted via disulfide bond with L-cysteine (FA-EuGd-MSNs-SS-Cys). It may provide an all-in-one therapeutic and diagnostic instrument with various significant functionalities such as tracing, imaging, and therapeutic drug delivery. To create the carrier (EuGd-MSNs), Europium (Eu³⁺) and Gadolinium (Gd³⁺) were doped into MSNs and the conjugation of the Cys on the surface of EuGd-MSNs is performed through disulfide bond linkage [69]. Hence, simple penetration is allowed into the cell while the controlled-release of the drug therapy. Moreover, FA targeting was obtained more efficiently with phagocytosis specificity and selectivity. The findings revealed that multifunctional theranostic FA-EuGd-MSNs-SS-Cys can be effective nanoplatforms for imaging-guided cancer treatment and simultaneous therapeutic agents. Evaluating the cellular uptake indicated that more cancer cells are trapped by FA-EuGd-MSNs compared to EuGd-MSNs. The cell materials revealed that Eu³⁺ emitted the intense red fluorescence, a considerable quantity of FA-EuGd-MSNs is swallowed with the Hela cells. Also, the photoluminescence sensitivity is enhanced by the paramagnetic functionality of the Gd³⁺ through MRI. The Cys appeared as an anticancer reagent in a cytotoxicity assessment of FA-EuGd-MSNs-SS-Cys using 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Excellent features were also revealed by EuGd-MSNs such as the nonexistence of cytotoxicity, stability, and decent biocompatibility when cultivating with normal L929 cells [68]. Advantageously, this approach can operate as a useful nano platform for a simultaneous therapeutic agent and imaging-guided treatment for cancer. Simultaneous diagnosis and treatment in this research are an important benefit over previous studies.

MNPs-based hyperthermia therapy has a variety of benefits comparing conventional hyperthermia therapy including targeted delivery resulting in more selective and effective treatment, localized hyperthermia, efficient blood-brain barrier (BBB) crossing, reduction of the needed effective dose of toxic chemotherapeutic drugs, etc. [70], [71], [72]. In this regard, a magnetic with potential chemo- hyperthermia therapeutic properties was established in terms of thermo-responsive copolymer-coated magnetic mesoporous silica NPs (MMSNs) with poly(N-isopropyl acrylamide-co-methacrylic acid) (P(NIPAM-co-MAA)). Loading of the model anti-cancer drug, doxorubicin hydrochloride (DOX.HCl), was performed over MMSNs@P(NIPAM-co-MAA). Temperature- and pH-responsive drug release performance was exhibited by DOX-MMSNs@P(NIPAM-co-MAA) and MMSNs@P(NIPAM-co-MAA). The DOX release was accelerated by a lower pH environment and hyperthermia temperature. The results of cell culture revealed hyperthermia, leading to a higher efficacy for killing cancer cells. Hence, MMSNs@P(NIPAM-co-MAA) present an auspicious platform for cancer treatment.

In another study, a tumor microenvironment-responsive biodegradable MnSiO₃@Fe₃O₄ nanoplatforms was provided for dual-mode MRI-oriented combinatorial cancer treatment. Anti-cancer drugs were loaded efficiently into the nanoplatforms in which Fe₃O₄ NPs block the pores of MnSiO₃ NPs, reducing the drug leakage under normal physiological circumstances. Under high-concentration of glutathione (GSH) or weakly acidic conditions, the nanoplatforms were broken leading to the Fe₃O₄ NPs separation and fast release of the Mn²⁺ ions and drug. Besides, the specific surface area of magnetic particles can be enhanced by the exfoliated Fe₃O₄ nanocrystals while improving the catalytic activity of the Fenton-type reaction into the cancer cells. Hence, more OH is generated enhancing the apoptosis of HeLa cells. Based on the in vitro and in vivo tests, outstanding improvement was obtained on the dual-mode MRI contrast and anti-cancer activity of the produced nanoplatform along with decreased systemic toxicity. Also, paramagnetic manganese (Mn²⁺) might play a role in reducing disturbance and T₁ and T₂ relaxation times at the same time. Such a multifunctional nanoplatform could efficiently decrease the adverse effects of the drug and might be useful to the real-time monitoring of drug release. Hence, this can be an auspicious option for synergistic cancer therapy and pH-responsive MRI in clinical uses [73].

For effective treatment of tumor-based bone defects, it is yet a big challenge to design and construct multifunctional biomaterials. Both chitosan (CS) and bioglass (BGs) were extensively found for bone repair use owing to their brilliant osteoconductivity, proper biodegradability, and good biocompatibility. SrFe₁₂O₁₉ (strontium hexagonal ferrites) as a MNPs was modified with mesoporous CS/BG porous scaffold and illustrated antitumor function and bone regeneration. It was found that the stem cell osteogenic differentiation and regeneration of new bone were considerably promoted by magnetic SrFe₁₂O₁₉ NPs in modified-mesoporous bioglass (BG)/CS porous scaffold (MBCS) through the activated BMP-2/Smad/Runx2 pathway. Furthermore, it presented perfect photothermal agents for killing residual cancer cells via NIR photothermal treatment. By irradiating near-infrared (NIR) laser, tumor apoptosis and ablation were triggered by the raised temperatures of tumors cocultured with MBCS. Compared to the pure scaffold group, the excellent antitumor efficacy was shown by MBCS/NIR group against osteosarcoma hyperthermia ablation. Advantageously, the multifunctional MBCS with superior photothermal therapy functions and bone regeneration can be effectively used for treating tumor-based bone defects [74].

With current progress in nanocarriers synthesis, it is allowed to use dual-drug delivery systems for encapsulating two drugs and improve the treatment impacts. In this regard, the Fe₃O₄@SiO₂@tannic acid NPs were used as a pH-responsive drug delivery system for simultaneous delivery of methotrexate (MTX) and DOX anticancer drugs. Studies were performed on in vitro drug release and loading performances. Loaded MTX and DOX nano-carriers exhibited pH-controlled-release of drugs in a sustained mode. According to the cytotoxicity study of blank nano-carrier versus MCF-7 cell lines possesses a cytocompatible future. Nevertheless, the co-administrating DOX with MTX possessed considerable cytotoxicity to the MCF-7 cell lines as a result of the pseudo peptide skeletons formation in the nanocarrier. Minimal drug leakage was shown by in vitro drug release performance at pH 7.4 from the Fe₃O₄@SiO₂ @Tann. This reduces the adverse impacts on the normal tissues. So, drug release is considerably higher at pH 5 enhancing the cytotoxicity for tumor tissues. Moreover, the MTT test revealed that the MTX-DOX-loaded nanocarrier possessed greater cytotoxicity against MCF-7 cells comparing the free drugs. The findings revealed that the Fe₃O₄@SiO₂@Tann could be used as a potential targeted drug delivery system to cancer tissues. Moreover, the potential for anticancer treatment was found by the prepared dual anti-cancer drug-loaded pH-responsive dual core-shell MNPs [75]. The advantages of this approach include biocompatibility, thermal stability, rich variety, and easy control of morphology, structure, and size. Also, the simultaneous use of two drugs can greatly enhance their therapeutic effect.

Presently, a huge deal of interest has been attracted by the bimodal photoluminescence-MRI method as a result of its greater potential in clinical practices and biomedical researches. A new tumor-targetable bimodal nano-probe, FA-Gd-Tb@SiO₂ was made by Song et al. through covalent binding of a luminescent Tb³⁺ complex, N, N, N, N-(4 -phenyl-2,2:6,2 -terpyridine-6,6 -diyl) bis (methylenenitrilo) tetraacetate-Tb) into the silica NPs framework, as along with their surface bonding of a tumor-targeting molecule (folic acid, FA) and an MR contrast agent gadoteridol (Gd- DO₃A) (Fig. 1). The created nanoprobe displays high r₁ and r₂ relaxivities, tumor-targeted binding, and stronger long-lived luminescence. Based on in vitro cellular time-gated luminescence (TGL) imaging the FA-Gd-Tb@SiO₂ nanoprobe can be identified and accumulated in tumor cells overexpressing the FA receptor. Moreover, in vivo assessment indicated that the as-prepared nano-probe can efficiently improve TGL intensity and T₁-weighted MR contrast in cancer tissue. Hence, it contributes to the accurate tracing and detection of tumor cells, and the identification and treatment of tumors clinically. Advantageously, this study suggests a new method for the design of a very targeted, multifunctional, size-controlled nano-drug with an outstanding photothermal effect and excellent pH-responsive performance in drug release and loading [76].

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Fig. 1. The synthesis process of bimodal TGL/MR imaging nanoprobe and its use for tracing tumor cells in the tumor-bearing mic. (Reprinted from publication Ref. [76], Copyright (2021),with permission from Elsevier (license code; 5157770388261).

Interesting research was reported for a combination of photothermal and chemotherapy treatment with DOX-loaded Fe₃O₄@SiO₂ nano-drug system. Using a simple solvothermal technique, it was prepared by Fe₃O₄ MNPs to control the ratio of the reactants for obtaining magnetic Fe₃O₄ particles with a modifiable size (20∼400 nm). Loading DOX onto the Fe₃O₄@SiO₂ composite particles pH-sensitive and simply release occurred in an acidic setting. This is vital for the particular drug release of tumor cells since the tumor cells possessed acidic internal settings reducing the toxic side impacts on the normal cells. By NIR light (808 nm) irradiating, photothermal therapy was induced by the photothermal effect created by Fe₃O₄@SiO₂@DOX while enhancing drug release. Cellular uptake and cytotoxicity of Fe₃O₄@SiO₂@DOX nano-drugs were assessed in A549 lung tumor cells. Almost 82.8% of A549 lung cancer cells could be killed by treatment with Fe₃O₄@SiO₂@DOX containing only 10 μg/mL of DOX. Moreover, 81.3% of lung carcinoma A549 cells were killed during incubation with Fe₃O₄@SiO₂@DOX that comprises just 0.5 μg/mL of DOX and 15 min of NIR irradiation, thus proposing an exceptional synergistic chemo/photothermal effect in the treatment of cancer [77].

Recently, a facile technique to construct IONP-hollow mesoporous silica spheres (IONP-HMSs) was designed and established through the oil in water microemulsion approach. This drug delivery system has many advantages including simple large-scale generation, adjustable uniform pore size, high surface area, and large pore volumes. In this study, cetyltrimethylammonium bromide (CTAB) encapsulated IONP spheres were provided the template to construct mesoporous silica shells. In the release and loading of DOX in vitro, the IONP-HMSs were utilized as a nanocarrier. Moreover, analysis was performed on the efficacy of DOX-loaded IONP-HMSs for cancer treatment and its biocompatibility through cellular cytotoxicity examinations. The findings revealed that IONP-HMSs possessed a high efficiency of drug loading that allows the pH-trigged release of DOX in vitro. Furthermore, the IONP-HMSs represented outstanding bio-compatibility and increased DOX therapeutic effect to the HeLa cells [67].

2.3. Magnetic gold materials for cancer therapy

Plasmonic NPs like gold are utilized for the controlled-release drugs as a result of their high photo energy conversion into heat [78]. This can activate the preloaded drug release [79]. For cancer therapeutics, multifunctional nanocomposites with interface interactions and controlled structures are attractive carriers [80]. Magnetically and optically activated nanocomposites like dumbbell-like NPs comprising two chemical surfaces which are appropriate for pH-sensitive drug delivery and synchronized cell targeting [81], [82]. Nevertheless, a pH-responsive system might not act well in complex environmental changes when interfering with other factors with the release procedure. In the following, we will review the recently published studies of magnetic gold materials for cancer therapy.

Presently, Jian et al. synthesized positively charged dumbbell-like gold MNPs (Au-Fe₃O₄ NPs) for targeted VEGF aptamers' delivering into ovarian tumor cells. The dominance interaction between DNA aptamers and targeting VEGF with the surface of Au-Fe₃O₄ is electrostatic absorption. Confocal microscopy was used to observe the targeted recognization of ovarian tumor cells via the aptamers-functionalized Au-Fe₃O₄ NPs (Apt-Au-Fe₃O₄ NPs). It was found that Apt-Au-Fe₃O₄ NPs specifically binds with SKOV-3 ovarian tumor cells, resulting in the marked intracellular release of aptamers over plasmon resonant light radiation. Hence, the in vitro inhibition is enhanced versus the proliferation of tumor cells. The findings revealed the high potential of Apt-Au-Fe₃O₄ NPs as a targeted cancer hyperthermia carrier through remote control with high temporal/spatial resolution. The unique features and aptitudes of aptamers include great binding affinity, small size, high specificity, non-immunogenicity, and ease of modification comparing the traditional monoclonal antibodies. The main drawbacks of aptamers for clinical uses contain low selectivity that restricts them in cell targeting and exact release of aptamers. For efficient therapeutic and highly sensitive diagnostics applications, the dumbbell-like Au-Fe₃O₄ NPs will possess large potential as nano-carriers [84].

The efficiency of photothermal therapy in treating cancer has been demonstrated in former studies. However, it is not probable to assure the selective and complete elimination of all cancer cells, because that numerous cells may escape and causing cancer recurrence [85]. Therefore, combining two or more therapeutic approaches can overcome the severe restrictions encountered by the separate utilization of each treatment [86], [87], [88]. Adjuvant-targeted chemo/photothermal therapy is one of the integrated oncological modalities. This could be applied for drug delivery and incrementing the local temperature at the tumor site while not influencing the normal adjacent tissues [89], [90], [91], [92]. This integrated treatment could be obtained utilizing an all-in-one nanohybrid. It may be triggered using laser beams serving as the external stimulus to induce photothermally and act as drug nanocarriers [93]. Moreover, the thermal effects can increment cellular responses for chemotherapeutic drugs. Hence, this therapy is allowed to administer in lower doses [94], [95]. Recently, further efforts have been assigned to designing potent theranostic NPs and integrate diagnostic and therapeutic agents, for effective cancer therapy. Elbialy et al. established multifunctional magnetic gold NPs (MGNPs) for selective delivery of the drug to the tumor site in a controlled-release mode by utilizing magnetic targeting; stimulate photothermal therapy with generating heat by near-NIR laser absorption, and serve as contrast agents for MRI. The produced MGNPs were characterized via various physical methods. Then, they were conjugated with PEG and DOX to form MGNP-DOX conjugates. The higher efficiency of MGNP-DOX for integrated chemo/photothermal treatment was found both in vivo and in vitro. The immunohistochemical studies and histopathological examination confirmed the efficiency of MGNP-DOX as theranostic material. Furthermore, MGNP-DOX represented decent potential as MRI contrast agents for directed chemo/photothermal synergistic therapies. This work enhances the comprehension of this therapeutic policy, thus optimizing and using MGNPs as the multifunctional drug delivery systems [96]. Also, in another study, a multifunctional drug delivery system has developed based on red blood cells (RBCs) for drug delivery and imaging-guided combination therapy of cancer. MNPs coated with chlorine e6 (Ce6), were attached to the RBCs membrane and then DOX was loaded within the RBCs. Ex vivo and in vivo imaging data showed the very efficient magnetic field-induced tumor homing of those RBCs after intravenous injection into mice [97].

Triple-negative breast cancer (TNBC) is a kind of greatly aggressive cancer, which is difficultly cured via common chemotherapy. The reason is mostly the TNBC drug resistance and lack of efficient tumor-targeting capability of the present drugs [98]. Hence, it is urgently required to develop new approaches for high-efficient and precise TNBCs therapy.

A multifunctional magnetic gold nano-heterostructure was fabricated with photosensitizer Ce₆ loading (MF-MGN@Ce₆) for synergistic photodynamic and photothermal treatment (PTT/PDT) of TNBC (Fig. 2). The mitochondria-targeting molecular and cell membrane-targeting peptide of cRGD of TPP was functionalized over the nanosystem to obtain MF-MGN@Ce₆@RT. Both in vitro and in vivo assessments revealed superb biocompatibility of MF-MGN@Ce₆@RT. The findings revealed cRGD/TPP dual targeting design guarantee the accurate delivery of MF-MGN@Ce₆@RT to TNBC tumors. It also enhanced considerably the nanosystem’s phototherapeutic effects. The heterostructure of MF-MGN@Ce₆@RT integrating both components of gold and iron oxide, MF-MGN@Ce₆@RT was revealed as a superior contrast factor for MRI/CT/PA trimodal imaging of in vivo tumors. Hence, it leads to complete tumor growth suppression. Their results, present new nanoplatforms for high-efficient and precise identification and treatment of TNBCs [99].

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Fig. 2. Schematic diagrams for fabrication of MF-MGNs@Ce₆@RT and its application in multimodal diagnosis, phototherapy combined photothermal and photodynamic treatment. (Reprinted from publication ref. [99], Copyright (2021), with permission From Elsevier (license code; 5157770618319).

2.4. Magnetic chitosan-based for cancer therapy

Recently, the application of polysaccharides has attracted much attention in nanomedicine [100], [101]. Particularly, chitosan (CS) as a natural polysaccharide has been utilized in some medical uses [102], such that the cancer therapies by CS as the drug delivery carrier have been extensively described to be a promising and beneficial method with large flexibility, bio-compatibility, and efficacy [103], [104]. With the advancing polysaccharide-based studies, large advancements have been achieved in the field of targeted drug delivery at the clinical trials as well as research [105], [106]. Here, we will discuss the recent advancement of magnetic CS-based material for cancer therapy.

Shanavas et al. assessed hybrid MNPs with PLGA ‘core’, and surface modified with folate-CS conjugate ‘shell’ as MRI contrast and simultaneous anticancer therapeutic agents. The folate-CS conjugates were prepared utilizing carbodiimide crosslinking chemistry for covering well-packed SPIONs with a further layer of PLGA loaded docetaxel. To better encapsulate, the crystals inside the polymer matrix, an optimal ratio of SPION to PLGA was fixed at 1:10 to provide a considerable magnetization feature to the nanocomposite for use as an MR contrast agent. The cancer drugs release from the CS polymer is carried out by external and internal stimuli (Fig. 3). In this study, at acidic pH, the pH-sensitive CS coating triggered drug release from NPs. The receptor-targeted SPION and docetaxel delivery was provided by biocompatible hybrid NPs for anti-cancer treatment and MRI respectively, as examined in both folate receptor-negative and positive cancer cells. Better cellular uptake was shown by folic acid receptor targeting, hence, cytotoxicity was increased against folate receptor overexpressing KB cells. The enhanced cellular uptake directly increased anticancer effectiveness and decreased the T₂ relaxation time of the tumor cell environment. Hence, darker T₂-weighted magnetic resonance contrast images were provided in comparison with the control cells. The immense potential of this receptor-targeted bio-compatible hybrid core/shell theranostic agent was found for simultaneous MR imaging and treatment of cancer [107].

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Fig. 3. Anticancer drugs release from chitosan nanocarriers in response to internal/external stimulus. (Reprinted from publication ref. [107], Copyright (2021), with permission from Elsevier (code of 5157790417598).

Anti-proliferative and antiangiogenic activity of artemisinin was found as a natural anti-malarial agent in the cancer cells with very lower toxicity to the normal cells. It has limited application in cancer treatment owing to its high lipid solubility, since achieving therapeutic concentration lacking toxicity to the normal cells is difficult [108]. Recently, the natural polymer CS was utilized as the formulating agent for loading artemisinin to MNPs. Uniform size NPs are made by optimization of the formulation circumstances. The particles represented good drug loading capability and an effective drug encapsulation with suitable magnetic features. The efficiency of drug encapsulation was found as 55%−62.5% along with the drug loading capacity of 20%−25%. After 48 h, artemisinin was released (almost 62%−78%) from the artemisinin MNPs. Regarding physiologically acceptable external magnetic fields, an improved accumulation of NPs was shown by fluorescein isothiocyanate (FITC) conjugated artemisinin MNPs within the BALB/c mice model’s 4T1 breast tumor tissues [109]. For higher drug loading, more specific drug-release, and more anticancer activity, the below strategy was applied.

Adimoolam et al. established a formulation including DOX conjugated to MNPs via a pH-sensitive imine linkage with glutaraldehyde as a crosslinker. Using a simple hydrolysis technique, synthesizing various quantities of CS functionalized MNPs was performed in situ at room temperature. For the lysosomes and endosomes pH drug release investigations, the as-synthesized DOX conjugated MNPs were utilized at various pH buffer solutions. Cell viability tests on the SKOV3 and MCF7 cell lines revealed that the MNPs conjugated DOX represented an improved therapeutic impact in comparison to equivalent concentrations of the free drug. Another advantage of MNPs is their decreased toxicity to the normal cells as a result of their targeting ability [110].

The chemical crosslinked interaction between synthetic terephthaloyl diisothiocyanate as a crosslinker and CS polymeric chains was accomplished by Eivazzadeh-Keihan et al. [111]. Three-dimensional (3D) crosslinked CS hydrogel was fabricated with high stability, porosity, and homogeneity and then used as the novel substrate to generate novel magnetic terephthaloyl thiourea crosslinked CS nano-composite. The designed magnetic nano-composite performance was assessed by the magnetic fluid hyperthermia process. The specific absorption rate (66.92 w/g) was defined by the alternation of magnetic field (AMF) with a magnetization value of 78.43 emu/g.

Recently, a CS-derived polymer was successfully produced by Zhao et al. via chemical conjugation of CS, gadopentetic acid (GA), and octadecanoic acid (OA) (Fig. 4). The achieved Gd-CS-OA/Ce₆ represented improved MRI ability with desirable biocompatibility and stability. Moreover, the Gd-CS-OA/Ce₆ improved the Ce₆ uptake into 4 T₁ cells both in vitro and in vivo tests. Gd-CS-OA/Ce₆ can realize MRI-guided PDT in both tumor-bearing models and 4 T₁ cells representing improved anticancer advantages compared to free Ce₆. Thus, Gd-CS-OA/Ce₆ was indicated as a capable theranostics DDS for efficient cancer treatment [112].

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Fig. 4. The figure shows preparation, MRI guided PDT of Gd-CS-OA/Ce₆ and drug loading. (Reprinted from publication Ref. [112], Copyright (2021), with permission from Elsevier (license code;5157780028007).

2.5. Magnetic metal-based material for cancer therapy

Metal-based NPs have diverse sizes and shapes and have been studied for their role in the detection and targeted drug delivery [113], [114]. The unique features of metal NPs, for instance, high surface area to volume ratio, facile chemical synthesis, wide optical characteristics, and easy surface functionalization hold promise in the bio-medical field for cancer therapy [115], [116], [117]. These NPs could also be simply functionalized with numerous moieties, e. g. antibodies, peptides, DNA, or RNA to particularly target various cells [118] and with bio-compatible polymers to extend their in vivo circulation for gene and drug delivery uses [119], [120]. Besides, they could effectively convert radiofrequency or light into heat, therefore allowing thermal tumor ablation [121], [122].

Tumor surgical excision is a conventionally therapeutic approach against breast cancer-induced bone metastases; nevertheless, it can cause bone defects and cancer recurrence. For overcoming these problems, Zhao et al. fabricated the multifunctional GdPO₄/CS/Fe₃O₄ scaffolds where the hydrated GdPO₄ nanorods were organized in the magnetic bioactive CS matrices for photothermal cancer therapy and bone regeneration. The Fe₃O₄ NPs in the scaffolds can apply as the photothermal agents for oncotherapy, and the greatly arranged GdPO₄·H₂O nanorods can promote osteogenesis and angiogenesis abilities. Under the irradiation of NIR laser, local temperatures surrounding the GdPO₄/CS/Fe₃O₄ scaffolds were enhanced to promote tumor cell apoptosis and avoid cancer recurrence. The new blood vessels provided nutrients and oxygen for osteogenesis. Besides, the GdPO₄ nanorods in the scaffolds stimulated BMP-2/Smad/RUNX2 signaling pathway that assisted cell proliferation, differentiation, and bone tissue regeneration. Thus, the new GdPO₄/CS/Fe₃O₄ scaffolds with bone defect healing function and photothermal therapy of tumor can become an auspicious platform for the efficient treatment of breast cancer bone metastases [123].

Photosensitizer and nanoparticle conjugates capable of X-ray-induced photodynamic therapy (X-PDT) are a research focus owing to their promising uses in cancer therapy. Jain et al. developed the magnetic-luminescent Gd_2.98Ce_0.02Al₅O₁₂@mSiO₂@rose bengal (GAG@mSiO₂@RB) nanocomposite to be used as an X-PDT agent. The developed GAG@mSiO₂@RB nanocomposite exhibited an effective Fluorescence Resonance Energy Transfer (FRET) upon loading with RB due to great spectral overlap between the RB and GAG. It was found that underexposure with low energy X-rays, the GAG@mSiO₂@RB nanocomposite produced 4 times greater singlet oxygen. Effective PDT of MDA-MB-231 cells incubated with GAG@mSiO₂@RB nanocomposite was attained upon irradiation with blue light, comparing RB alone. The GAG@mSiO₂@RB nanocomposite efficiently generated ROS upon excitation with X-rays. Besides, due to the presence of Gd in the crystal lattice of garnet, the suggested nanocomposite system indicated paramagnetic nature, that can overcome the problems of restricted light penetration for cancer theranostics. Biocompatibility, non-immunogenicity, optimal photoluminescence efficiency, and magnetic properties without any harmful effects in the absence of light, propose GAG@mSiO₂@RB nanocomposite as an attractive candidate for its applications. This new magnetic-luminescent nanoplatform is promising for future uses in the simultaneous diagnosis and treatment of deep-lying cancers [124].

Drug delivery systems (DDS) increase the potential of the drug in treatments because of protecting the drugs from fast degrading. Nontoxic MMSN have been applied for the controlled release of drugs and targeting. Fe₃O₄@mSiO₂ NPs were modified with polyethyleneimine linked folic acid (PEI-FA) to enhance their water solubility as well specificity for tumor cells (Fig. 5). Therefore, the cancer-selective disulfiram (DSF) carrier system (mMDPF) was manufactured with an enhanced surface-area-to-volume ratio. The drug loading capability of mMDPF was calculated as 4.35% via HPLC and the best drug release kinetics of mMDPF were detected at pH 6.0 and 37 °C that is the pH in the endosome. The mMDPF cytotoxicity on the MCF-7 cells was enhanced by using mMDPF with sodium or copper nitroprusside. They found that mMDPF was taken up more using MCF-7 cells and its toxicity on MCF-7 cells was much greater than nontumorigenic cells. Advantageously, high solubility and specificity, non-toxicity, selective killing of cancer cells, targeting, and controllable release of drugs are among the benefits that can be mentioned for this drug delivery system [125].

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Fig. 5. Schematic diagram of targeted cancer selective therapy with magnetic mesoporous DSF-loaded NPs. (Reprinted from publication Ref. [125], Coppyright (2021),with permission from Elsevier (license code; 5157780228470).

Early-stage detection is crucial for the effective treatment of cancer. Nevertheless, a single mode of MRI is hard to please the high necessities of precise diagnosis due to the innate defects. Jian-Hua et al. constructed a Fe₃O₄@MnO₂@polyacrylic acid NPs (Fe₃O₄@MnO₂@PAA) for the pH-responsive T₁/T₂ double-model MRI-guided photothermal therapy. The Fe₃O₄ core provided Fe₃O₄@MnO₂@PAA NPs with the realization capability of T₂-weighted magnetic resonance contrast agents, and MnO₂ nanoshells proposed a large potential for pH-responsive T₁-weighted MRI. This pH-responsive T₁/T₂ double-model MRI enhanced the specificity and sensitivity and also offered more inclusive data for cancer diagnosis. Additionally, Fe₃O₄@MnO₂@PAA NPs showed great photothermal performance due to the powerful NIR absorption performance, achieving the aim of killing tumor cells without harming the normal cells. Thus, It was revealed that this nanocomposite can be a hopeful pH-responsive theranostic agent for offering accurate and detailed information for the detection and treatment of cancer [126].

2.6. Magnetic carbon-based materials for cancer therapy

In recent years, carbon-based nanomaterials are attracting much attention owing to their capability to operate as a platform for attaching ligands or drugs [127]. Simple models are frequently applied in cancer studies, in which carbon nanomaterials are conjugated to a ligand that is particular to an overexpressed receptor for drug delivery and imaging in cancer therapy [128], [129]. These carbon nanomaterials present unique features to the delivery vehicle or imaging because of their high fluorescence qualities and their nontoxic nature [130]. We look into recently published studies of magnetic carbon-based materials for cancer therapy in the following.

Recently, the therapeutic impacts of NIR irradiation on DOX-resistant A549 cells were assessed and the equivalent in vivo investigations was conducted to assess the behavior of the synthesized substances over targeted chemo/photothermal treatment (chemo-PTT). Aptamer-functionalized Fe₃O₄@carbon@DOX NPs (Apt-Fe₃O₄@C@DOX) was reported for synergetic chemo-PTT of cancer (Fig. 6). By the excellent active tumor-targeting ability of Apt-Fe₃O₄@C@DOX NPs, the simultaneous recognition of target tumors was allowed via MR imaging. Based on in vitro cytotoxicity assay, the integrated chemo-PTT is further toxic to A549 cell lines as compared with PTT or chemotherapy agent alone. The explained therapy reduced tumor growth rates while existing even low quantities of DOX. This is likely caused by intracellular heat generation induced by the photothermal effect. It diminishes the metabolism of DOX and increments DOX accumulation in tumor cells. Such results revealed that the proposed chemo-PTT combination therapy can obtain high therapeutic efficiency against A549-based tumors with outstanding biocompatibility [131].

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Fig. 6. Schematic illustration of the preparation of Apt-Fe₃O₄@C@ DOX NPs and internalization of Apt-Fe₃O₄@C@DOX NPs into tumor cells for chemoephotothermal combination treatment. (Reprinted from publication Ref. [131], Copyright (2021),with permission from Elsevier (license code; 5157780336267).

It is still challenging to deliver across the BBB and target the brain tumors such as glioblastoma [132]. Hence, novel therapeutic approaches and drug delivery carriers are intensely sought. In this regard, Wu et al. [131] changed the formerly presented concept of particle and made a surfactant-free aqueous ferrofluid. It comprised SPIONs covered with carbon shells and silicate mesolayers. The double covering on SPIONs influenced numerous biological and physicochemical features such as cancer-targeting efficacy and colloidal stability. NPs reduced the viability of osteosarcoma and glioblastoma tumors comparing their non-transformed and primary analogs. A better preference was represented for cancer cells as a result of an enhanced uptake rate of the cells and noticeable adherence to the tumor cell membrane. Sufficient heat was generated by NPs even in an ultralow alternate magnetic field to lead to tumor death. In the basolateral compartments, NPs were found. Moreover, assessing LAMP1 revealed that NPs traversed the BBB transcellular, and escaped the lysosome while localizing to the optic lobes of the third instar larval brains of Drosophila melanogaster. The noninvasive passage resulted in low adverse systemic impacts to the animals. It is deduced that such nanoparticulate ferrofluids attach to cancer cells and, thus, reveal higher toxicity in these cells in comparison to primary cells. Hence, they have higher in vitro effectiveness against solid tumors and can path the BBB in Drosophila. These particles are also non-toxic according to the evolving studies on flies grown in ferrofluid-infused media [131].

There has been a huge deal of interest in new multifunctional core-shell NPs as a result of their abundant functional groups and easy-to-modify surface properties. Recently, Ag@Fe₃O₄@C-PEG-FA NPs was synthesized with regular structure, uniform size, and higher loading capacities of DOX. Advantageously, the as-synthesized Ag@Fe₃O₄@C-PEG-FA/DOX NPs had good photothermal impacts and improved DOX release by irradiation of 808 nm light. Furthermore, Ag@Fe₃O₄@C-PEG-FA/DOX NPs possessed outstanding biocompatibility, stability, synergistic treatment, and cancer cell targeting without any toxic side effects in the treated animals. A superior capacity is provided by multi-armed PEG at the edges of Ag@Fe₃O₄@C NPs for the materials for loading DOX. As a result of the superior near-infrared (NIR) absorbance capacity of the carbon layer, it can be utilized as a photothermal, Fe₃O₄ was employed as a reagent for MRI. Multimodal imaging specificities were included for DOX FL imaging and T₂-enhanced MR imaging in the tumor area and a decent inhibitory impact on tumor growth synergistic chemo/photothermal treatment. There were no obvious side effects and toxicity in the control and treated animals. Hence, the Ag@Fe₃O₄@C-PEG-FA NPs are perfect nanoplatforms for chemo/photothermal therapy and multimodel imaging [133].

2.7. Magnetic PEG-modified materials for cancer therapy

PEG-based materials, as a promising candidate for targeted therapy of various cancers, could self-assemble into NPs in the aqueous medium, and offer a stealth surface that might decrease reticuloendothelial system (RES) recognition of NPs and can extend the blood circulation time [134]. In theory, amphipathic PEG-assembled NPs may not be opsonized at all and remain in the blood circulation till penetrates leaky vasculatures in the tumor [118], therefore enhancing the possibility to get their action site. The incorporation of a small part of PEG-based amphiphilic material diminishes RES uptake and opsonization, enhances surface hydrophilicity and the liposome circulation time that contributes to enhancing the concentration of drug in the malignant effusion [135], [136]. So, amphiphilic nanomaterials based on PEG play a key role in passive targeting therapies. Here, we look into recently published studies of magnetic PEG-modified materials for cancer therapy.

A polysuccinimide (PSI) grafted copolymer was synthesized as a cross-linked polymer precursor for the fabrication of biodegradable and biocompatible cross-linked MNPs. The MNPs were covered with the amphiphilic PSI grafted with alkyl and folate-conjugated PEG chains. Over the internal shell of the NPs, the succinimide units were crosslinked and transformed into a biodegradable and biocompatible structure comprising amide bonds. They were more utilized to tolerate free amine groups on the cross-linked MNPs (CMNPs) surface. Ultimately, the CMNPs were conjugated with the near-infrared (NIR) fluorescent dye Cy5.5 for application in particular cancer-targeted magnetic resonance or optical imaging uses. The resultant folate- and Cy5.5- conjugated CMNPs had a diameter of approximately 45 nm, representing brilliant suitability and a higher T₂ relaxivity coefficient. Based on the in vivo and in vitro studies, the potential efficacy of CMNPs-Cy5.5-fol is demonstrated as double imaging probes for specific cancer-targeted NIR/MR imaging uses. Advantages of CMNPs include biocompatibility, biodegradability, excellent structural stability in vivo and multifunctionality, specific cancer-targeting, and dual imaging modalities [137].

Presently, monoclonal antibodies are utilized for the treatment of numerous diseases including cancer[138]. Regarding specific tumor-targeted drug delivery, there are numerous efforts to make antibody-conjugated NPs that can show highly improved therapeutic effect in different cancers [139]. Generally, both CD133 and CD44 are accepted as gastric cancer stem cell markers. In a recent study, gastric cancer stem cells were targeted via CD133 and CD44 antibody-conjugated all-trans-retinoic acid-loaded PLGA-lecithin-PEG NPs (ATRA-PLPN) (Fig. 8). Their therapeutic effects were examined against gastric cancer stem cells and the results proved the efficient and special delivery of CD133/CD44 to CD44++ and CD44++ or CD133 gastric cancer stem cells. Hence, growth inhibitory effects were enhanced to gastric cancer stem cells in comparison with single targeted and nontargeted NPs. The present work has reported the elevation of NPs delivery to two groups of gastric cancer stem cells via antibodies. Usually, cancer includes distinct groups of cancer stem cells with many phenotypes. Hence, our dual targeting NPs create efficient drug delivery platforms to target numerous populations of cancer stem cells into cancer. Effective and specific targeting, increased biodistribution and enhanced endocytosis of NPs in tumor cells are some benefits of this drug delivery platform. However, due to being the low number of gastric cancer stem cells in the tumor mass, the optical imaging of the targeting of CD44/CD133-ATRA-PLPN to gastric cancer stem cells in vivo is difficult [140].

Recently, Fe₃O₄-polymer composite microcapsules with a normal diameter of 885.6 and 587 nm were presented for the magnetic resonance (MR)-guided focused ultrasound surgery (MRgFUS) [141], [142]. They can enhance the energy deposition and ultrasonic wave absorption in the target tissue, hence, the tumor ablative impacts of MRgFUS are increased [141]. The creation of an active targeting PEGylated Fe₃O₄ NPs platform was demonstrated. Anti-EGFR was used to decorate the surfaces of PEGylated Fe₃O₄ NPs, for guided delivery to the liver cancer via EGFR overexpression. Furthermore, based on the studies in vitro cellular uptake and cytotoxicity to Hep G2 cells, the EGFR receptor enabled endocytosis can enhance the PEGylated Fe₃O₄ NPs uptake rate. Thus, the established targeting PEGylated Fe₃O₄ NPs system might possess the excellent potential for the MRI therapy of liver cancer [143].

IONPs can be collected in the tumor tissues due to their outstanding magnetism. Such particles are T₂ contrast agents found via MRI for monitoring its tumor accumulation. Based on previous studies, cancer cells produced hydrogen peroxide (H₂O₂) at a speed of 0.5 nmol·10 cells each hour [144]. PDT as an FDA-approved cancer therapy modality utilizes non-toxic photosensitizer, O₂, and light-generating cytotoxicity ROS mostly O₂ for most typical photosensitizers to oxidative damage cancer cells. Nevertheless, the inadequate tumor-targeting capacity of O₂ and photosensitizer supply within the solid tumor, the restricted diffusion range of O_2, and the short lifetime powerfully limit the efficiency of PDT. For zinc phthalocyanine (ZnPc) delivery, IONPs were loaded within the self-assembly stomatocytes-like structure of poly(ethylene glycol)-block-polystyrene (PEG-b-PS) as nanomotors to transfer photosensitizers to the tumor tissues and enhance PDT efficiency. Under magnetic field, the hybrid nanomotors (iron oxide NPs loaded stomatocytes@ZnPc nanomotors, called as ISP-NMs) could be collected in cancer tissues as a result of IONPs magnetism. After trapping by cancer cells, the decomposition of endogenous H₂O₂ can be catalyzed by IONPs generating O₂ as the propelling force for ISPNMs movement. The distribution of ZnPc was expanded by the motion features of ISP-NMs enlarging ROS reactive distribution and improving the PDT activity. Moreover, the created O₂ may be delivered for the PDT procedure ensuring its great performance. Moreover, ISP-NMs possessed a nuclear MRI function because IONPs are effective T₂ contrast agents (Fig. 7) [145].

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Fig. 7. Schematic illustration of magnetic field assistant tumor targeting of ISP-NMs and their ¹O₂ production and PDT procedure for cancer therapy. (Reprinted from publication Ref. [145], Copyright (2021),with permission from Elsevier (license code; 5157780493034).

Since an effective strategy is provided by integrating PTT with immunotherapy in the cancer therapy, an MNPs delivery system was made to load immunostimulatory R837 hydrochloride (R837) and indocyanine green (ICG) for spatiotemporally immunotherapy/PTT synergism in cancer. Such a delivery system comprises PEG as the coating layer to load R837 and Fe₃O₄ MNPs as the core to load ICG. Using intravenous injection, the DPA-PEG coating led to the long circulation, and the superparamagnetism magnetization, PA and PTT function of the Medical Internal Radiation Dose (MIRD) empowered photoacoustic/photothermal multimodal imaging and the magnetic targeting. Here, potent prophylactic and therapeutic impacts with the few side effects were demonstrated systematically. Advantageously, the synergism of the immunotherapy and PTT can prevent, tumor growth, recurrence, and metastasis. Therefore, potent anticancer therapeutic impacts were resultant representing an opening and promising new area for future research [146].

2.8. Biocompatible magnetic polymers for cancer therapy

The development of NPs based on biodegradable and biocompatible polymers for example poly (lactic acid) and poly (glycolic acid), and their copolymers are very interested in researchers. Even with being synthetic, these polymers are degraded in the body into monomers and oligomers that are more removed via the normal metabolic pathways, such as the Krebs cycle [147], [148], [149], [150]. Once polymer NPs are intravenously administered they are subjected to the opsonization reaction, which causes their phagocytosis through the monocyte–macrophages. For overcoming this problem, the particles could be coated with hydrophilic polymers for instance PEG, which avoids recognizing the NPs using the reticuloendothelial system [151], [152]. Recent examples of biocompatible polymers used for cancer therapy are reviewed below.

A new thermo- and pH-sensitive amphiphilic copolymer grafted MNPs was designed and synthesized containing biodegradable and hydrophobic PLA block and hydrophilic P(NIPAAm-co-HEMA-co-MAA-co-TMSPMA) section via a combination of free radical polymerization and ring-opening approaches. Two anticancer drugs MTX and DOX were simultaneously loaded to nano-composite for combination cancer chemotherapy aims. DOX/MTX simultaneous release showed tumor niche (pH≤5.4 and temperature=41 °C) aided release behavior. Cytotoxicity findings disclosed the nontoxicity of newly developed nano-composite to MCF7 cell lines. The anti-tumor feature of DOX/MTX-loaded nano-composite was greater than free drugs discovered by 4',6-diamidino-2-phenylindole (DAPI) staining, MTT assay, RT-PCR, and cell cycle analysis on MCF-7 cell lines. The results exposed that this engineered nano-composite might be successfully utilized in the targeted delivery of MTX and DOX to the tumorous tissues and for more in vivo and clinical applications. Biodegradability, biocompatibility, nontoxicity, targeted drug release, stability in the bloodstream, and proficiency to keep the drug against in vivo decomposition are some benefits of the engineered nano-composite used in this study [153].

In another study, a biocompatible poly-L-lysine-coated MNPs were reported for the combined magnetic resonance imaging and the magnetic hyperthermia to unify the diagnostic and therapeutic method. In this study, biocompatible amino modified MNPs were conjugated to specific antibodies. Then the samples were exposed to calorimetry measurements. According to approximated heating rates the specific absorption rates for the poly-L-lysine modified MNPs (MFPLL) were estimated. Computed specific absorption rate (SAR) values are appropriate for the future study concentrating on the detection of cancer cells mediated with antibodies and on therapy in combination with hyperthermia and MRI. Obtained results showed the important effect of MFPLL on transversal relaxation time T₂ with the relaxivity r₂ equal to 487.94 mM. It found that combination signifies a substantial advance in cancer disease therapy and a significant enhancement in oncological patients’ survival. The results disclosed specific binding of antibody conjugated MFPLL to carbonic anhydrase IX (CA IX) protein in three-dimensional spheroidal culture. Previous researches have revealed antibody-induced receptor internalization features of VII/20 Mab [154] that may be crucial for the delivery of conjugates into cancer cells and probable usage of this conjugate is combined anti-cancer therapy. The main advantage of MFPLL is selective targeting of colorectal cancer cells that can be important for the possible use of this conjugate combined anticancer therapy [155].

A magnetic pH-responsive natural hydrogel was developed as the effective drug delivery system for the treatment of cancer. Alginate (Alg) was firstly oxidized, afterward, gelatin (Gel) was cross-linked with Alg to yield Alg-Gel chemical hydrogel via a “Shift-Base” condensation reaction. Then, Fe₃O₄ NPs were integrated into the hydrogel via an in-situ chemical coprecipitation method. The achieved Alg-Gel/Fe₃O₄ was loaded with DOX, and encapsulation efficiencies, its drug loading, and its anti-cancer activity were studied against Hela cells. In pH = 4 (acidic condition) the Alg-Gel/Fe₃O₄-DOX showed a greater drug release value than those of the pH 7.4 and 37 °C (physiological condition). It has shown that the constructed magnetic hydrogel has brilliant potential as a drug delivery system (DDS) for the cancer chemotherapy mostly owing to its greater performance than those of the free DOX in terms of pH-dependent drug release behavior, slow drug release profile, magnetic feature for diagnosis through MRI and isolation at the targeted area. Based on the results, the Alg-Gel/Fe₃O₄ magnetic hydrogel may be studied as a smart DDS for cancer diagnosis and therapy. The advantages of Alg-Gel-DOX and Alg-Gel/ Fe₃O₄-DOX over free DOX include low toxicity, high biodistribution, slow drug release, and low drug degradation [156].

Zhang et al. successfully developed multifunctional NPs encapsulated with superparamagnetic Fe₃O₄ NPs. The olaparib (Olb) drug was loaded and the formulation was used for the multimodal treatment of triple-negative breast cancer. Low molecular weight hyaluronic acid (HA) was chosen for coating NPs. Owing to the high affinity between CD44-receptor on the cell surface of triple-negative breast cancer (TNBC) and hyaluronic acid, an effective targeting could be achieved to apply the synergistic antitumor effects both in vivo and in vitro. Using rotating magnetic field (RMF) treatment, HA-Olb-PPMNPs (multifunctional polymeric NPs) generated a physical transfer of mechanical force with an imperfect rotation that the shear forces generated by the rotation, therefore, injured lysosomes and disrupted the cell membrane integrity after HA-Olb-PPMNPs internalized into the cells, by which damaging “two strikes” effects were evident via confocal laser scanning microscopy (CLSM) and scanning electron microscope (SEM) (Fig. 8). So, Olb and the mechanical force apply dual antitumor effect to attain synergistic therapeutic in the presence of RMF. Therefore, magnetic excitation through mechanical force offers an exciting approach to remotely control cell functions for cancer therapy [157].

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Fig. 8. Schematic illustration of the cell damage visualized by SEM and TEM. (A) Illustration of the anticancer mechanisms of magneto-cell-apoptosis and magneto-cell-lysis (B) The SEM images of cell membrane integrity damaged using the action of the HA-PPMNPs/HA-Olb-PPMNPs activated by the RMF therapy (red arrow). (C) Illustrative TEM images of magneto-cell-apoptosis triggered by HA-PPMNPs/HA-Olb-PPMNPs under RMF treatment (blue arrow: apoptotic bodies, yellow arrow: intracellular bubbles, and green arrow: karyorrhexis and karyopyknosis. (Reprinted from publication Ref. [157], Cpyright (2021),with permission from Elsevier (license code; 5157780661963).

2.9. Other magnetic materials for cancer therapy

NPs-based theranostics have rapidly emerged in the past decade and have been extensively utilized in the diagnosing and treating of some tumors such as breast cancer and liver cancer. Though, there are limited findings for skin cancers. Hou et al. successfully synthesized multifunctional IR820-grafted CS-Fe₃O₄ NPs (via grating IR820 onto the surface of CS-coated magnetic iron oxide) for melanoma theranostic uses. This theranostic nanoparticle shows an excellent MRI ability and cytotoxic effects against melanoma under irradiation with a near-infrared laser in vitro. Moreover, they have insignificant cytotoxicity and high stability in the aqueous solution, up to 8 days. Owing to the unique properties, the IR820-CS-Fe₃O₄ NPs offered a noticeable cytotoxic effect on A375 cells after the irradiation under a NIR laser than conventional PDT. The results showed the good potential of IR820-CS-Fe₃O₄ NPs for the diagnosis and treatment of melanoma [158].

Biomineralized bacterial magnetic particles (BMPs) have been extensively researched for bio-medical uses with their magnetic features and a layer of bio-membrane. BMPs have been utilized for magnetically targeted drug delivery, magnetic hyperthermia, MR imaging, magnetic detection, and separation [159], [160], [161]. Advantages of the BMPs over MNPs include good dispersion, large production, high crystallinity, and close-to-bulk magnetization [159], [162]. Wang et al. firstly applied BMPs for magnetically targeted photothermal therapy of tumors in vivo. The BMPs were inoculated into the tumor tissue by the self-built C-shaped bipolar constant magnet with a great gradient magnetic field at the tumor site. For the in vitro simulated experiment, BMPs had a great maintenance rate in the magnetically targeted area with diverse flow rates. With the magnetic targeting, the inoculated BMPs with NIR light irradiation for the photothermal therapy can cause a complete tumor eradication. It offers an effective method for the bio-medical uses of BMPs [163].

In recent years, the synergistic combining plasma technology and NPs chemotherapeutic delivery system has shown its capacity in the treatment of cancer [164]. The unique advantages of CAP including sterilization, wood healing, blood coagulation, tooth bleaching, skin regeneration, and cancer therapy have assisted recent biomedical uses [165], [166], [167], [168], [169], [170], [171]. Nevertheless, no report exists on CAP combining iron oxide-based MNPs. The impact of co-treatment of the iron oxide-based MNPs and cold atmospheric plasma (CAP) were reported both in vivo and in vitro for the targeted lung cancer therapy. In this regard, the synergistic impacts of iron oxide-based MNPs and CAP on the expression of EGFR, cellular bioactivity, and EGFR downstream signaling pathways were studied (Fig. 9). The results revealed that the co-treatment of the iron oxide-based MNPs and CAP can efficiently avoid cell proliferation through viability reduction and apoptosis induction. In vivo setting reveals that the CAP combining MNPs is useful at suppressing xenograft tumors. Therefore, the combination of CAP and the iron oxide-based MNPs offers a hopeful tool for developing a novel cancer therapy approach [172].

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Fig. 9. Schematic illustration of the molecular mechanisms of MNPs increasing tumor-selective killing impact of CAP. CAP-originated reactive species will result in a significant increase of intracellular H₂O₂, Fe²⁺/Fe³⁺ released from the lysosome comprising MNPs can catalyze H₂O₂ into OH., which results in the carcinoma cells damage, e. g. making mitochondria-induced apoptosis and double-strand DNA breaks. (Reprinted from Ref. [172], Copyright (2021),with permission from Elsevier (license code; 5157780788522).

Munir et al. for the first time demonstrated that capping agents increase the magnetization power while decreasing the particle size too. In this study, the synthesis of un-capped, and malic acid (MA)-capped and citric acid (CA)-capped iron oxide NPs was done by the coprecipitation approach. For the in vivo bioassay, the capped MNPs were inoculated within the tumor cells followed by exposure to alternating magnetic fields. Generally, the results showed the best suitability of MA and CA-capped iron oxide NPs for treating the mice breast cancer through hyperthermia therapy. Exposure to the alternating magnetic field (AMF) of 15 mT and the frequency of 100 kHz for 1 h resulted in an increase in the temperature (from 37 to 48 ^oC) and also caused cellular injury and following apoptotic cell death. Overall, functionalized Fe₃O₄-NPs showed a reduction in particle size, enhanced features and enhanced efficiency for carcinoma therapies by hyperthermia. Hence, the CA-capped iron oxide NPs claims significant outcome that might be in future very assisting for overcoming the enormous casualties owing to cervical/breast cancer.

The developing nano- catalytic therapy can in situ catalyze the endogenous substances into very toxic species and then effectively kill the tumor cells, nevertheless, the lack of high-performance nano-catalysts hampers their wide clinical translation. For the first time, Dai et al. have successfully developed, nano-sized zero valences crystalized iron-polyvinyl pyrrolidone NPs (nZVCI-PVP NPs) for in situ causing nano-catalytic Fenton reaction inside TME to generate large quantities of the hydroxyl radicals and then kill the tumor cells, that might be more synergistically increased by magnetic or photonic hyperthermia as aided with these iron NPs acting as magneto-thermal or photo-thermal conversion nano-agents, respectively (Fig. 10). This study not only offers a new kind of iron-based NPs for bio-medical use but also reveals the high efficacy of nano catalytic cancer treatment as aided by both magnetic and photonic hyperthermia [173].

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Fig. 10. The figure shows the nZVCI-PVP for in vivo T2-weighted MR imaging-guided synergistic nanocatalytic treatment and photonic and magnetic hyperthermia of cancer. (a) modification of surface PVP of nZVCI NPs, (b) MR imaging functions of nZVCI-PVP NPs, (c) synergistically increased nanocatalytic treatment and photothermal tumor ablation (d) synergistically increased nanocatalytic tratment and magnetic tumor ablation as aided using nZVCI-PVP NPs. (Reprinted from publication Ref. [173], with permission from Elsevier (license code; 5157780928927).