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Mokhosi, S.; Singh, M.; Mdlalose, W.B.; Nhlapo, A. Iron Oxide Nanoparticles in Cancer Diagnostics and Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/23456 (accessed on 07 December 2025).
Mokhosi S, Singh M, Mdlalose WB, Nhlapo A. Iron Oxide Nanoparticles in Cancer Diagnostics and Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/23456. Accessed December 07, 2025.
Mokhosi, Seipati, Moganavelli Singh, Wendy Bonakele Mdlalose, Amos Nhlapo. "Iron Oxide Nanoparticles in Cancer Diagnostics and Therapy" Encyclopedia, https://encyclopedia.pub/entry/23456 (accessed December 07, 2025).
Mokhosi, S., Singh, M., Mdlalose, W.B., & Nhlapo, A. (2022, May 26). Iron Oxide Nanoparticles in Cancer Diagnostics and Therapy. In Encyclopedia. https://encyclopedia.pub/entry/23456
Mokhosi, Seipati, et al. "Iron Oxide Nanoparticles in Cancer Diagnostics and Therapy." Encyclopedia. Web. 26 May, 2022.
Iron Oxide Nanoparticles in Cancer Diagnostics and Therapy
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14050937

Cancer theranostics remains a vital research niche as a result of the rising mortality rates caused by various cancers globally. This is excarcebated by challenges related to conventional therapies. Iron-oxide-based NPs that possess characteristically large surface areas, small particle sizes, and superparamagnetism have been cited in applications geared towards diagnosis, and targeted drug delivery. When an external magnetic field is applied to superparamagnetic iron oxide NPs (SPIONs), the domains are aligned to the field. Once the field is removed, they return to a non-magnetic state. The NP magnetic moments turn to flip in the direction of the applied field. This flipping of the magnetic moments generates heat, which forms the basis of tumour ablation therapy through hyperthermia. Substituted iron-oxides or ferrites (MFe2O4) have emerged as interesting magnetic NPs due to their unique and attractive properties such as size and magnetic tunability, ease of synthesis, and manipulatable properties. In recent years, they have been explored for use in targeted therapy and drug delivery for anti-cancer treatment.

ferrites magnetic nanoparticles cancer therapy hyperthermia MRI drug delivery

1. Magnetic Hyperthermia

In hyperthermia therapy, an alternating magnetic field (AMF) is applied to the NPs, resulting in elevated temperatures between 42 and 45 °C [1][2]. The heat is generated due to the magnetic hysteresis loss, Néel relaxation, and Brown relaxation. Hysteresis losses are observed in iron oxide NPs that have multiple magnetic domains. The resulting continuous alignment and differences in energy released can lead to heat generation [3]. On the other hand, in Néel relaxation, there are rapidly occurring changes in the direction of magnetic moments relative to the crystal lattice. This relaxation is delayed by the energy of anisotropy that tends to orientate the magnetic domain in a given direction relative to the crystal lattice [4].
In contrast, the Brownian relaxation results from the physical rotation of particles within a medium in which they are placed. The delay, in this case, is due to the stickiness that tends to counter particles’ movement in the medium [4]. The heat generation is influenced by parameters such as size, shape, and the magnetic properties of the NPs. At sizes of <20 nm, the heat release mechanism is by Neel relaxation, while larger NPs use the Brown relaxation mechanism [5]. At these temperatures, apoptosis is induced, as tumour cells are sensitive to temperatures above 41 °C due to their higher metabolic rates [6]. This method has been used complementary to the existing radiation and chemotherapy in cancer therapy [6][7][8]. As previously mentioned, the most widely used iron oxide NPs for magnetic hyperthermia are magnetite and maghemite NPs, owing to properties such as biocompatibility, non-toxicity, and excellent magnetisation [8].
Superparamagnetism in magnetic NPs has resulted in more heat generation than ferromagnetic NPs, owing to higher hysteresis losses from the single-domain structure [9]. Other important factors include the frequency and the square of the amplitude of the external AMF. It has been proposed that for safe application in patients, the amplitude should not be more than 5 × 109 Ams−1 [10]. With this targeted approach, the heating of cancer cells can be attained without damaging surrounding normal tissue, thus increasing the effectiveness and safety of hyperthermia. In a recent report, hyperthermia therapy was employed through utilising cobalt ferrite NPs where 90% doxorubicin delivery was achieved in 6 h at 44 °C [11]. Nanotherm® is an FDA-approved formulation comprising iron oxide NPs coated with aminosilanes (Table 1) [12] and is indicated for hyperthermia treatment of the malignant glioblastoma multiforme [13][14]. The administered treatment consists of water-dispersed NPs with a diameter of 15 nm. Cancer cells subjected to the Nanotherm® treatment have been found to exhibit greater sensitivity when complemented with radiotherapy or chemotherapy [13].
Table 1. Iron oxide NPs in clinical trials for cancer imaging and therapy (adapted from [15][16][17]).
Trade/Generic Name/Clinical Trial ID Nanocomposite Material Application (Cancer Type)
Abdoscan®/Ferristene/OMP (Nycomed) Polystyrene-coated iron oxide NPs MRI imaging: gastrointestinal tract
Combidex® (USA), Sinerem® (EU),
Ferumoxtran-10/AMI-277 (Guerbet/AMAG Pharmaceuticals Inc)		 Iron oxide coated with dextran (T10) MRI imaging: prostate, breast, bladder, genitourinary cancers, and lymph node metastases
Feraheme® (USA),
Rienso® (EU)/Ferumoxytol (AMAG Pharmaceutical Inc.)		 Polyglucose-sorbitol-carboxymethyl-ether-coated iron oxide (γ-Fe2O3) Imaging: rectal, oesophageal, bone, colorectal, prostate, bladder, kidney, lymph node, head and neck, breast, non-small cell lung, and pancreatic cancers; osteonecrosis, soft tissue sarcoma, chondrosarcoma, glioblastoma; melanoma
Feridex I.V. (USA), Endorem™ (EU), AMI-25/ferumoxides (AMAG Pharmaceuticals) Iron oxide coated with dextran (T10) MRI—liver/spleen imaging
Lumirem® (USA), GastroMARK® (EU), AMI- 121 (AMAG Pharmaceuticals Inc/Guerbet) Siloxane-coated iron oxide NPs MRI Imaging: gastrointestinal tract
Resovist® (USA, Japan, EU)
Cliavist® (France), Ferucarbotran/ SHU555A (Bayer Schering Pharma)		 Carboxydextran-coated iron oxide (γ-Fe2O3) MRI imaging: liver/spleen tumours
Nanotherm™ (Magforce Nanotech AG) Aminosilane-coated iron oxide NPs Thermal ablation, hyperthermia local ablation in glioblastoma.
MagProbeTM (University of New Mexico) Magnetic iron oxide NPs Leukaemia
Magnablate I (University College London) Iron NPs Prostate cancer
NC100150/Clarisan/Feruglose/PEG-fero (Nycomed) Carbohydrate-polyethylene-glycol-coated ultra-superparamagnetic iron oxide NPs MRI imaging: tumour microvasculature
Sienna+® (Endomagnetics Ltd.) Carboxydextran-coated iron oxide NPs Breast and rectal cancer
NCT01895829
NTC03179449
NTC04369560		 Polyglucose sorbitol carboxy methyl ether coated SPIONs MRI detection for the spread of head and neck cancer
MRI detection of inflammation (macrophage) in childhood brain neoplasm
MRI detection for urinary bladder neoplasms
NCT01749280
NCT04316091		 USPIONs MRI to predict the growth of abdominal aortic aneurysms
Neoadjuvant chemotherapy+
SPIONs/spinning magnetic field; evaluate tolerability, safety, and efficacy of the treatment: osteosarcoma
Ferumoxytol USPIO-MRI Enhanced MRI Enhanced MRI in imaging lymph nodes in patients with locally advanced rectal cancer: head and neck cancer
Ferumoxytol MIONs Ferumoxytol Pilot feasibility study of MIONs MR dynamic contrast-enhanced MRI for primary and nodal tumour imaging in locally advanced head and neck squamous cell carcinomas
In contrast to magnetic hyperthermia, another useful strategy, referred to as nano-magnetomechanical activation (NMMA), which involves the low frequency (<1 KHz) activation of magnetic NPs in a non-heating alternating magnetic field, has been reported [18]. This approach can be employed to facilitate the release of therapeutic molecules from the functionalised magnetic NP carrier or to change the bound biomolecule’s chemical properties. This technique can produce site-specific tissue regeneration or lead to the destruction of malignant cells. Although this process has the advantages of being regulated, non-invasive, selective, and relatively safe, it needs the MNPs to undergo rotational oscillations [19], and the force used could stimulate tumour growth due to collateral impact on the surrounding normal tissue [20].

2. Targeted Drug Delivery

Since the coining of the term “magic bullet” by Paul Elrich in 1906 [15], significant research milestones have been reached in designing and developing targeted nanotherapeutics geared for enhanced and site-specific delivery [21][22]. An essential advantage of using iron-oxide-based NPs is the ease of preparation and functionalisation for tailored specificity [23]. Furthermore, introducing an external alternating magnetic-field-induced oscillation delivery facilitates magnetic targeting, with drug leakage or exposure of healthy cells to the drug until it reaches the target site [21]. The brief introduction of the external magnetic field circumvents challenges such as non-specificity in distribution and delivery, toxicity in healthy cells, and overall diminished therapeutic efficacies. Once the NP reaches the site, controlled drug release mechanisms often utilise parameters such as pH, light, thermal stimuli, and redox stimuli [21][24].
Owing to the nano-sizes of NPs, there is a tendency for passive accumulation in tumour tissues due to enhanced permeability and retention (EPR) [13]. This passive targeting exploits the compromised vasculature and the micro-tumour environment with different pH values and temperature and poor lymphatic drainage [25]. 
Solid tumours, however, present with other challenges, such as tumour heterogeneity and matrix barriers, e.g., fibrosis collagen. In active targeting, NPs can be functionalised or tailored for specific ligand receptor recognition or antigen–antibody interactions [26][27]. The overexpression of certain receptors triggers receptor-mediated transcytosis found only in cancer cells, allowing for internalisation of the NP carrying the therapeutic [28]. Polymer-coated iron oxide NPs allow drug for encapsulation within the matrix, which can be trigger-released upon reaching a tumour site [29]. A significant number of reports have shown functionalised magnetites being suitable carriers of anticancer drugs such as doxorubicin, 5-FU, morin, and ciprofloxacin [30][31][32]. Figure 1 illustrates the changed vasculature in cancer cells that potentiate the EPR effect.
 
Figure 1. Illustration of the enhanced permeability and retention effect in cancer cells allows for passive targeting (Created with BioRender.com, accessed on 28 March 2022).
Recently, ferrites have emerged as suitable biocompatible NPs in drug delivery for anticancer treatment, with increased studies on ferrites for targeted drug delivery. A finding showed that manganese ferrite NPs coated with chitosan and PEG exhibited high encapsulation efficiency of methotrexate [33], while chitosan-functionalised Mg0.5Co0.5Fe2O4 NPs enhanced 5-FU delivery in MCF-7 cells in vitro [34]. A pH-responsive drug release was activated in both studies under acidic conditions. A similar stimuli-responsive drug delivery using ZnFe2O4 and Ag1−xZnxFe2O4 NPs was observed under different pH conditions [35]. The ZnxMg(1−x) Fe2O4 NPs for drug delivery were also investigated, confirming their good drug loading capacity and drug release profiles [36]. Furthermore, Gd3+ ion-doped CoFe2O4 NPs studied for targeted drug delivery and contrast enhancement in MRI showed sustained drug release of 90.6 to 95% over 24 h at a pH of 7.4 [37]. Lime peel extract was also used to produce NiFe2O4 NPs that were investigated as antioxidant, anticancer, and antibiotic agents [38]. In another study, bismuth-doped Ni-ferrites (NiFe2−xBixO4) NPs were synthesised via the co-precipitation method and proposed as being useful in targeting magnetic carriers [39].

3. Imaging Systems

MRI is a vital visualisation tool in clinical diagnostics, such as in detecting tumours. The effectiveness of MRI is influenced by the magnetic resonance signal of the examined tissues by the contrast agents. There are two major types of MR contrast agents: positive (T1-weighted agents) and negative (T2/T2-weighted agents) contrast agents. Positive contrast agents can shorten the longitudinal relaxation time (T1) of protons and result in a bright image. Negative contrast agents shorten the transverse relaxation time (T2) of protons and tend to decay rapidly in the traverse direction, leading to a dark image [1][6]. T1 gadolinium (Gd)-based contrast agents have been the most employed in clinical settings for brighter images with better resolution [2][40]. However, these display disadvantages such as short lifespan, poor cellular uptake, and risk factors in patients with kidney and liver diseases. The free Gd ions cannot be effectively cleared post-administration, resulting in toxicity in natural settings [18].
Superparamagnetic iron-oxide NPs have been widely employed and reported to exhibit higher MRI signal contrast than the Gd-based ones due to the high saturation magnetisation [1]. Additionally, by nature of the Fe being a biomineral used by the body, they may be biodegradable and biocompatible in vivo compared to metal or metal alloy-based contrast agents [16][17]. When coated with PEG, PVA, dextran, or modified chitosan, these NPs have been proven to be superior due to low long-term toxicity and long shelf lives [16]. Ferrites such as CoFe2O4 are currently being explored as T2 MRI contrast agents; however, more research is necessary to determine their cytotoxicities over time before clinical trials [41][42]. Their potential as T1 MRI contrast agents is currently under investigation, where parameters such as size, shape, and surface coatings need to be considered. For example, these NPs should optimally be < 5 nm for an excellent T1 image resolution [42][43]. Additionally, the type of surface modification on the NP affects the relaxation time [41]. It has been observed that hydrophilic coatings, which stabilise water molecules around the NPs, have an adverse effect on T2 by lowering it [17]. CoFe2O4@MnFe2O4 NPs were reported to enhance targeted MRI and fluorescent labelling in MGC-803 cell lines and tumours [44].

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Subjects: Biochemistry & Molecular Biology
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