Therapeutic applications of iron oxide based nanoparticles in cancer: basic concepts and recent advances

Madiha Saeed ab, Wenzhi Ren ab and Aiguo Wu *a
aCAS Key Laboratory of Magnetic Materials and Devices, & Key Laboratory of Additive Manufacturing Materials of Zhejiang Province, & Division of Functional Materials and Nanodevices, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, 315201, P.R. China. E-mail: aiguo@nimte.ac.cn; Fax: +86-57486685163; Tel: +8657487617278
bUniversity of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing, 100049, P.R. China

Received 1st November 2017 , Accepted 22nd December 2017

First published on 22nd December 2017


Nanotechnology has introduced new techniques and phototherapy approaches to fabricate and utilize nanoparticles for cancer therapy. These phototherapy approaches, such as photothermal therapy (PTT) and photodynamic therapy (PDT), hold great promise to overcome the limitations of traditional treatment methods. In phototherapy, magnetic iron oxide nanoparticles (IONPs) are of paramount importance due to their wide range of biomedical applications. This review discusses the basic concepts, various therapy approaches (PTT, PDT, magnetic hyperthermia therapy (MHT), chemotherapy and immunotherapy), intrinsic properties, and mechanisms of cell death of IONPs; it also provides a brief overview of recent developments in IONPs, with focus on their therapeutic applications. Much attention is devoted to elaborating the various parameters, intracellular behaviors and limitations of MHT. Bimodal therapies which act alone or in combination with other modalities are also discussed. The review highlights some limitations in the explored research areas and suggests future directions to overcome these limitations.


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Madiha Saeed

Madiha Saeed completed her B.S. in Bioinformatics from GC University and received her M.S. in Biotechnology from the National Institute for Biotechnology and Genetic Engineering (NIBGE), Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad, Pakistan. She won the highly competitive CAS-TWAS President's Ph.D. Fellowship in 2014. Currently, she is pursuing her Ph.D. degree under the guidance of Prof. Aiguo Wu at Ningbo Institute of Materials Technology & Engineering (NIMTE), Chinese Academy of Sciences, China. Her research focuses on the theranostic applications of magnetic nanocomposites in cancer.

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Wenzhi Ren

Wenzhi Ren got his B.S. from the Department of Biotechnology in Shanxi Agricultural University and received his M.S. in Microbiological Pharmacology from Shanghai Normal University in China. In 2010, he joined Prof. Aiguo Wu's group in Ningbo Institute of Materials Technology & Engineering (NIMTE), Chinese Academy of Sciences (CAS). Now, his research interest focuses on biological effects of nanomaterials.

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Aiguo Wu

Aiguo Wu got his bachelor's degree from the Department of Chemistry in Nanchang University in China and received his PhD from Chinese Academy of Sciences supervised by Prof. Erkang Wang and Prof. Zhuang Li at the State Key Laboratory of Electroanalytical Chemistry in Changchun Institute of Applied Chemistry, China in 2003. He stayed at the University of Marburg (Prof. Norbert A. Hampp group) in Germany during 2004–2005, California Institute of Technology (Prof. Ahmed Zewail group) in the USA during 2005–2006 and Feinberg School of Medicine in Northwestern University (Prof. Gayle E. Woloschak group) in Chicago, USA during 2006–2009. In 2015, he returned to the University of Marburg, Germany as a visiting Professor. In 2009, he joined Ningbo Institute of Materials Technology & Engineering (NIMTE), Chinese Academy of Sciences (CAS) as a PI. Prof. Wu has published over 140 papers in peer-reviewed journals, one book and three book chapters, and applied for 97 patents (awarded 43 invention patents). His lab focuses on using nanoprobes for early diagnosis, imaging, therapy and theranostics of diseases, particularly on iron oxide-based nanoprobes in cancer etc. Homepage: http://wuaiguo.nimte.ac.cn/.


1. Introduction

A talk by Richard Feynman in 1959 ignited interest in what would later become known as nanotechnology; he declared that “there is plenty of room at the bottom”, suggesting that to complement their interest in “big science”, scientists should understand phenomena on a small scale.1 The term “nanotechnology” was first defined by Norio Taniguchi in 1974. Nanotechnology is a scientific field that utilizes materials and equipment to manipulate the chemical and physical properties of a substance at molecular levels or larger. Generally, nanotechnology deals with the development of materials, devices, and structures with at least one dimension of less than 100 nanometers. On the other hand, biotechnology usually deals with metabolic and physiological processes of biological organisms. In biotechnology, knowledge and molecular biology techniques are used to manipulate cellular, molecular and genetic processes for the improvement of products and services. The combination of these two technologies, i.e. nanobiotechnology, plays a fundamental role in the development and implementation of several valuable tools to study life.2

Cancer is a major fatal disease worldwide.3 For cancer therapy, nanotechnology approaches such as photothermal therapy (PTT), photodynamic therapy (PDT), magnetic hyperthermia therapy (MHT), chemotherapy and immunotherapy have been extensively utilized.4–12

Magnetic iron oxide nanoparticles (IONPs) have been received tremendous attention due to their wide range of biomedical applications in cellular labeling, drug delivery, gene delivery, MRI biomedicine, hyperthermia, etc.13–15 Clinical use of IONPs has been approved for magnetic resonance imaging (MRI).16 Many formulations of IONPs are under clinical investigation; some have been approved as contrast agents, such as dextran-coated Endorem (EU) and Feridex (USA).17 Ferumoxytol (carbohydrate-coated superparamagnetic IONPs) is approved by the U. S. Food and Drug Administration (FDA) for iron deficiency anemia treatment.18 Iron-based NPs can be externally controlled for diagnosis and targeted therapy. Meanwhile, IONPs can be exploited for imaging-guided delivery and multimodal theranostics,19 where more than one cancer modality is combined, such as PTT, PDT, MHT, chemotherapy, and immunotherapy. Tailored design of magnetic NPs is crucial to determine the effectiveness of NPs for a desired biomedical application. The synthesis, surface functionalization, and tumor targeting strategies of magnetic NPs are discussed elsewhere.10,17,20,21

This review will focus on the aforementioned therapeutic applications of iron oxide-based nanoparticles.

2. Photothermal therapy (PTT)

PTT is a non-invasive cancer therapy approach which utilizes visible or NIR light. In the presence of photo-absorbers such as NPs, laser energy converts into thermal energy, which leads to thermal ablation of cancer.22–24 Clinical trials of PTT are ongoing.25 PTT is expected to be a promising alternative cancer therapy approach that can effectively kill tumor cells based on the fact that these cells are more sensitive to temperature changes than normal tissues.26 Thermal ablation damages cell membranes and subcellular levels. There are two phases of tumor destruction, termed direct and indirect mechanisms. A thermal ablated tumor has three zones: first, the central zone, which undergoes coagulative necrosis; second, the peripheral zone, which mostly undergoes apoptosis and reversible injury; third, normal surrounding tissues, which are not affected by thermal ablation but can stimulate the immune system.8,27 In PTT, the mode of cell death can be necrosis or apoptosis depending on applied parameters, such as laser power and time of exposure; high laser power may cause necrosis, while low laser power can lead to apoptosis.28

NP-based therapies are less-invasive, efficient, controllable, and promising alternative future therapy approaches which can effectively reduce tumor growth. Multifunctional nanoparticles (NPs) have attracted tremendous attention in functional theranostics. However, NPs used for phototherapy are potentially toxic and biopersistent.29 There is an unresolved debate on the toxicity of NPs;30 especially, gold, carbon nanotubes and graphene may be biopersistent,31 which will inevitably limit their clinical applications. Non-degradable NPs can readily accumulate in the body and stimulate oxidative stress and injury pathways.31,32 Therefore, there is an urgent need to explore biocompatible, biodegradable and potentially non-toxic NPs for phototherapy applications.

IONPs are believed to be safe,33 non-toxic, biocompatible, dissolvable, biodegradable and trace elements in metabolism.31,34 Under biological conditions, the dissolution of IONPs is a dynamic process, while other NPs may be non-biodegradable and insoluble.31 After the endocytic pathway, IONPs enter endosomes and lysosomes, where hydrolytic enzymes metabolize them into elemental iron and they subsequently become part of the body.35 The possible side effects of free iron ions can be overcome by maintaining iron homeostasis, where the released iron ions are incorporated into ferritin proteins (iron detoxification). Cytotoxicity of dextran-coated NPs (concentrations up to 1 to 2 μg ml−1) was not observed for human monocyte-macrophages.36

Moreover, IONPs are suggested to be a highly versatile tool in functional theranostics owing to their therapeutic and diagnostic applications; recently, they have also attracted attention due to their attractive magnetic and therapeutic properties.37–40 IONPs are generally considered to be an important material that can be manipulated and guided by an external magnetic field. In addition, IONPs can be exploited for hyperthermia and multimodal theranostics.19,41,42

Targeted delivery of NPs is of paramount importance; delivery methods include active targeting and passive targeting. Tumor-specific targeting ligands are conjugated to NPs for active targeting delivery. However, differences in the expression of receptors in different patients, expression of the same receptors in normal tissues, and the size and poor stability of NPs may limit their clinical applications. The enhanced permeability and retention (EPR) effect can be exploited for passive targeting; however, tumor heterogeneity, intra-patient variations, and the sizes, morphologies, and natures of coated polymers, etc. can affect its efficiency. Hence, efficient targeted delivery of NPs is still a challenge. Recently, tumor targeting by an external magnetic field has drawn significant attention. In this approach, magnetic NPs are attracted to the target site (tumor) by applying an external magnetic field or by attaching a magnet to the tumor. Magnetically guided targeted delivery can efficiently improve the delivery efficiency of therapeutic agents to a tumor. The major advantage of using IONPs for hyperthermia treatment of cancer is the enhancement of both passive and active targeting of delivered magnetic nanoparticles to cancerous tumors by applying an external magnetic field.

2.1. Iron oxide NPs for PTT

Shen et al. investigated the photothermal therapy effects of carboxymethyl chitosan (CMCTS)-coated Fe3O4 177 nm in diameter in KB (human oral squamous carcinoma cell line) and MCF-7 (human breast carcinoma cell line) cancer cell lines. During in vivo experiments, an external magnetic field was applied to enhance accumulation in the tumor. Then, upon exposure to an 808 nm laser at 1.5 W cm−2 power density, the temperature reached 52 °C.38 Chen et al. presented anti-biofouling polymer-coated IONPs 24 nm in diameter as a photothermal therapy agent; they used an 885 nm diode laser at a power of 2.5 W cm−2 for thermal therapy in SUM-159 cancer cells.40 Shen et al. compared the photothermal therapy effects of individual and clustered Fe3O4 NPs and reported that clustered Fe3O4 NPs are better than individual Fe3O4. In vitro and in vivo experiments were performed on A549 cancer cells which were irradiated with an 885 nm diode laser at a power of 5 W cm−2; apoptosis was proposed as the mode of cell death.39 A series of Fe3O4 NPs (size range 60 to 310 nm) were synthesized, and it was found that the behavior of the nanoparticles inside cells depended on their sizes. In vitro results demonstrated that smaller NPs (60 nm) showed deeper penetration and cellular internalization and induced higher photothermal efficacy to kill tumor cells under 808 NIR laser (1.5 W cm−2) irradiation, while large NPs induced tumor growth inhibition more efficiently in vivo.43 A high laser power can damage healthy tissues. Some strategies to improve its performance are discussed here.

It was demonstrated that magnetic guidance can enhance accumulation of PEGylated Fe@Fe3O4 NPs at tumor sites using a Nd-Fe-B magnet which was attached beside a tumor in the HeLa tumor model; the PTT effects of the NPs were investigated at low power (0.3 W cm−2) under 808 nm laser irradiation.37 One strategy to improve therapy efficacy is targeted delivery. Mitochondria are cell organelles that are susceptible to increases in temperature. Mitochondrial targeted delivery of coumarin-based fluorescent IONPs showed an enhanced PTT effect. NPs were activated with a 740 nm NIR laser at 2.0 W cm−2 for mitochondria-directed hyperthermia.44 MNC@RBCs were designed by a fusion process of magnetic clusters (MNCs) and red blood cell (RBC) membranes, which inherited prolonged iron oxide blood retention and low macrophage uptake from natural RBCs. MNC@RBCs showed dramatically altered in vivo behavior, such as low nonspecific biodistribution (in the liver), prolonged blood retention time and high tumor accumulation. As a result, the therapy efficacy of iron oxide was greatly improved (Fig. 1).45


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Fig. 1 Schematic of the preparation process of MNC@RBCs and its applications in MRI and PTT of mice. Reprinted from ref. 45, copyright (2016), with permission from Elsevier.

Another recent study introduced an all-in-one magnetic nanoparticles (MNs) platform. Platelet-derived vesicles (PLT-vesicles)-coated Fe3O4 MNs, termed PLT-MNs, inherited prolonged blood circulation and cancer targeting properties from the PLT membrane shell and optical and absorption properties from the MN core. PLT-MNs exhibited improved in vivo PTT efficiency due to the enhanced permeability and retention (EPR) effect and immunocompatibility because PLT-vesicles were collected from mouse blood and then re-injected after being coated with MNs, as shown in Fig. 2.46


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Fig. 2 Platelet-mimicking magnetic nanoparticles for enhanced cancer imaging and therapy. (A) Platelets (PLTs) were separated from mouse blood. (B, C) PLT membrane-derived vesicles (PLT-vesicles) along with membrane proteins were collected from the PLTs and further coated onto Fe3O4 magnetic nanoparticles (MNs). (D) Subsequently, the resulting PLT membrane-coated MNs (PLT-MNs) were intravenously (i.v.) injected back into the donor mice. (E, F) After systematic circulation, the PLT-MNs were enriched in the tumor site via the enhanced permeability and retention (EPR) effect. (G) Attributed to the cancer targeting ability inherited from PLTs, the PLT-MNs closely bonded to cancer cells. (H, I) To exploit the magnetic properties and optical absorption ability of MNs, our biomimetic PLT-MNs were then used for enhanced in vivo tumor magnetic resonance imaging (MRI) and photothermal therapy (PTT). Reprinted from ref. 46, copyright (2017), with permission from John Wiley and Sons.

2.2. Iron oxide based nanocomposites for imaging-guided PTT

Researchers are exploring iron oxide-based nanocomposites (NCs) as potential imaging and photothermal agents. These composites can be guided by an external magnetic field for imaging-guided PTT. To monitor therapy performance, Li et al. demonstrated an effective magnetic targeting strategy using IONC@Au-PEG as a theranostic agent in cancer. Magnetic guidance-enhanced accumulation of NPs was observed in a tumor in comparison to a tumor without a magnetic field. As a result, this strategy showed effective tumor ablation under comparatively low power density (0.8 W cm−2) and demonstrated dual-modal (MRI and photoacoustic) time-dependent imaging before, during and after treatment (Fig. 3).47 To enhance and monitor PTT efficacy, Fu et al. reported diffusion-weighted magnetic resonance imaging (DW-MRI) under different conditions and concluded that magnetic guided delivery of GO-IONP-PEG NPs to a tumor is an effective strategy to enhance PTT effects.48 Lin et al. introduced Fe3O4@polydopamine core–shell NCs (Fe3O4@PDA NCs) for multimodal imaging-guided photothermal therapy and intracellular mRNA detection.49 Wu et al. developed a rattle-type Fe3O4@CuS NPs for hyperthermia at first (808 nm) and second (1064 nm) NIR windows; magnetically guided photothermal ablation of a tumor was performed to evaluate both laser exposures. The results showed that the 1064 nm laser exhibited better efficacy than the 808 nm laser. Consequently, the tumor was completely removed at 1064 nm, while 808 nm irradiation resulted in effective inhibition of growth.50 Meng et al. fabricated FeS2 (“all-in-one” type) NPs which efficiently ablated tumors under 915 nm laser irradiation. Prussian blue (PB)-coated superparamagnetic Fe3O4 demonstrated targeted PTT of cancer under magnetic guidance.51 In another study, ultrasmall Fe3O4@Cu2−xS core–shell nanoparticles (<10 nm) were activated at 960 nm for efficient photothermal therapy.52 Some recent studies also demonstrated Fe-based NCs, such as Fe3O4/ICG@PLGA/PFP,53 fluorescent dye indocyanine green-coated (ICG@MCNPs),53 chitosan-coated magnetic iron oxide, IR820-CS-Fe3O4,54 Fe3O4@Au core/shell nanostars,55 bioeliminable magnetoplasmonic nanoassembly (MPNA),56 and well-defined peapod-like magnetic nanoparticles (Fe3O4@SiO2, p-FS),57 for effective imaging-guided photothermal therapy.
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Fig. 3 Magnetic targeting-enhanced theranostic strategy using IONC@Au-PEG nanoparticles under guidance by multimodal imaging. In this experiment, IONC@Au-PEG is intravenously injected into a mouse bearing two tumors, one of which is exposed to an external magnetic field while the other is not. As the theranostic nanoparticles circulate in the bloodstream, they will be trapped in the magnetic field created by the nearby magnet, resulting in enhanced enrichment and prolonged retention in the targeted tumor. Dual modal MR and photoacoustic imaging was carried out to monitor and understand the tumor homing of the theranostic nanoparticles for therapeutic planning. IR thermal imaging was conducted during NIR laser irradiation for real-time monitoring of the photothermal effects for better therapeutic control. MR imaging after photothermal therapy was finally performed for post-treatment prognosis. Reprinted from ref. 47, copyright (2013), with permission from John Wiley and Sons.

The advantage of photothermal therapy is the ability to deliver thermal energy (heat) at much greater rates. PTT effectively treats defined tumor sites and tumors which cannot be treated by surgery, such as liver, uterus and prostate cancers. PTT is a non-invasive method, and different strategies are discussed to improve its efficiency. Magnetic-guided targeted delivery can efficiently improve the delivery efficiency of iron oxide-based NPs to a tumor, and therapeutic efficiency can be monitored by MRI. However, this method has some limitations; it cannot be applied to all types of cancer (e.g. soft tissue sarcomas) and widely spread tumors. Moreover, PTT has some drawbacks; for example, high laser power can damage surrounding healthy tissues,15 and NPs that are used for PTT may be toxic, non-dissolvable and biopersistent. The laser intensity and concentrations of NPs must be optimized to minimize their toxicity. This is currently in the proof-of-principle, experimental animal or preclinical phase. Further investigation and clinical trials are clearly needed.

3. Photodynamic therapy (PDT)

Photodynamic therapy (PDT) is a clinical cancer therapy method that destroys cancer cells with a combination of non-toxic components such as photosensitizers (PS), a laser source which activates the release of reactive oxygen species (ROS), and sufficient molecular oxygen in the cells. PDT acts in three steps: excitation of PS, activation of oxygen species, and finally cell death. In 1903, Von Tappeiner and Jesionek demonstrated the first clinical application of PDT using basal cell carcinomas; currently, it has been approved to treat various cancers, such as melanoma, oesophagal cancer, and bladder cancer.58,59 Apoptosis, also called programmed cell death, is considered to be the main mechanism of PDT-induced cell death. Stimulation of apoptosis involves a cascade of signaling pathways, such as caspase activation or mitochondrial release of proapoptotic factors and cysteine–aspartic acid protease activation.60 It is different from PTT, which utilizes heat for thermal ablation.11

However, PS has many limitations, including limited delivery to target tissues and poor penetration of the excitation wavelength. On the other hand, delivery of PS with NPs can overcome these limitations, such as non-specific targeting, facile photodecomposition, hydrophobicity, and toxicity.19 Iron oxide NPs act as PS carriers for imaging-guided PDT. These NPs can effectively overcome most of the limitations of classic PS due to their diverse and non-toxic natures. IONPs can also be used with inorganic PS (TiO2) for PDT and imaging.61

This section describes how iron oxide-based NPs can improve the efficiency of PDT.

3.1. Iron and composites for imaging guided PDT

Magnetically responsive targeted delivery of a photosensitizer, chlorin e6 (Ce6), has been demonstrated as an effective strategy for PDT. Polyethylene glycol (PEG)-coated iron oxide nanoclusters (IONCs) were loaded with Ce6, termed (IONC–PEG–Ce6), to deliver a therapeutic agent to the targeted region by applying an external magnetic field. IONC–PEG–Ce6 shifted the excitation peak of Ce6 in the NIR region for deep penetration and exhibited prolonged blood circulation, improved cellular uptake and enhanced PDT effects. The PDT efficiency was monitored by dual modal imaging (MRI and fluorescence). In vivo PDT efficiency was greatly improved in comparison to that of the free photosensitizer and without magnetic targeting because magnetic targeting enables enhanced accumulation of Ce6 in a tumor (Fig. 4).62
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Fig. 4 (A) Schematic illustrating in vivo magnetic tumor targeting. (B) Ce6 fluorescence signal intensities in magnetic field (MF)-targeted and non-targeted tumor regions. (C) T2-Weighted MR signals of untreated, MF-targeted and non-targeted tumors. (D) In vivo fluorescence image of a 4T1 tumor-bearing mouse. (E) In vivo T2-weighted MR images of a mouse taken before injection (top) and 24 h post injection (bottom). The white and red arrows point to tumors without and with a magnet attached, respectively. (F) Representative photos of mice after various treatments. The white and red arrows point to tumors without and with magnetic targeting, respectively. Reprinted from ref. 62, copyright (2013), with permission from Elsevier.

The biological system has its own natural carriers for intracellular transportation of biological agents. Silva et al. exploited these carriers as Trojan horses, termed “theranosomes”. The theranosomes, which exhibited the inherited properties of natural vesicles, were loaded with magnetic NPs and a PS to efficiently deliver payloads to cancer cells. This method was used for effective PDT, and the distribution of the payloads was monitored by dual-mode imaging (MRI and fluorescence).63

Ling et al. fabricated tumor pH-sensitive magnetic nanogrenades, termed PMNs, which generated singlet oxygen to selectively kill cancer cells by photodynamic therapy.64

Zeng et al. designed PEG-coated Fe3O4@ NaYF4:Yb/Er NCs and conjugated them with tetra-sulfonic phthalocyanine aluminium (AlPcS4) photosensitizers (NPs-AlPcS4) for PDT and imaging. NPs-AlPcS4 showed PDT performance in MCF-7 cells under a 980 nm laser.61 A similar study was performed with folic acid (FA) targeting ability; PS-loaded Fe3O4@NaYF4:Yb/Er nanocomposites, named FA-NPs-PS, were used for targeted PDT under 980 nm laser irradiation and demonstrated effective imaging and PDT performance in MCF-7 and HeLa both in vitro and in vivo.65 Yin et al. presented an ultra-small nanoplatform with diameters of 4, 8 and 13 nm for PDT using Fe3O4@polymer-NPO/PEG-Glc@Ce6 nanoprobes.66 Moreover, Fe3O4-functionalized heparin–pheophorbide-A conjugates (PheoA–Hep–Fe3O4 nanoparticles)67 and a multifunctional nanoplatform, Fe3O4@g-C3N4–UCNPs–PEG,68 have also demonstrated effective PDT performance.

Recently, some groups have explored iron-based NCs for MRI-guided synergistic PDT and PTT phototherapy; for example, Zhang et al. fabricated a porphyrin-metal organic framework (PMOF) as a photosensitizer on an Fe3O4@C core for dual-modal imaging-guided bimodal-therapy. The Fe3O4@C core was used for imaging and PTT, while PMOF was selected for PDT and fluorescence imaging.69 Yang et al. introduced a nanocomposite by assembly of iron oxide (Fe3O4) NPs and Au NPs on black phosphorus sheets, termed BPs@Au@Fe3O4, for synergistic PDT and PTT.70

Well-designed iron oxide-based PDT nanocarriers exhibit superior antitumor effects and may make large strides in resolving some limitations of traditional PSs. However, there are still several considerable challenges, including limited depth of treatment. An external magnetic field with adequate strength can precisely focus on targeted deep tissues. NIR laser irradiation raises an important concern for NIR light-induced phototherapy. It is necessary to optimize the excitation power density within a safe dose (∼0.33 W cm−2 for an 808 nm laser). A systematic investigation of the collaborative effects of PDT and other therapeutic modalities is crucial for improving therapeutic efficiency. Most of the research in this field is limited to subcutaneous tumor models on small animals. However, many tumors are embedded in other tissues or located inside the human body. Therefore, in vivo studies should be carried out on tumors inside the bodies of animals. Future research on practical strategies to design suitable nanosystems for clinical use is still required.

4. Intrinsic ROS-related properties of iron NPs for cancer therapy

Chen et al. revealed the enzyme-like (peroxidase and catalase-like) activities of iron NPs under acidic and neutral conditions of the intracellular microenvironment.71 Recently, Zhang et al. proposed an application of IONPs in cancer therapy. This study suggested that amorphous iron nanoparticles (AFeNPs) can be used for cancer therapy by exploiting the Fenton reaction in the tumor microenvironment. Three requirements for producing reactive OH species are iron NPs, hydrogen peroxide (H2O2) and acidic conditions. Effective therapeutic performance was demonstrated by magnetic targeted delivery of AFeNPs in 4T1 tumor-bearing mice.72 Tumor cells require abundant glucose in comparison to normal cells,73 and natural glucose oxidase (GOD) can catalyze the transformation of glucose into H2O2.74 Exploiting these facts, further exhibition of the Fenton effect was reported by Huo et al., who introduced a strategy for efficient tumor therapy and successfully demonstrated sequential catalytic therapeutics of GOD-Fe3O4@DMSNs nanocatalysts (GFD NCs) (Fig. 5a). Natural glucose oxidize (GOD) and ultrasmall Fe3O4 NPs were integrated into dendritic mesoporous silica nanoparticles (DMSNs) to fabricate a biocompatible and biodegradable composite nanocatalyst; the GFD NCs performed a dual function due to their unique catalytic performance. They effectively depleted glucose to starve the tumor cells (nutrient deprivation) and elevated the H2O2 levels in a tumor for peroxidase-like Fenton reactions of ultrasmall Fe3O4 NPs in the acidic microenvironment of the tumor, resulting in tumor-cell apoptosis (Fig. 5b) both in vitro and in vivo. GFD NCs showed effective therapeutic performance toward 4T1 mammary tumor xenografts and U87 tumor xenografts after both intravenous and intratumor injections.75
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Fig. 5 Fabrication and catalytic-therapeutic schematics of sequential GFD NCs. (A) Synthetic procedure for Fe3O4@DMSNs nanocatalysts and GOD-Fe3O4@DMSNs nanocatalysts. The sizes of the prepared Fe3O4 nanoparticles and adopted GOD are indicated in the scheme. (B) Scheme of the sequential catalytic-therapeutic mechanism of GFD NCs in the generation of hydroxyl radicals for cancer therapy. Reprinted from ref. 75, copyright (2017), with permission from Nature Publishing Group.

Huang et al. demonstrated a new strategy to improve the efficiency of an anticancer drug, β-lapachone (β-lap), by using pH-responsive SPION-micelles. The pH-responsive SPION-micelles released iron ion selectively in cancer cells due to their specific pH. The released iron ions reacted with H2O2 generated by β-lap and consequently produced ROS. Therefore, SPION-micelles enhanced the efficiency of β-lap.76

Recently, Ma et al. designed iron oxide nanocarriers to sensitize a drug (cisplatin). Fe3O4 NPs were integrated and co-delivered with anticancer drugs to form a composite, FePt-NP2, which preferentially increased drug and Fe accumulation in the target site (tumor) by an external magnetic field and could be monitored by MRI. Cisplatin-activated adenine dinucleotide phosphate (NADPH) oxidase (NOX) triggered a cascade reaction and generated H2O2; meanwhile, the iron NPs enhanced hydroxyl radical formation by the Fenton reaction and thus increased apoptosis of cancer cells (Fig. 6). A mechanistic study revealed mitochondrial depolarization and dysfunction due to FePt-NP2, which activated the apoptotic cascade and induced cell death by the ROS/Cyt C/caspase-3 pathway.77 Another study demonstrated an iron-dependent drug delivery system (HA-mFe3O4/ART) for combined chemo-magnetotherapy under AMF irradiation.78


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Fig. 6 Maximizing cisplatin efficacy by constructing self-sacrificing iron oxide nanoparticles with cisplatin(IV) drugs (FePt-NP2) for synergistic actions. (A) Cisplatin activates NOX, which catalyzes the formation of superoxide and H2O2 from O2; iron catalyzes the Fenton reaction to transform H2O2 into highly toxic ˙OH. (B) Construction of self-sacrificing iron oxide nanoparticles with cisplatin(IV) prodrug (FePt-NP2) circumvents the endocytosis of cisplatin into the cells. In this way, excess ˙OH is formed, which results in fast lipid and protein oxidation and DNA damage as well as apoptosis via the ROS/Cyt C/caspase-3 pathway. Reprinted from ref. 77, copyright (2017), with permission from American Chemical Society.

Iron oxide-based nanomaterials have shown promising applications by exploiting the Fenton reaction to produce ROS, which ultimately kills cancer cells. However, this is a comparatively less explored research area, and much remains unknown about its exact mechanism. Additional research is needed to explore the mechanism of cell death and the redox activities of iron NPs under different bio-microenvironmental conditions.

5. Magnetic hyperthermia therapy (MHT)

Magnetic hyperthermia therapy (MHT) is a clinical cancer therapy approach which exploits the heating effect of magnetic NPs placed in an external alternating magnetic field (AMF). It is a noninvasive method to generate heat that penetrates in tissues to destroy the tumor. Gilchrist et al. first introduced magnetic particles for hyperthermia in 1957,79 and in 1979, Gordon et al. demonstrated the intracellular application of magnetic NPs using a high-frequency magnetic field.80 Jordan et al. measured the specific loss power (SLP)/specific absorption rate (SAR) of various magnetic NPs and introduced the mechanism of transformation of magnetic energy into heat.81 Later, successful in vitro82 and in vivo experiments were performed using magnetic fluid hyperthermia.83 The first clinical MHT treatment system was developed in 2004 at Charité Medical University of Berlin.84 Currently, Magforce® has obtained European regulatory approval for use in magnetic hyperthermia for the treatment of brain tumors.85 It is in clinical trials for other cancers, such as pancreatic cancer, esophageal cancer and prostate cancer.86–88

5.1. Néel/Brownian relaxation and hysteresis losses

The heating effect in magnetic fluids is due to Brownian–Néel relaxation and hysteresis losses.89,90 In a Brownian mechanism, the magnetic moment is locked to the crystal axis, and the particle rotates with the alignment of the magnetic moment while the magnetic moment rotates within the crystal in Néel relaxation.89 The heating effect depends on the frequency and amplitude of the applied magnetic field as well as on the size, morphology and composition of the magnetic NPs.89,90 Fortin et al. studied the effects of the particle size, field characteristics, material, and viscosity and revealed that Brownian relaxation is the main rotation mechanism for larger NPs dispersed in low viscosity media, while Néel relaxation overcomes Brown relaxation if the particle size is below 15 nm.91

5.2. Parameters affect magnetic hyperthermia properties

The heating efficiency of nanomaterials (NMs) is represented by the specific loss power (SLP) or specific absorption rate (SAR), which is the ratio of the heat power dissipated and the mass of the magnetic NPs, in watts per gram. SLP values depend on the magnetization, relaxation time,89,90 size, morphology, composition, saturation magnetization and magnetic anisotropy of the magnetic NPs.92–95

This section briefly discusses various morphologies, sizes, and compositions of magnetic NPs which have been developed in an attempt to optimize their magnetic properties and to obtain higher SLP values. In recent years, IONPs with different sizes and morphologies, such as nanospheres, nanocubes, and nanoflowers, have been explored. Bae et al. coated ferrimagnetic iron oxide nanocubes (IONCs) with chitosan oligosaccharide for MHT and observed caspase-mediated apoptosis cell death in treated A549 cancer cells.96 In another study, the hyperthermia performance of cube-shaped IONCs with various cube edge lengths (13 to 40 nm) was investigated, and IONCs with 19 nm cube edges with high saturation magnetization (80 emu g−1) were reported to show the highest SAR values of up to 2452 W g−1 Fe at 520 kHz and 29 kA m−1. In vitro studies were performed on KB cancer cells, and 50% cell mortality was recorded at an equilibrium temperature of 43 °C after 1 h of treatment.97

Hugounenq et al. demonstrated that maghemite nanoflowers show higher SLP values (1992 ± 34 W g−1) due to their magneto-structural properties.95 Lartigue et al. investigated the role of the architecture of iron oxide nanoparticles and demonstrated that the internal organization of multi-cores or nanoflowers influences and enhances their magnetic properties. The results showed that nanoflowers composed of an assembly of merged cores (having the same facets) do not behave magnetically like individual particles; however, the nanoflowers show enhanced magnetic properties due to their reduced anisotropy and larger apparent magnetic size.93 Citrate-stabilized nanostructures of various sizes were synthesized, and it was observed that multi-core NPs retained their superparamagnetic properties. As a result, these materials have enhanced transverse relaxivities, good longitudinal MRI contrast and higher SAR values for magnetic hyperthermia. Nanoflowers of iron oxide 11 nm in size were reported to show enhanced magnetic properties and higher SLP values than single-domain maghemite NPs of the same size (11 nm).95 Lartigue et al. performed a similar study to Hugounenq et al.;95 they compared the magnetic properties of single-core 10 nm NPs to those of multi-core magnetically cooperative 30 nm NPs. Enhanced magnetic properties were recorded in the multi-core structures compared to the single-core structures. Under all conditions, a 2 to 10-fold SAR increase for the multi-core structures was observed in comparison to the single-core materials.93 It was described that the SAR of iron oxide nanostructures could be enhanced by tuning their aspect ratios, and Fe3O4 nanorods showed superior magnetization SAR values compared to cubic and spherical nanoparticles with similar volumes.98 In a similar study, SAR was enhanced up to 70% by tuning the size of the NPs. Size-dependent changes in SAR value were reported for octopods (deformed cubes).99 Hemery et al. also reported the synthesis of magnetic NPs with various sizes and shapes and evaluated the effects of the shapes on their magnetic heating properties.100 Moreover, nanoclusters of iron oxide have been evaluated for MHT;101,102 the nanoclusters were reported to have higher magnetization than similar unclustered magnetic nanoparticles.103

Noh et al. compared the spherical morphology to other shapes; their results demonstrated that a Zn0.4Fe2.6O4@CoFe2O4 cubic core–shell structure 60 nm in diameter exhibited a 14-fold increase in coercivity compared to that of a pure CoFe2O4 nanocube analog. As a result, the core–shell structure had an ultra-high SLP value of 10[thin space (1/6-em)]600 W g−1.92 Jeun et al. tuned magnetic properties by controlling cation concentration, and the best SAR values were reported for superparamagnetic Mg0.285Mn0.715Fe2O4 nanoferrite particles with a mean particle size of 7.5 nm.104

5.3. Intracellular behavior of NPs under an alternating magnetic field

Most studies explored magnetic hyperthermia performance in solution and reported higher SLP values; however, studies measuring SLP values in biological environments are rare.94 In 1979, Gordon suggested that the cell membrane acts as an insulator. As a result, in the thermal sense, intracellular hyperthermia would be better than extracellular hyperthermia.80 Other groups have also reported intracellular-based magnetic hyperthermia.105,106 On the other hand, Rabin rejects the assumption that intracellular hyperthermia is more effective than extracellular hyperthermia in the thermal sense.107 Moreover, the intracellular heating mechanism and behavior of NPs inside the cell have remained unexplored.108 This section describes some developments in understanding the behavior, intracellular heating and SLP values of NPs in cellular environments.

Particles with permanent magnetization are called magnetically blocked particles. Brownian relaxation of magnetically blocked particles can occur due to scattering of the particles in solution because the particles are free to move; meanwhile, superparamagnetic iron oxide nanoparticles (SPIONs) can also relax by Néel relaxation.

A strong heating effect was observed in both relaxation mechanisms when NPs were suspended in water. However, when magnetically blocked particles were suspended in viscous media such as glycerol, a loss of heating effect was observed because reduced mobility can suppress the Brownian mechanism. On the other hand, SPIONs can still undergo Néel relaxation (Fig. 7). The magnetization relaxation mechanisms of blocked particles and SPIONs were also evaluated during internalization in live cells and subsequent release by cell lysis. The results demonstrated that the mobility of the NPs was greatly affected by the microenvironment, which ultimately influences their magnetic response. Cellular internalization can suppress Brownian relaxation, while SPIONs can still undergo Néel relaxation irrespective of their microenvironment. This study highlights the importance of intrinsic magnetic properties in the cellular environment, where particles become immobilized and which may result in insufficient magnetic hyperthermia. However, after cell lysis, the NPs were released and Brownian relaxation was restored due to the preserved magnetic core and citric acid coating.108


image file: c7bm00999b-f7.tif
Fig. 7 Schematics of the Brownian and Néel relaxation mechanisms of nanoparticles (A) and their corresponding AC susceptibility curves in water (B) and in glycerol (C), representing low and high viscosity dispersions, respectively. The in-phase and out-of-phase components of the complex AC susceptibility are labeled in the usual notation as χ′ and χ′′, respectively. Reprinted from ref. 108, copyright (2015), with permission from American Chemical Society.

Dong and Zink introduced a method to monitor the interior temperature of dual-core mesoporous silica NPs that contain both a nanothermometer (NaYF4:Yb3+,Er3+ nanocrystals) and a nanoheater (superparamagnetic nanocrystals) in their interiors. The detection analysis was based on the temperature-dependent intensity ratio of luminescence bands in the emission spectrum of the NaYF4:Yb3+,Er3+ nanocrystals. The change in temperature of the surrounding nanoenvironment was continuously monitored during the oscillating magnetic field. This method may be employed in biomedical applications to control the local temperature during magnetic hyperthermia.109 Pinol et al. demonstrated a similar study; however, they also performed mapping of the intracellular local temperature using the ratio of the Eu3+/Tb3+ intensities. In this fabricated nanoplatform, the thermometer (Eu3+ and Tb3+ complexes) was placed just on the surface of the heater (iron oxide) to reduce the distance between the heater and thermometer and then coated with a diblock copolymer (P4VP-b-P, designated as PMEGA-co-PEGA).110 Kolosnjaj-Tabi et al. evaluated the efficacy of PEG-coated iron oxide nanocubes (19 nm) after injection into epidermoid carcinoma xenografts in mice and monitored the heating effects of the nanocubes in a tumor environment. The results demonstrated that heat-generating nanocubes interfere with the tumor extracellular matrix under magnetic stimuli and can destructure the matrix. The nanocubes retained their magnetic properties throughout the treatment and became inefficient after cell internalization.111 The arrangements of the NPs are also of paramount importance in magnetic hyperthermia. In order to study the particle arrangements, this study demonstrated the use of small nanoobjects confining a fixed distribution of magnetic NPs.112 Di Corato et al. evaluated the magnetic properties and heating power of NMs with different shapes and sizes both in a controlled cellular environment and in solution. A systematic decrease in heating power was observed in all types of NMs following attachment to the cell membrane and an obvious decrease in SLP was monitored after cell internalization, suggesting blocking of the Brownian relaxation in a cellular environment. The amplitude of the heating decrease was dependent on the morphology of the NMs; nanocubes showed comparatively better performance in the cell environment.94

It is generally believed that during magnetic hyperthermia, cancer cells are killed due to temperature changes up to 43 °C. Creixell et al. presented epidermal growth factor receptor (EGFR)-targeted delivery which resulted in significant cell death using targeted intracellular hyperthermia without a perceptible temperature increase.113 In a similar study, lysosomal death pathways were targeted for cancer treatment. Targeted delivery of iron oxide magnetic nanoparticles (MNPs) to the EGFR selectively induced lysosomal membrane permeabilization in cancer cells under the action of an alternating magnetic field. Generation of ROS was also observed during lysosomal membrane permeabilization. Fig. 8 depicts a schematic of the lysosomal membrane permeabilization.114 Some other studies also suggested that the lysosomal death pathway occurs after targeted intracellular delivery.9


image file: c7bm00999b-f8.tif
Fig. 8 Schematic of lysosomal membrane permeabilization by magnetic nanoparticles in an alternating magnetic field. No targeted nanoparticles are taken up by nonspecific mechanisms, whereas targeted nanoparticles are taken up into endosomes and lysosomes due to receptor-mediated endocytosis of the targeted receptor. When an alternating magnetic field is applied, both types of particles dissipate heat; targeted magnetic nanoparticles deliver heat specifically to endosomes and lysosomes, resulting in their permeabilization and the release of their contents into the cytoplasm. Reprinted from ref. 114, copyright (2013), with permission from American Chemical Society.

Recently, Shen et al. demonstrated mechanical destruction of lysosomal membranes under a low frequency rotating magnetic field. Zinc-doped cubic iron oxide NPs were functionalized with the epidermal growth factor (EGF) peptide for targeted delivery to cancer cells. At a low frequency rotating magnetic field (RMF) of 15 Hz and 40 mT, NPs consistently interacted with membranes via mechanical force and damaged the plasma and lysosomal membranes. The lysosomal and plasma membranes were dramatically damaged and released lysosomal hydrolases into the cytosol, which resulted in programmed cell death and necrosis (Fig. 9).115


image file: c7bm00999b-f9.tif
Fig. 9 Proposed mechanism of lysosome and cell membrane destruction under RMF and cell apoptosis. EGF-functionalized MNPs link to the EGFR membrane receptor and are then internalized in cancer cells, mainly accumulating in lysosomes. Upon application of the RMF, the MNPs form elongated aggregates which may produce torque and associated forces required to mechanically disrupt lysosomal membranes and also the plasma membrane. The permeabilization of the membranes leads to direct cell destruction or apoptosis. Reprinted from ref. 115, copyright (2017), with permission from Ivyspring International.

5.4. Magnetic and bimodal hyperthermia for cancer therapy

MHT has been approved as a clinical approach for brain tumors in Europe and is in clinical phases for the treatment of other cancers, such as pancreatic, esophageal and prostate cancer.85–88 However, it is still not widely used in clinics for cancer treatment. It is necessary to design and optimize the performance of magnetic NPs to overcome the limitations of MHT. To improve its efficacy, various kinds of NPs and NCs have been fabricated; also, MHT has been combined with other modalities, such as PTT and PDT, for bimodal therapy.

A recent study explored the development of SPION-loaded nanocapsule hydrogels (SPION-NHs) as an injectable, thermosensitive biodegradable system. At body temperature, the injectable SPION-loaded nanocapsule solution was transformed into a hydrogel due to a sol–gel phase transition. As a result of prolonged retention of SPIONs up to three weeks within tumors, multiple MHT was possible; this was examined by T2-weighted MRI, as shown in Fig. 10. Apoptosis was seen as the dominant cellular pathway after a single MHT gradually evolved to necrosis by multiple MHT, and the results showed necrotic cells after four cycles of MHT.116 In another study, biodegradable and injectable Calcium Phosphate Cement (CPC) containing Fe3O4 NPs was used for magnetic hyperthermia ablation. The injectable magnetic CPC was directly injected into a tumor for in vivo ablation of the tumor.117


image file: c7bm00999b-f10.tif
Fig. 10 Schematic of (A) the composition of the SPION-loaded nanocapsules and their thermosensitive phase transition from solution to hydrogel and (B) theranostic SPION-NHs for simultaneous multiple MHT and long-term MRI monitoring. Reprinted from ref. 116, copyright (2016), with permission from Elsevier.

Espinosa et al. adapted a magnetophotothermal approach as a bimodal cancer treatment. In this method, MHT and PTT were combined to obtain better efficiency; this is designated as dual or bimodal treatment. An acceptable laser power (0.3 W cm−2) and an alternating magnetic field (520 kHz, 25 mT) generated efficient hyperthermia using iron oxide nanocubes. It was described that dual-mode treatment can amplify the heating effect 2 to 5-fold in comparison with magnetic stimulation alone, which results in higher heating powers and SAR values up to 5000 W g−1. In vivo results also demonstrated complete tumor regression after dual-mode treatment and much better performance than individual modalities such as MHT and laser (Fig. 11). The mechanism of cell death was evaluated, and the expression of apoptosis-related proteins after different treatments suggested apoptosis-mediated cell death.118


image file: c7bm00999b-f11.tif
Fig. 11 (A) Scheme of the experimental device for combined hyperthermia experiments, consisting of a magnetic coil in which the sample is placed so that it can be illuminated by near-infrared (NIR) laser (808 nm). The temperature increase was recorded with an infrared thermal imaging (IR) camera located at the end of the coil cavity. (C) (Left) Panel of thermal images acquired by the IR camera on samples at the same iron concentration ([Fe] = 12 and 25 mM) measured inside the coil setup (MHT at 520 kHz, 25 mT; LASER at 0.3 W cm−2). The images correspond to cross-sectional views of the bottom of the samples. (Right) Temporal response curves for [Fe] = 12 and 25 mM. Temperature increase for different concentrations ([Fe] = 0 to 25 mM) after 5 min of each treatment. (C) Thermal images obtained with the IR camera in mice after intratumoral injection of nanocubes (50 μL at [Fe] = 250 mM) in the left-hand tumor and after 10 min application of magnetic hyperthermia (MHT, 110 kHz, 12 mT), NIR-laser irradiation (LASER, 808 nm at 0.3 W cm−2), or DUAL (both effects). Reprinted from ref. 118, copyright (2016), with permission from American Chemical Society.

Das et al. combined the MHT and photothermal properties of magnetite and silver by fabricating core–shell Ag/Fe3O4 nanoflowers.119 To achieve enhanced therapy efficacy, Di Corato et al. designed an optimized smart nanoplatform based on hybrid liposomes. The aqueous core of the liposomes was filled with iron oxide NPs, while the lipid bilayer was loaded with a photosensitizer. The double cargo performed double functionality, such as MHT and PDT: heat generation under an alternating magnetic field along with singlet oxygen generation under laser activation. In this study, apoptotic signaling was suggested as the cell death pathway.120 Amphipathic tail-anchoring peptide (ATAP) was used to trigger mitochondria-dependent apoptosis. Shah et al. fabricated ATAP with magnetic core–shell nanoparticles for mitochondrial targeted delivery in metastatic breast cancer and malignant brain cells. Enhanced apoptosis was observed as a result of mitochondrial dysfunction in both cancer cells.121

The utilization of IONPs as a potential source to generate magnetic hyperthermia has tremendous potential. MHT can overcome the limitations of deep tissue treatment, which is a major challenge in PTT and PDT due to limited absorption and dispersion of light. It can be applied to potentially treat various tumors by using properly designed magnetic coils. This may be of great importance in treating metastatic cancers. There appears to be experimental support to deliver heat at the nanoscale using magnetic NPs; however, the exact mechanisms, especially inside cells are less explored. There are several factors that need to be considered to enhance MHT efficiency. It is imperative to design NPs with higher SLP values as efficient hyperthermia agents and to develop a standardized method of measuring hyperthermia efficiency. Moreover, the combination of other modalities with magnetic hyperthermia can be an effective theranostic approach. Most research in MHT involves direct administration of NPs in a tumor to achieve satisfactory antitumor efficacy. However, systemic injection is desirable to target and treat metastases and remote tumor areas. Future research should explore alternative methods for homogeneous and efficient distribution of NPs in cancer tissues and real-time monitoring of heat distribution.

6. Applications of iron oxide in chemotherapeutics and biotherapeutics

In addition to different therapy approaches, IONPs have been used as carriers for chemotherapeutic drugs or gene delivery in numerous studies. To date, various hydrophilic or hydrophobic drugs, such as doxorubicin (DOX), gemcitabine, paclitaxel, and DNA or small interfering RNA (siRNA), have been delivered using magnetic NPs through covalent bonding or non-covalent loading for cancer treatment.122–126 The magnetic properties of iron oxide nanocarriers can not only be utilized for magnetic guided cancer targeting and controlled drug release but can also trigger magnetic field-mediated hyperthermia synergistic chemotherapy. Moreover, drug loading capacity is an evaluating standard for carriers. Therefore, IONPs have been synthesized with various morphologies, composites and structures in an attempt to increase their loading capacity and enhance their therapeutic efficiency. Porous hollow Fe3O4 or mesoporous SiO2-coated Fe3O4 NPs have been reported to enhance drug loading.127,128 Organic polypyrrole, inorganic gold, graphene oxide, etc. have been fabricated with iron oxide nanocarriers in order to enhance therapy efficiency and to form photothermal therapy synergistic drug delivery systems.129–131 This section summarizes the applications of magnetic field-responsive iron oxide based nanocarriers in magnetically targeted drug delivery, magnetically controlled drug release, magnetic field-mediated synergistic treatment, and effective drug carriers.

Traditional chemotherapy drugs do not have specific tissue distribution or sufficient accumulation in tumor tissues, which results in unsatisfactory treatment and severe side effects. To overcome this problem, targeting strategies of drug delivery systems have been applied for tumor-selective distribution, such as NP size-dependent passive targeting systems, tumor special ligand-mediated active targeting systems, and magnetic field-guided magnetic NPs tumor targeting systems. In the magnetic targeting strategy, Shevtsov et al. applied an external magnetic field to enhance the accumulation of magnetic NPs in tumor tissues.132

Several parameters must be monitored in magnetic targeting of drug delivery systems to achieve efficient tumor targeting, enhanced accumulation of NPs in the tumor region and improved treatment. A high saturation magnetization of the nanoparticles, at least larger than 20.0 emu g−1, is the primary requirement for rapid response to an external magnetic field.133 Deng et al. reported silicon-coated IONPs with a saturation magnetization of 53.3 emu g−1 for magnetic targeted cancer therapy.134 In addition to saturation magnetization, the magnetic field strength and gradient as well as hydrodynamic and physiological factors, including the infusion route, blood half-life, reversibility strength of the drug-carrier bond, and the tumor volume, are substantial parameters for a successful magnetically targeted drug delivery system.10 Magnetically targeted drug delivery systems not only enhance drug accumulation in tumor tissue but also enhance drug distribution in nearby normal cells and have local side effects on normal cells. Therefore, efficient magnetically targeted drug delivery strategies should be introduced to enhance drug distribution in tumor cells without accumulation in normal tissue for clinical applications. Very recently, to avoid nonspecific uptake by normal healthy cells and enhance the accumulation of nanocarriers in a tumor, our group and co-workers designed a pH-sensitive MPEG polymer-coated cancer-targeting peptide, RGD2, conjugated with very small iron oxide nanoparticles for DOX delivery. In the physiological environment, where the pH value is 7.4, the MPEG polymer hides the RGD2 peptide; therefore, the nanoparticles cannot be taken up by normal healthy cells with non-specific receptors. When the nanoparticles arrive in tumor tissue, in which the MPEG polymer is shed due to the mildly acidic environment, the RGD2 peptide is exposed and binds with its receptor, integrin αvβ3. The IONPs are then taken up by the cancer cells. Our results indicate that this strategy can enhance the accumulation of NPs in tumors and therefore enhance T1-weighted MR imaging of the tumor as well as the chemotherapy efficiency (Fig. 12).135


image file: c7bm00999b-f12.tif
Fig. 12 Scheme of the pH-sensitive MPEG polymer-coated cancer targeting peptide RGD2 conjugated with very small iron oxide nanoparticles for DOX delivery. Reprinted from ref. 135, copyright (2017), with permission from American Chemical Society.

After a drug delivery system reaches tumor tissue, the drug release efficiency decides its subsequent cancer cell-killing effects. Therefore, efficient release of drugs from carriers is another important consideration for a successful drug delivery system. It has been demonstrated that for non-covalent drug loading, the acidic environment of lysosomes and heat can promote drug release.123,136 It is well known that nanocarriers stay in the lysosome after cellular uptake; therefore, heating the nanocarriers in cancer cells can effectively release the drug. Moreover, magnetic NPs, such as iron oxide, can be heated in AMF and exhibit magnetic field-controlled drug release. Many studies have explored magnetically controlled drug release systems. Riedinger et al. reported azo-functionalized iron oxide NPs for alternating magnetic field-controlled drug delivery.137 In this study, different molecular weights of poly(ethylene glycol) (PEG)-coated IONPs were modified with a thermal decomposition temperature probe molecule, azobis[N-(2-carboxyethyl)-2-methylpropionamidine], to form azo-functionalized iron oxide nanocarriers. After conjugation with fluoresceinamine dye or doxorubicin, the nanocarrier exhibited AMF-triggered distance-dependent drug release in KB cancer cells which was based on AMF-induced heat decomposition of azobis. Very recently, Christine Ménager et al. reported biocompatible, pH-responsive, magneto-responsive, and thermo-responsive nanogels for enhanced cancer treatment efficiency.138 The nanocarriers exhibited swelling–deswelling behavior at their volume phase temperature transition around 47 °C. When AMF triggered γ-Fe2O3 to produce heat, the nanogels shrank and released DOX by as much as 2 fold.138

In order to further enhance therapy efficiency, many synergistic cancer treatments have been explored using magnetic targeting drug delivery systems, such as photothermal therapy and synergistic drug and gene delivery. Chen-Sheng Yeh et al. reported Fe3O4-@Au@ mSiO2 core–shell NPs for co-delivery of oligonucleotide (dsDNA) and DOX. After targeted accumulation of the NPs in a tumor by a magnetic field, 808 nm NIR light was applied in the tumor region to trigger the photothermal effects of the Au NPs, which produced heat and promoted dsDNA and DOX release.139 In contrast to synthesized NPs, which can be readily taken up by the reticuloendothelial system and accumulate in the liver and spleen, natural biocompatible cell systems have been used as effective drug carriers, as shown in Fig. 13.


image file: c7bm00999b-f13.tif
Fig. 13 Scheme of (A) magnetic field magnetically controlled drug release system, reprinted from ref. 138, copyright (2017), with permission from American Chemical Society, (B) magnetic field-guided synergistic cancer treatments. Reprinted from ref. 139, copyright (2014), with permission from American Chemical Society.

Wang et al. reported novel drug carriers using red blood cell-loaded IONPs, a photodynamic agent, Ce6, and DOX for imaging-guided synergistic photodynamic chemotherapy of cancer. The results indicated that the red cell carriers not only prolonged blood circulation but also reduced retention in the reticuloendothelial system. Meanwhile, AMF-controlled targeted delivery enhanced accumulation of iron oxide NPs and drugs and greatly inhibited tumor growth.140

Currently, cancer resistance to apoptosis is considered to be a major obstacle for traditional chemotherapy. Therefore, it is urgent to explore efficient death signaling pathways to overcome cancer resistance towards apoptosis. The lysosomal death pathway increases the permeability of the lysosome membrane and releases digestive enzymes to kill cancer cells. It has been demonstrated as an efficient pathway to induce death of apoptosis-resistant cancer cells. Domenech et al. conjugated epidermal growth factor (EGF) and selectively induced lysosomal membrane permeabilization in cancer cells by applying an alternating magnetic field. This work suggests that magnetic guidance can regulate the lysosomal death pathway and therefore can be a promising strategy for apoptosis-resistant cancer treatment.114 For clinical applications, efficient magnetically targeted drug delivery strategies should be introduced to enhance drug distribution in tumors without accumulation in normal tissue.

7. Cancer immunotherapy

In contrast to other cancer therapy approaches, such as PTT, PDT, MHT, and chemotherapy, cancer immunotherapy is a different but promising treatment. In immunotherapy, the target is not tumor cells/tissues but the body's immune system. The strategy of cancer immunotherapy is to selectively kill cancer cells and eliminate tumor tissues by activating dendritic cells, T-cells or even macrophages.141 Generally, cancer immunotherapy consists of three main steps; (1) native dendritic cells (DCs) are stimulated to mature DCs by tumor-associated antigens, (2) the mature DCs are injected into the body and then migrate to nearby lymph nodes to active T cells, (3) the activated T cells attack cancer cells.142 From this procedure, it is clear that tumor-associated antigen-activated native DCs is the first key step in successful immunotherapy.

7.1 Applications of iron oxide in cancer immunotherapy

It is a challenge to efficiently deliver sufficient amounts of antigen into DCs to activate enough cytotoxic T cells and CD4+ helper T cells for subsequent cooperative attack of cancer cells.143 Attributed to their large specific surface areas and feasible targeting by molecular modification, NPs have been demonstrated as desirable carriers for transporting tumor-associated antigens into DCs.144,145Fig. 14 shows the scheme of NP-based cancer immunotherapy. In addition to delivery of antigens alone, NPs have also been used to co-deliver tumor antigens-chemotherapeutic drugs or antigens-small interference RNA for synergistic enhanced therapy.146–148 In addition, an advantage of NP-based immunotherapy is tracing mature DCs and pre-estimating the treatment effects using nano-contrast agents as antigen carriers, such as IONPs as an MRI contrast agent.149,150 Cho et al. reported Fe3O4–ZnO core–shell nanoparticles where ZnO can image mature DCs in vitro by its green fluorescence emitted at 470 nm, while Fe3O4 can trace the mature DCs in vivo by enhanced MR T2 imaging. The results indicated that the designed system can effectively accumulate DCs within one hour and trigger special tumor T-cells to destroy cancer cells effectively.151
image file: c7bm00999b-f14.tif
Fig. 14 Scheme of nanoparticle-based cancer immunotherapy. Nanocarriers activate DCs or directly stimulate T cells to attack cancer cells. Reprinted from ref. 144, copyright (2015), with permission from Elsevier Inc.

Compared with traditional NP-activated DCs and T-cell immunotherapies, IONPs have been applied for macrophage-activated cancer immunotherapy. It is well known that macrophages have two different activated states: M1 and M2. M1 macrophages can secrete ROS and pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α) and Interleukin-1 (IL-1), to kill cancer cells or invading microbes, while M2 macrophages have an opposite function of reducing inflammation and repairing tissue.152,153 Recently, Zanganeh et al. described a breakthrough using ferumoxytol, an FDA-approved iron oxide NP-mediated cancer treatment. Their results indicated that intravenous injection of ferumoxytol can inhibit the growth of early breast cancer cells and prevent lung cancer cells from metastasizing to the liver and lungs in a mouse tumor model. A further study demonstrated that ferumoxytol can stimulate tumor-associated macrophages to differentiate into M1 activated types, secrete ROS and pro-inflammatory factors, and subsequently activate caspase-3 pathway-induced cancer cell apoptosis.154

In addition to immunotherapy, IONPs have been used for stem cell therapy, autophagy, and tumor vascular blockade. The EGFR overexpressed stem cells are then attracted by tumor-secreted EGF and migrate to tumor tissue, inhibiting EGF/EGFR signaling pathway-mediated tumor growth as well as tumor angiogenesis.155 Autophagy (a process in which the cell degrades its own cytoplasmic proteins or organelles for survival) has been applied in the field of cancer treatment. Khan et al. reported that IONPs exhibit cytotoxicity to human lung cancer cells but not to normal lung fibroblast cells. Further study showed that IONPs can induce ROS, mitochondrial damage, and autophagy and subsequently kill cancer cells.156 Tumor vascular blockade is an important clinical cancer treatment method which can eliminate and prevent metastasis of cancer cells by the destruction of tumor angiogenesis. Agemy et al. reported that targeting peptide-modified superparamagnetic nanoparticles can reduce blood flow in tumor vessels and cause tumor necrosis.157

7.2. Iron oxide nanoparticles for magnetically controlled apoptosis

Apoptosis is a programmed cell death process for maintaining homeostasis and removing unnecessary or abnormal cells. It is controlled by the cell death signaling pathway and considered to be a desirable cancer elimination method.158 Cho et al. reported zinc-doped magnetic NPs conjugated with targeting antibodies for death receptor-mediated apoptosis. Their results indicated that when the magnetic switch is in on mode, NPs can aggregate and bind to death receptor 4 on the cell membrane and induce apoptosis signaling pathways in colon cancer cells and zebrafish. This study confirms for the first time that apoptosis signaling can be turned on in in vitro and in vivo models by using magnetic switch-controlled iron oxide NPs (Fig. 15).159
image file: c7bm00999b-f15.tif
Fig. 15 Antibody conjugated zinc-doped iron oxide nanoparticles bind to death receptor 4 and trigger extrinsic apoptosis signaling in colon cancer cells and in zebrafish when the focused magnetic field switch is maintained in the on position. Reprinted from ref. 159, copyright (2012), with permission from Macmillan Publishers Limited.

8. Summary and future outlook

Cancer is a major fatal disease and a worldwide problem. Nanotechnology approaches such as PTT, PDT, MHT, chemotherapy, and immunotherapy have been utilized to treat cancer. These approaches hold great promise to overcome the limitations of traditional treatments. However, NPs that are used for therapy are potentially toxic and biopersistent. Magnetic iron oxide nanoparticles (IONPs) have advantages over other NPs because iron is non-toxic, biocompatible, dissolvable and a biodegradable trace element in metabolism; also, it has been approved for MRI.

In PTT and PDT, high laser power can damage surrounding healthy tissues as well; magnetically targeted delivery can overcome this problem. Iron-based NPs can be used for imaging-guided delivery and multimodal theranostics. PTT can effectively kill tumors based on the fact that tumor cells are more sensitive to temperature changes. In PDT, photosensitizers (PS) are activated by lasers that generate ROS to kill cancer cells without a significant increase in temperature. However, PS has many limitations. Iron oxide NPs act as effective carriers to deliver photosensitizers to tumors by applying an external magnetic field. Meanwhile, IONPs can be used for imaging-guided PTT and PDT. Despite the many successful demonstrations of therapy approaches in killing cancer cells, most of the research involves direct administration of NPs in a tumor to achieve satisfactory therapy efficacy. However, systemic injection is desirable to target and treat metastases and remote tumor areas. It is necessary to implement standardized and validated methods for measuring therapy efficiencies, including a set of reference materials.

It is also important to develop validated assays to investigate the toxicological and biological behavior of nanomaterials. To date, less attention has been paid to investigate the mechanisms of cell death after these treatments. PTT is an experimental cancer treatment and is in the preclinical stage. Key issues must be addressed before it is implemented in the clinic. Furthermore, in a cellular environment, IONPs show enzyme-like activity and intrinsic properties to kill cancer; these activities must be deeply explored. Additional research is needed to explore the mechanism of cell death and the redox activities of iron NPs under different bio-microenvironmental conditions.

Tunable drug release is possible by exploiting the magnetic targeting properties of IONPs. Effort should be focused on increasing their specificity, affinity to target cells, drug loading capacity, and microenvironment-dependent controlled drug release. Moreover, efficient magnetically targeted drug delivery strategies should be introduced to enhance drug distribution in tumor tissue without accumulation in normal tissues. Immunotherapy is an exciting therapeutic approach; however, a potential challenge is to efficiently deliver sufficient amounts of antigen into DCs.

The combination of different therapy modalities with immunotherapy can be an effective theranostic approach. MHT has various advantages, such as remote control activation and local heat to destroy cancer cells. Additionally, it can be used alone or in combination with other modalities, such as PTT, PDT chemotherapy, and immunotherapy. In MHT, the heating effect is measured by the SLP value; the heating efficiency depends on various parameters of the magnetic NPs, such as size, morphology, composition, magnetization and relaxation time, as well as on the frequency and amplitude of the applied magnetic field. These parameters should be carefully optimized to obtain higher SLP values. Most studies have explored magnetic hyperthermia performance in solution and reported higher SLP values; however, studies measuring SLP values in a biological environment are rare. Moreover, intracellular heating mechanisms and NP behavior inside cells have remained less explored. It is necessary to design and optimize the performance of magnetic NPs, which may overcome the limitations of MHT. MHT also has some limitations in the cellular environment. It is necessary to address the problems of poor heating efficiency, especially inside cells, and the intratumor mode of injection. It is imperative to develop a standardized method of measuring hyperthermia efficiency.

Future research should explore alternative methods for homogeneous and efficient distribution of NPs in cancer tissues and real-time monitoring of heat distribution. Moreover, there is limited understanding of the behavior of NPs in biological environments. Hence, more attention should be paid to understand nano-bio interactions.

Abbreviations

PTTPhotothermal therapy
PDTPhotodynamic therapy
MHTMagnetic hyperthermia therapy
MRIMagnetic resonance imaging
ROSReactive oxygen species
NIRNear-infrared
IONPsIron oxide nanoparticles
NPsNanoparticles
NCsNanocomposites
PSPhotosensitizer
AMFAlternating magnetic field
SLPSpecific loss power
SARSpecific absorption rate
SPIONsSuperparamagnetic iron oxide nanoparticles
NMsNanomaterials

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors acknowledge financial support from the National Natural Science Foundation of China (U1432114 and 81401452), Key Breakthrough Program of Chinese Academy of Sciences (KGZD-EW-T06), Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase to Aiguo Wu, U1501501), and the Hundred Talents Program of Chinese Academy of Sciences (2010-735). Ms Madiha Saeed thanks the Chinese Academy of Sciences and TWAS for awarding her a CAS-TWAS President's PhD fellowship (2014A8017407006). The authors also acknowledge the Science & Technology Bureau of Ningbo City (2014A610159, 2015C50004, 2015B11002, and 2017C110022), Zhejiang Province Financial Supporting (2017C03042, LY18H180011), Shanghai Synchrotron Radiation Facility at Line BL15U (No. h15sr0021) used for X-ray fluorescence imaging, National Synchrotron Radiation Laboratory in Hefei used for soft X-ray imaging (No. 2016-HLS-PT-002193), and CAS Interdisciplinary Innovation Team.

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Footnote

These authors contributed equally to this work.

This journal is © The Royal Society of Chemistry 2018