REVIEW ARTICLE

Multifunctional modification of Fe3O4 nanoparticles for diagnosis and treatment of diseases: A review

  • Miao QIN 1 ,
  • Mengjie XU 1 ,
  • Lulu NIU 3 ,
  • Yizhu CHENG 1 ,
  • Xiaolian NIU 1 ,
  • Jinlong KONG 1 ,
  • Xiumei ZHANG 1 ,
  • Yan WEI 1,2 ,
  • Di HUANG , 1,2
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  • 1. Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan 030024, China
  • 2. Shanxi Key Laboratory of Material Strength & Structural Impact, Institute of Biomedical Engineering, Taiyuan University of Technology, Taiyuan 030024, China
  • 3. Wellead Medical Co. Ltd., Guangzhou 511434, China

Received date: 31 Oct 2020

Accepted date: 16 Dec 2020

Published date: 15 Mar 2021

Copyright

2021 Higher Education Press

Abstract

With the rapid improvements in nanomaterials and imaging technology, great progresses have been made in diagnosis and treatment of diseases during the past decades. Fe3O4 magnetic nanoparticles (MNPs) with good biocompatibility and superparamagnetic property are usually used as contrast agent for diagnosis of diseases in magnetic resonance imaging (MRI). Currently, the combination of multiple imaging technologies has been considered as new tendency in diagnosis and treatment of diseases, which could enhance the accuracy and reliability of disease diagnosis and provide new strategies for disease treatment. Therefore, novel contrast agents used for multifunctional imaging are urgently needed. Fe3O4 MNPs are believed to be a potential candidate for construction of multifunctional platform in diagnosis and treatment of diseases. In recent years, there are a plethora of studies concerning the construction of multifunctional platform presented based on Fe3O4 MNPs. In this review, we introduce fabrication methods and modification strategies of Fe3O4 MNPs, expecting great improvements for diagnosis and treatment of diseases in the future.

Cite this article

Miao QIN , Mengjie XU , Lulu NIU , Yizhu CHENG , Xiaolian NIU , Jinlong KONG , Xiumei ZHANG , Yan WEI , Di HUANG . Multifunctional modification of Fe3O4 nanoparticles for diagnosis and treatment of diseases: A review[J]. Frontiers of Materials Science, 2021 , 15(1) : 36 -53 . DOI: 10.1007/s11706-021-0543-y

Contents

Introduction

The preparation of Fe3O4 MNPs

Co-precipitation method

Thermal decomposition method

Hydrothermal method

Microemulsion method

Other methods

Modification strategies based on Fe3O4 MNPs

Modification strategies based on Fe3O4 NPs for expected dispersibility

Modification strategies based on Fe3O4 NPs for hydrophilia

Modification strategies based on Fe3O4 NPs for targeting

Modification strategies based on Fe3O4 NPs for multi-mode imaging

Modification strategies based on Fe3O4 NPs for therapy

Modification strategy for drug release carrier

Modification strategies for multifunctional platforms of diagnosis and treatment based on Fe3O4 MNPs

Conclusions and outlook

Acknowledgements

References

Introduction

As we all know, nanoparticles (NPs) have the length in the range of 1–100 nm [12], which exhibit distinctive size effects [3]. With the development of nanotechnology, NPs have been widely applied in multiple domains over past decades ranging from medical and pharmaceutical domain [46] to electronic industry [79], environment protection field [1012], agriculture [1314], food [1516], etc., which is attributed to their special size [17]. Especially in biomedical field, NPs exert special functions induced by special size, for instance, quantum effect and high surface-to-volume ratios, which provide more possibilities in the application of NPs [1819]. In recent years, Fe3O4 magnetic nanoparticles (MNPs) as one type of the most promising NPs gain attentions from researchers among diverse NPs since they are prone to be modified and possess good biocompatibility [2021].
Among diverse applications of Fe3O4 MNPs, the most mature aspect about it is reflected in magnetic resonance imaging (MRI). When the diameter of Fe3O4 MNPs is larger than 5 nm, they show superparamagnetic property and generate darker signals in T2-weighted imaging (T2WI) [22]. Furthermore, Fe3O4 MNPs (diameter of MNPs<5 nm) could express paramagnetic and generate brighter signals in T1-weighted imaging (T1WI) [2324]. Therefore, the application of Fe3O4 MNPs incorporated with MRI for the diagnosis of disease has broad prospects [25]. There are plenty of products based on Fe3O4 MNPs up to now, which are at the commercialized stage or different clinical stages, for instance, Resovist (for liver imaging), Combidex (lymph contrast agent) and Clariscan (for imaging of liver and lymph) [26]. Fe3O4 MNPs play an important role in MRI as the contrast agent. The inherent magnetic property of Fe3O4 MNPs endows them with the hyperthermia potential for malignant tumors [2728]. Furthermore, Fe3O4 MNPs have been utilized as drug delivery carriers as well due to the biocompatibility [2930]. Owing to the favorable characters of Fe3O4 MNPs, a variety of multifunctional platforms have been constructed based on it towards diagnosis and treatment of diseases. Here, we will introduce the preparation methods and modification strategies of Fe3O4 MNPs.

The preparation of Fe3O4 MNPs

During past twenty years, the techniques regarding the preparation of Fe3O4 MNPs have been developed and a variety of mature technologies have hitherto been formed, which are divided into chemical methods and physical methods in general. Physical methods such as gas phase deposition method [3133] and ultrasonic method [3435] maintain unsatisfactory performance in the control of the particle size distribution. Chemical preparation technologies including co-precipitation method [36], thermal decomposition method [37], microemulsion method [38] and hydrothermal method [39] are commonly used at present to generate Fe3O4 MNPs with appreciable controllability in diameter, structure, shape and dispersibility. Therefore, chemical methods are believed as the optimal way to produce Fe3O4 MNPs that possess better performance in physical and chemical properties.

Co-precipitation method

Up to date, co-precipitation method as a traditional and simple technique is commonly used to obtain Fe3O4 MNPs owing to its lower demand of experimental equipment. At room temperature or high temperature, Fe3O4 MNPs were obtained from the reaction of aqueous solution containing Fe2+/Fe3+ and alkaline substances assisted with nitrogen using co-precipitation, which abide by the reaction principle as given below:
Fe2++ 2Fe3+ + 8OH Fe 3 O4+ 4H2O
The shape, the size and the component of Fe3O4 MNPs depend on the temperature, the pH of reaction, the species of iron salts, the ratio of Fe2+/Fe3+ and other factors at a great extent [4041]. The obtained Fe3O4 MNPs by using this method are aqueous, which have no limitations in application. However, there still are shortcomings referring the method, for instance, wide range of size distribution, unsatisfactory dispersibility and low repeatability, which are inevitable phenomena and have undesirable influence on properties. They are urgent obstacles that the co-precipitation method needs to remove in terms of biomedical application. Consequently, great efforts have been made towards this aspect to achieve effective improvement in recent years. For enhancing the monodispersity and stability of Fe3O4 MNPs, polymers [42], small molecule compounds [43], surface active agents [4445] and other substances like bovine serum albumin (BSA) [46] are introduced into the reaction, which were as stabilizing agents in the reaction system to acquire expected dispersity or obtain narrow size distribution of particles. Fe3O4 MNPs coated with poly(ethylene glycol) (PEG) were fabricated using co-precipitation by Balamurugan et al. [47], which possess narrow particle size distribution with the homogeneous spherical shape.
It is reported that Feridex as the MRI contrast agent withdrew from the American market, which is caused by low repeatability and unstable particle size distribution [48]. As a result, low repeatability is considered as a key factor that affects the usage of Fe3O4 MNPs as well. Lacking understanding in the mechanism of particle formation leads to the situation that intermediate phases remain in final product, and finally causes low repeatability. Thanh et al. [49] utilized a flow reactor to control the homogeneities of reaction pH and temperature to the greatest extent to study the growth mechanism of Fe3O4/γFe3O4 MNPs (γFe3O4 MNPs are the oxidation products of Fe3O4 MNPs) (Fig. 1). The study demonstrated that two intermediates including iron carbonate plates and ferrihydrite phase have been formed until the formation of Fe3O4/γFe3O4 MNPs, in which iron carbonate plates offer iron ions for particles growth and occurrence of phase change and ferrihydrite as the seeds to grow into Fe3O4/γFe2O3 MNPs. In the reaction system, Fe3O4/γFe2O3 MNPs have been formed after mixtures react for 2–3 min. And after the reaction for 4 min, there is no intermediate in products. This research elaborates the formation mechanism of Fe3O4 MNPs, which could help researchers control the size and enhance the repeatability of Fe3O4 MNPs.
Fig.1 (a) Schematic illustration of the reactor. Reproduced with permission from Ref. [49]. (b) Schematic illustration of the growth mechanism. Reproduced with permission from Ref. [49].

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Thermal decomposition method

Thermal decomposition method as one of the most successful technologies for preparing Fe3O4 MNPs with great dispersibility, high degree of crystallinity and narrow range of particle size distribution has attracted researchers’ attention over past years. Fe3O4 MNPs were fabricated relying on the decomposition of organic metal precursors containing ferrum element in organic solvent with high boiling point under the addition of surface active agent [50]. In 2004, Hyeon et al. [37] reported their study firstly about the preparation of Fe3O4 MNPs by thermal decomposition, in which the obtained Fe3O4 MNPs display high monodispersity with the particle size of 12 nm and they do not need further size-sorting procedure. Meanwhile, Fe3O4 MNPs synthesized by this method have a huge output of 40 g, which enhances the practical value of Fe3O4 MNPs. In the reaction system of thermal decomposition, a number of parameters including temperature, species of metal precursors, surface active agents and reaction time play important roles in the shape, the size, the nucleation and the growth process of obtained Fe3O4 MNPs, which will further affect the physical and chemical properties of Fe3O4 MNPs. There are a plethora of studies concerning the influence of different parameters on the shape and the size of Fe3O4 MNPs that are summarized in Table 1 [37,5154]. Even though the as-synthesized Fe3O4 MNPs using the thermal decomposition method possess good performance in the particle size distribution and the degree of crystallinity, there is a critical disadvantage that restricts their application, i.e., the obtained Fe3O4 MNPs by this method are hydrophobic. Based on this situation, a variety of hydrophilic substances like PEG, SiO2 [55] and dopamine [56] have been used as modifications to endow hydrophobic Fe3O4 MNPs with hydrophilia. Tan et al. [57] fabricated Fe3O4 MNPs coated with oleic acid (OA) and then OA on the surface of NPs was exchanged by dopamine or 3,4-dihydroxyhydrocinnamic acid (DHCA) using the ligand-exchange method, which not only rendered NPs hydrophily, but also provided active groups such as the amino group of dopamine and the carboxyl group of DHCA for further functionalization. Despite that thermal decomposition is a mature and efficient technique in laboratory for the preparation of Fe3O4 MNPs, there still are problems to be solved in industrial application. For instance, complicated procedures, high cost, low yields and dangers induced by high temperature have been the challenges in further development and exploration of thermal decomposition technique.
Tab.1 The shape and the size of Fe3O4 MNPs at different reaction parameters [37,5154]
Precursor T/°C Surfactant η t/h δ/(°C·min−1) Size/nm Shape State Ref.
Iron oleate 290 OA 0 1 10 4–6 SC monodisperse, SC [51]
320 OA 0 1, 10 10 6–10 spherical monodisperse, SC [51]
320 OA 25:1 24 10 13–24 spherical & cubic monodisperse, SC [51]
260 OA 2:1 24 3.3 9 spherical polydisperse, PC [37]
320 OA 2:1 0.5 3.3 12 spherical monodisperse, SC [37]
Iron pentacarbonyl 283 OA 2:1 1.5 immediately 14 spherical & cubic monodisperse, SC [51]
Iron oxyhydroxide 320 OA 15:1 24 15 22–33 spherical & facetted monodisperse, SC [51]
Iron acetylacetonate 300 OAm 26:1 1 20 3–6 spherical monodisperse, SC [52]
265 OA & OAm 5:1 a) 2 immediately 9 spherical & cubic monodisperse, SC [53]
Iron glucuronate 320 OA 1.2:1 0.5 immediately 11 cubic monodisperse, SC [54]

Notes: η, molar ratio of surfactant to precursor; δ, heating rate; OA, oleic acid; OAm, oleyamine; PC, poor crystalline; SC, single crystalline; T, temperature; t, time.

a) The molar ratio of OA to OAm in the surfactant is 3:2.

Hydrothermal method

In fact, hydrothermal method is an excellent candidate for the preparation of Fe3O4 MNPs with high degree of crystallinity, high controllability of particle size and good dispersibility. In addition, the acquired Fe3O4 MNPs using this method are hydrophilic and they do not require further modification due to the hydrophilia of reaction solvent. Generally, raw materials containing Fe2+ or Fe3+ as the iron source and aqueous solution as the reaction medium were placed in an autoclave for reaction under the environment of high temperature and high pressure [58]. Similar to other methods, the heating temperature, the reaction time, the molar ratio of surfactant to precursor and other reaction parameters are main factors in determining the size, the shape and the particle size distribution of Fe3O4 MNPs, and the desired MNPs can be acquired by the adjustment of such illustrated parameters. Different from the high temperature of thermal decomposition method, the reaction temperature of hydrothermal method is in the range of 125–200 °C, which is much safer than that of thermal decomposition method. Shi et al. [59] fabricated Fe3O4 MNPs coated with polyethyleneimine (PEI) by refluxing 3 h at 134 °C using the hydrothermal method, in which FeCl2·4H2O and PEI were as the ferrum source and the stabilizing agent, respectively. The obtained MNPs in this way were of spherical shape with a good dispersibility and the particle size was tunable according to the changes of reaction parameters. Overall, the hydrothermal method is an excellent and efficient technique in the preparation of MNPs. However, the high temperature and pressure conditions required for this reaction still restrict its industrial production. Besides above problems, the definite mechanism concerning the formation process of crystal nucleus and crystal growth has not been established yet. As a result, explorations and investigations based on above challenges are worth carrying out for researchers.

Microemulsion method

In two insoluble mutually liquids phase (water phase and oil phase), microdroplets will be formed at the interface between two insoluble phases, which could be used as microreactor to synthetize Fe3O4 MNPs [60]. Generally, the microemulsion method can be divided into two types according to the ratio between oil phase and water phase and the microstructure. One is oil-in-water (O/W), and the other is water-in-oil (W/O), which is a novel technique for the preparation of ultrasmall Fe3O4 NPs [61]. In the reaction system of W/O microemulsion method, the microemulsion containing ferrum ions and alkaline microemulsion were mixed for reaction, in which collisions, ruptures and combinations between microdroplets happened for production [62]. The particle size of Fe3O4 MNPs depends on many factors such as the ratio of water to surfactant, and the concentration of alkaline solution. Even though the situation that the obtained Fe3O4 MNPs using the microemulsion method have narrow size distribution and good dispersibility, there are still disadvantages that limit its application like low output, low crystallinity and huge demand of solvent, which must be improved for extensive application.

Other methods

Besides technologies illustrated above, there are many other technologies involved in the preparation of Fe3O4 MNPs, for example, the solvothermal method [6364], the sol–gel method [65] and the mechanical crushing method, which are not commonly used in current research. Detailed introduction referring to such methods can be seen in Table 2 [32,3639,6568].
Tab.2 The comparison on different methods of Fe3O4 MNPs preparation [32,3639,6568]
Method Advantages Disadvantages Surface property Ref.
Co-precipitation simple and easy to operate, low needs of reaction conditions wide range of particles size and poor dispersity hydrophilia [36]
Thermal decomposition high degree of crystallinity and narrow distribution of particles size hydrophobicity of products, danger for operator hydrophobicity [37]
Hydrothermal high purity and magnetism of products high requirements for reaction conditions hydrophilia [39]
Microemulsion simple experimental devices, easy to manipulate low crystallinity of products, low productivity and poor monodispersity hydrophilia or hydrophobicity [38]
Solvothermal high degree of crystallinity and monodispersity hydrophobicity of products hydrophobicity [66]
Sol–gel simple experimental equipment, good monodispersity low controllability, release of toxic organic substances during reaction hydrophobicity [65]
Vapor deposition simple devices, easy to control, high purity and good dispersity low productivity, high cost and difficult for collection of products hydrophilia [32]
Ultrasound good dispersity, easy to operate wide distribution of particle size hydrophilia [67]
Mechanical crushing low cost, high productivity, simple devices wide distribution of particle size, large particle size hydrophilia [68]
In a word, the co-precipitation method and the thermal decomposition method as preferred means still maintain dominant positions among all methods in the research of Fe3O4 MNPs. However, enhancing the dispersibility of Fe3O4 MNPs produced by co-precipitation and improving the hydrophilicity of Fe3O4 MNPs fabricated by thermal decomposition are major challenges in further researches. In addition, systematic theories and mechanisms concerning such means also need urgently to be studied and established by researchers.

Modification strategies based on Fe3O4 MNPs

To enhance the stability and versatility of Fe3O4 MNPs, a lot of modifiers like PEG [47,69] and SiO2 [7071] are utilized for the modifications of these fundamental and common strategies for Fe3O4 MNPs, which are necessary steps but not main research hotspots. In current researches, there are plenty of novel modification strategies for Fe3O4 MNPs to endow them with distinctive properties according to different usage purposes, for example, modifications of targeting protein endue MNPs with diagnostic targeting [72], modifications like Au (CT) [73] and 99mTc (PET/SPECT) [74] endow MNPs with property of multi-mode imaging, and modifications such as doxorubicin hydrochloride (DOX) [7576] make MNPs possess treatment capability. We will introduce a few multifunctional modification strategies of Fe3O4 MNPs for further application in various domains (Fig. 2).
Fig.2 Multifunctional modification strategies for Fe3O4 MNPs.

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Modification strategies based on Fe3O4 NPs for expected dispersibility

With the decrease of the particle size, both the specific surface area and the surface energy are increased. Therefore, the NPs are prone to aggregation and become large particles in the procedures of preparation and post-treatment [77]. The function of Fe3O4 MNPs relies on their special size largely, so it is essential to prevent them from being reunited. One strategy to solve the problem is to introduce surfactant into the preparation process of Fe3O4 MNPs, which could be coated with the surface of Fe3O4 MNPs assisted by hydrophobic interaction and electrostatic attraction [21]. Subsequently the surfactant can decrease the interfacial tension at the solid–liquid interface and then enhance the thermodynamic stability of dispersions. Sodium dodecyl sulfate (SDS) as a kind of anionic surfactant is a potent candidate for increasing the dispersibility of Fe3O4 MNPs [7879]. Samrot et al. presented a study regarding Fe3O4 MNPs coated with SDS using co-precipitation, which indeed exhibits better dispersibility compared with undecorated Fe3O4 MNPs [80]. However, the dispersibility of it is still not in ideal state due to the inherent shortcoming of the co-precipitation technique. OA is also a promising surfactant for the modification of MNPs in thermal decomposition method. Hyeon et al. fabricated Fe3O4 MNPs with high dispersibility, in which OA was used as the surfactant [37]. Another commonly used strategy is the introduction of polymers including dextran [8182], chitosan [8384] and β-cyclodextrin (β-CD) [85], which are modified in the surface of Fe3O4 MNPs through chemical bond caused by the reaction between functional groups of polymers and Fe3O4 MNPs. Afterwards, the polymers in the surface of Fe3O4 MNPs could inhibit the growth and aggregation of Fe3O4 MNPs to achieve the goal of good dispersibility [86]. Fe3O4 MNPs coated with dextran were synthetized by Ma et al., in which a great progress has been made in dispersibility compared to bare Fe3O4 MNPs from transmission electron microscopy (TEM) images. Moreover, dextran endows NPs with good biocompatibility due to its characterization of nontoxicity, and it also provides functional groups for bioconjugation to drugs or ligands [8788]. Besides above strategies, some small molecules like citric acid could be used to modify Fe3O4 MNPs for improving the dispersibility of them. Citric acid was employed as stability agent in the preparation of Fe3O4 MNPs by Montaseri’s group [36]. It can be observed that the dispersibility of NPs has been improved significantly compared to that of bare Fe3O4 MNPs group.

Modification strategies based on Fe3O4 NPs for hydrophilia

Thermal decomposition technique for the preparation of Fe3O4 MNPs occupies an unshakable position owing to its outstanding superiorities such as high degree of crystallinity and monodispersity. However, the fabricated NPs in this way are hydrophobic, which is the fatal flaw in the application in biomedical fields. As a result, hydrophilic modifications are necessary for obtained hydrophobic Fe3O4 MNPs. There are two strategies for the modification:
One is ligand encapsulation technique [89], in which PEG, SiO2 and polymethyl methacrylate (PMMA) are commonly used. PEG as a kind of amphiphilic ligand is extensively applied in the modification of Fe3O4 MNPs. The hydrophobic end of PEG reacts with the group in the surface of NPs to form a micelle through Van der Waals hydrophobic interaction, thereby NPs exhibit aqueous because the hydrophilic ends are exposed to the outside [90]. The technique usually increases the particles size. Zhang et al. fabricated Fe3O4 MNPs using thermal decomposition and coated them with PEG/PEI, which not only endows NPs with hydrophilicity but also offers them biocompatibility, greatly significant for their further application [91]. In addition, a lot of investigations demonstrate that PEG is a commonly used polymer for enhancing the biocompatibility of NPs [9293]. SiO2 as a small inorganic molecule is also utilized to modify Fe3O4 MNPs using ligand encapsulation technique, which is the earliest and the most extensive method in this respect. Fe3O4 MNPs were modified with SiO2 using the sol–gel method by Minetti et al. [71], which could be dispersed in aqueous medium and maintain a stable colloidal suspension. Furthermore, the introduction of amino groups in the surface of SiO2 provided the possibility of loading drugs [94]. It is worth noting that the shell thickness of SiO2 coating should be adjusted in case of excessive SiO2 content that affects the magnetic property of Fe3O4 MNPs.
The other strategy for hydrophilic modification is ligand exchange technique, which is dependent on hydrophilic ligands with anchor groups to replace hydrophobic ligands on NPs [95]. In general, the method has less influence on the particle size. Dopamine with anchor groups is used for the modification of Fe3O4 MNPs, which display good hydrophilia, as shown by Hussain et al. [56]. However, due to the low toxicity and ligand exchange efficiency of dopamine, other potential substances with anchor groups have been studied as well. Tan et al. developed Fe3O4 MNPs modified with DHCA, which not only exhibited hydrophilia but also demonstrated good biocompatibility due to the nontoxicity [96]. Furthermore, carboxyl groups on DHCA were also utilized to react with amino groups on fluoresceinamine for detecting the effect of functionalization, indicating that DHCA can be functionalized effectively.

Modification strategies based on Fe3O4 NPs for targeting

Over the past years, the concept of targeting diagnosis has attracted much attention from researchers due to its sensitivity and specificity. The modifications of targeting ligands are carried out based on Fe3O4 MNPs assisted by the MRI technology, which could detect abnormal situations at the level of cell and molecule during the development stages of diseases. It is vital for the early diagnosis of disease, which can increase the survival rate of patients. In recent years, researchers have made great efforts in this area.
Malignant tumors have been thorny issues and the biggest threats for human health over past decades despite the situation that the technology of diagnosis and the treatment have improved. Earlier and specific detection of tumors is beneficial for the treatment [9798]. Therefore, many tumor targeting ligands including folic acid (FA) [99100], arginine-glycine-aspartic acid (RGD) peptides [101102], antibodies and aptamers are exploited to modify Fe3O4 MNPs for diagnostic targeting. FA receptor, which is a single chain glycoprotein with specific affinity for FA, is highly overexpressed in various tumor cells such as ovarian, gastric carcinoma, and oral cancer. Zhang et al. fabricated Fe3O4@PEI NPs, and then FA was PEGylated by PEG-COOH and conjugated to NPs through the reaction between carboxyl groups and amino groups [103]. FA-targeted-Fe3O4 NPs exhibit T2 MR imaging enhancement with high r2 value of 475.92 mmol−1·L·s−1 in vitro, and the MR imaging of xenograft ovarian tumor model mice demonstrated that FA-targeted-Fe3O4 NPs possess stronger T2 signal intensity compared with non-targeted-Fe3O4 (Fe3O4-PEG-COOH). RGD peptides can combine specifically with integrin αvβ3, which is overexpressed in blood vessels of tumor. As a result, it is an available target site as well for the malignant tumor detection. Wang et al. reported a study concerning RGD-PAA-USPIO NPs, in which the principle of conjugation is the reaction of carboxyl groups and amino groups as well [104]. T2WI on nasopharyngeal carcinoma (NPC) xenograft tumor mice demonstrates that the signal intensity of RGD-PAA-USPIO group has a significant enhancement compared to that of PAA-USPIO group. The above research conveys the conclusion that Fe3O4 MNPs coated with targeting ligands can increase the disease detection rate.
The growth and metabolism process of tumor cells is different from that of normal cells, in which the tumor microenvironment (TME) contains diverse cells, extracellular matrix, various cell factors and vascular networks surrounding tumor cells [105106]. The TME offers novel characteristic physical and chemical conditions for targeting delivery of NPs, e.g., weak acidic environment [107], high content of matrix metalloproteinases (MMP) [108], and high level of glutathione [109], which provide new strategies for targeting drug loading and treatment based on NPs as well. Gao et al. synthesized Fe3O4 MNPs coated with tumor targeting RGD peptides through formed covalent bonds with maleimide groups, and then the self-peptide was linked to RGD peptides through the conjugation of a disulfide bond, in which the self-peptide is as an antiphagocytosis surface coating (Fig. 3(a)) [110]. The NPs exhibit moderate dark signals in T2WI under normal physical conditions, and once they have penetrated tumor tissues, the disulfide bonds between RGD peptides and self-peptide break due to the high content of reductive GSH in tumor tissues. Meanwhile, the NPs aggregation is caused by the interparticle reaction of thiol groups on RGD peptides and maleimide residues from adjacent particles. On this condition, the aggregated NPs express darker signals in T2WI, and normal tissues show bright signals whereas tumor tissues show dark signals, which could enhance the contrast between normal and tumor tissues and eventually highlight the tumor. It can be observed that the signal intensity of GSH-responsive Fe3O4 MNPs is higher compared to that of nonresponsive MNPs, indicating that GSH-responsive modification improves the tumor contrast obviously, which is a promising modification strategy for increasing the tumor detection rate. Ling et al. fabricated ultrasmall iron oxide nanoclusters (USIONCs) with the diameter of 4 nm and modified them with i-motif DNA, which expressed sensitive pH-responsive transformation from single-stranded structure to quadruple-helical structure under weak acid environment (Fig. 3(b)) [111]. The obtained MNPs existed in the form of responsive iron oxide nanocluster assembly (RIA) with the diameter of 120 nm under normal condition, which exhibited dark signals in T1WI. When the RIA entered tumor tissues, it was disassembled into small scale RIA with the diameter of 20 nm induced by the weak acid environment due to the transformation of i-motif DNA, which expressed bright signals in T1WI. Subsequently, RIA and pH-irresponsive iron oxide nanocluster assemblies (IRIAs) were intravenously injected into liver tumor model mice separately. T1WI images of both groups demonstrated that bright and dark signals could be seen obviously in tumor and normal tissues, respectively. However, the contrast of the RIA group was significantly stronger than that of the IRIA group, which was more conductive to the diagnosis of small liver tumor.
Even though the strategies manifest outstanding results in diagnosis, there is only a single factor measured referring to TME. In fact, the formation of TME is caused by multiple factors that are correlational. Therefore, to further enhance the specificity and sensitivity of diagnosis, some dual-responsive probes base on Fe3O4 MNPs and TME features have been synthesized. Gao et al. designed pH and MMP-9 dual-responsive fluorescent probe based on Fe3O4 MNPs (Fig. 3(c)) [112]. Firstly, Fe3O4 MNPs coated with PEG were fabricated to obtain maleimide groups, and then they were linked with N-carboxyhexyl derivative of 3-amino-1,2,4-triazole fused 1,8-naphthalimide (ANNA)-labeled MMP-9 substrate peptides through the click reaction of maleimide groups of MNPs and a thiol group of peptides. Subsequently FA was conjugated with ANNA-labeled MMP-9 substrate peptides by the reaction of carboxyl groups and amino groups, and then the biotin was linked to MNPs assisted by maleimide groups. Finally, Cy 5.5 was linked to MNPs through specific reaction with biotin in MNPs. In this system, ANNA was pH-responsive fluorescence dye, which maintains a state of “off” when attached in MNPs in normal tissues. When MNPs entered tumor tissues, the high level of MMP-9 induced the cleavage of peptide linker, and ANNA was activated and the fluorescence of it can be detected, which made it possible to detect the environmental pH. Furthermore, fluorescence spectra indicated that the fluorescence intensity of activated ANNA was dependent on the concentration of MMP-9, so the content of MMP-9 could be quantitatively determined at the form of the ratio between ANNA and Cy 5.5 emission, in which Cy 5.5 was as an internal reference due to the character of pH-independence. In this way, the diagnosis results can be corroborated by T2WI detection, pH mapping and MMP-9 mapping, and the tumor related information can be qualitatively detected. This research offers a new idea for multifunctional modifications based on Fe3O4 MNPs in detailed diagnosis.
Fig.3 (a) Schematic drawing of the antiphagocytosis 99mTc-labeled Fe3O4 NPs and the diagnosis principle for tumors. Reproduced with permission from Ref. [110]. (b) Schematic illustration of RIA for diagnosis of small HCC. Reproduced with permission from Ref. [111]. (c) Schematic illustration of dual-ratiometric target-triggered fluorescent probe for diagnosis of tumors. Reproduced with permission from Ref. [112].

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Modification strategies based on Fe3O4 NPs for multi-mode imaging

With the enhancement of disease complexity, the single imaging technique is unable to meet the requirements of disease diagnosis. Multiple-mode imaging techniques are powerful tools in disease diagnosis because they can provide more comprehensive and accurate information related to the diagnosis. Considerable developments have been made in the aspects over the past years. In this section, many modification strategies of multi-mode imaging in the surface of Fe3O4 MNPs will be introduced.
T1T2 dual-modal contrast agents based on Fe3O4 MNPs have gained extensive attention during the past years because they can offer complementary diagnostic information, which can improve the sensitivity and reliability for detecting lesions [113]. The typical strategies for the preparation of T1T2 dual-modal contrast agents are to combine T1 contrast materials and T2 contrast materials. In current studies, the introduction of gadolinium element and manganese element based on Fe3O4 MNPs is the most commonly used technique. When T1 component is embedded into T2 component, its electron spin orientation is parallel to the direction of induced magnetic field, which is generated by T2 contrast materials assisted by external magnetic field. As a result, both T1 and T2 imaging effects can be enhanced at the same time. Gao et al. fabricated Gd-embedded iron oxide (GdIO) NPs with spherical shape by introducing the gadolinium element into the fabrication process of Fe3O4 MNPs, in which gadolinium and ferrum elements were uniformly distributed (Fig. 4(a)) [114]. The values of r1 and r2 were measured to be 146.5 and 69.5 mmol−1·L·s−1, respectively. T1WI and T2WI images on the orthotopic liver cancer model mice demonstrated that GdIO NPs possess T1 and T2 MR imaging enhancements simultaneously. Lu et al. reported a facile fabrication method of superparamagnetic spherical manganese-doped oxide iron oxide (MnO/Fe3O4) NPs with the diameter of 20 nm, which exhibited remarkable T1 imaging enhancement (r1 = (209.6±0.7) mmol−1·L·s−1) and T2 imaging effect (r2 = (22.8±0.3) mmol−1·L·s−1) in vitro (Fig. 4(b)) [115]. From T1WI and T2WI images, it could be observed that MnO/Fe3O4 NPs have the ability of T1 and T2 imaging contrast enhancement in liver.
Besides above T1T2 dual-modal probes, there are various modification strategies to design probes based on Fe3O4 MNPs for application of multi-modal imaging, in which multi-modal imaging represents MRI technique combined with other imaging techniques such as ultrasound (US), computed tomography (CT), and fluorescent imaging (FI). Such combined imaging technologies can exploit respective advantages and overcome their limitations, which enables diagnosis more accurate and reliable. Wu et al. designed PEGylated poly(lactic-co-glycolic acid) (PLGA) microcapsules (MCs) Fe3O4 NPs (Fe3O4@PEG-PLGA MCs) using the premix membrane emulsification method, which expressed good biocompatibility on cells and tissues (Fig. 4(c)) [116]. MCs were generally used in US imaging, and Fe3O4 MNPs were embedded in MCs to endow them with US/MR multimodal imaging effect. US imaging and MR imaging were performed on nude mice before and after intravenous injection of Fe3O4@PEG-PLGA MCs. The images of US imaging in liver exhibited strong contrast and the contrast enhancement could be observed in MR imaging of kidney, spleen and liver, indicating that Fe3O4@PEG-PLGA MCs as contrast agent possess the potential to be applied in US/MR multimodal imaging. Blower et al. designed Co0.16Fe2.84O4@NaYF4(Yb, Er)-bisphosphonate (BP)-PEG NPs and Fe3O4@NaYF4(Yb, Tm)-BP-PEG NPs [117]. In this system, the Co element was introduced to improve the magnetic property of Fe3O4 NPs, and lanthanide cations Er3+ or Tm3+ as active cations and Yb3+ as sensitizer were embedded into paramagnetic NaYF4 to form down-conversion and up-conversion materials for FI. In addition, the strong interaction between NaYF4 NPs and phosphonate groups endowed NaYF4 NPs with the ability of conjugation with efficiency [18F]-fluoride and bisphosphonate conjugates of 64Cu and 99mTc, which provided potential applications in PET and SPECT imaging. In vivo studies demonstrated that 18F-labeled Co0.16Fe2.84O4@NaYF4(Yb, Er)-BP-PEG had satisfactory imaging performance in MRI, PET/SPECT and up-conversion FI. Filice et al. presented a study concerning the design of tumor-targeting MRI/CT/optical imaging (OI) trimodal imaging probe Fe3O4@SiO2-Au-Alexa Fluor 647-cRGD NPs (Fig. 4(d)) [118]. Fe3O4 was coated with mesoporous silica in the form of the core–shell structure by the silanization/porogenic agent extraction strategy, and Au NPs were linked to the surface of Fe3O4 MNPs by the Pickering emulsion method. Then the fluorescent dye Alexa Fluor 647 was conjugated to the surface of Au NPs through the amide reaction between carboxyl groups of Au NPs and amino groups of Alexa Fluor 647. Finally cRGD peptides were covalently linked to the silica layer through the reaction of the aliphatic amine residue of cRGD peptides and isocyanate reactive groups. In the system, Au NPs endued composite NPs with the ability of CT imaging, cRGD peptides endowed them with targeting, and the addition of Alexa Fluor 647 made them acquire the property of OP. In vitro and in vivo experiments on fibrosarcoma-bearing model mouse indicated that the Fe3O4@SiO2-Au-Alexa Fluor 647-cRGD NPs possess a good imaging effect in MRI/CT/OI. Even though great developments have been made in multimodal imaging over the past years, there are still many challenges to be solved for the further application in clinical.
Fig.4 (a) The design principle of GdIO NPs. Reproduced with permission from Ref. [114]. (b) The design principle of MnO/Fe3O4 NPs. Reproduced with permission from Ref. [115]. (c) Structure and function of Fe3O4@PEG-PLGA MCs. Reproduced with permission from Ref. [116]. (d) Structure and function of Fe3O4@SiO2-Au-Alexa Fluor 647-cRGD NPs. Reproduced with permission from Ref. [118].

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Modification strategies based on Fe3O4 NPs for therapy

Fe3O4 MNPs with great biocompatibility and high stability are believed to be prospective drug release carriers in the drug delivery such as the anticancer drug delivery. The inherent superparamagnetic property of Fe3O4 MNPs endows them with the possibility of hyperthermia. Moreover, Fe3O4 MNPs are also used as a type of trackers in treatment under the guidance of MRI, which could obtain more useful information involved diseases and make the treatments visible. With the great developments in nanotechnology, diagnosis and treatments, the above illustrated strategies are no longer used lonely anymore, and the current research trend is to combine multiple strategies to construct a multifunctional platform of diagnosis and treatment simultaneously. In the following, modification strategies in these aspects based on Fe3O4 MNPs will be introduced.

Modification strategy for drug release carrier

The targeting drug delivery based on Fe3O4 MNPs has been research hotspot for many years since it can eliminate the side-effect of nonspecific drug release. DOX, a broad-spectrum anti-tumor medicine, was extensively used in research as a medicine model. Chen et al. designed a pH-responsive drug delivery system targeting tumors (Fig. 5(a)) [119]. They fabricated Fe3O4@SiO2 NPs at first, then amino groups were linked to the surface of NPs by a silane coupling agent 3-(aminopropyl) triethoxysilane (APTES), and finally Fe3O4@SiO2-Glu NPs were modified with carboxyl groups through the reaction of glutaric anhydride and amino groups. DOX with positive charge was loaded in Fe3O4@SiO2-Glu NPs with negative charge through electrostatic interactions. The in vitro study of drug loading and release showed that Fe3O4@SiO2-Glu NPs possess good drug loading ability and the system exhibit the property of pH-responsive drug release, which could release more drugs under acid environment. However, there is no experiment datum about in vivo studies presented in this research, and the drug release in vivo is unknown and needs to be further investigated.
Besides conventional chemotherapy drugs, Fe3O4 MNPs are utilized as delivery vehicles for gene. Ling et al. synthetized magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs)-engineered mesenchymal stem cells (MSCs) as carrier and tracker simultaneously for post-stroke recovery (Fig. 5(b)) [120]. MFIONs coated with polycaprolactone (PCL) were obtained by ligand-exchange, and then PEI was immobilized on it through electrostatic interactions. Plasmid DNA (pDNA) and extra PEI were linked to PEI layer by layer through electrostatic interactions between negative charge and positive charge, and finally the composite NPs were internalized into MSCs. In vivo investigations indicated that MFIONs-engineered MSCs exhibit a great performance in post-stroke recovery under the guidance of MRI.
In addition, adeno-associated virus (AAV) with safety and high gene transfection efficiency were extensively explored in gene delivery. The combination of both has attracted attention over the past years. Cheon et al. combined AAV and manganese-doped magnetism-engineered iron oxide (MnMEIO) NPs to make gene delivery visible (Fig. 5(c)) [121]. In the process of conjugation, the lysine residues of AAV were transformed into maleimide groups through the reaction with cross-linker, and then the MnMEIO NPs were linked to the surface of AAV through nucleophilic addition between maleimide groups of AAV and thiol groups of MnMEIO. In vitro experiments demonstrated that the composite have the potential of gene delivery under the guidance of MRI.
Fig.5 (a) Schematic illustration of Fe3O4@SiO2-Glu NPs synthesis. Reproduced with permission from Ref. [119]. (b) Schematic illustration of MFION-based engineering of MSCs for the recovery post-ischemic stroke. Reproduced with permission from Ref. [120]. (c) Schematic of the formation of AAV-MnMEIO hybrid NPs. Reproduced with permission from Ref. [121].

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Modification strategies for multifunctional platforms of diagnosis and treatment based on Fe3O4 MNPs

The inherent magnetic property endows Fe3O4 MNPs with the effect of magnetic hyperthermia for the application of tumors treatment. When Fe3O4 MNPs are under the alternative magnetic field, heat will be generated due to magnetic hysteresis loss, which provides possibility for ablation of tumors. Insausti et al. fabricated Fe3O4 MNPs coated with RGD peptides for potential targeting hyperthermia of tumors, which showed satisfactory specific power adsorption rate (SAR) in vitro, but the circumstances in vivo were still unknown [122]. Mei et al. designed injectable Fe3O4/magnetic calcium phosphate cement (MCPC) for magnetic hyperthermia towards tumors, in which Fe3O4 MNPs were distributed in CPC with PEG-600 as the liquid phase (Fig. 6(a)) [123]. In vitro and in vivo experiments indicated that MCPC have good ablation efficiency.
Despite that great efforts have been made in diagnosis and treatment of cancer, there are still huge obstacles to be overcome for modern medical technology. Lack of efficiency and targeting is the biggest problem in medical treatments of cancer. Therefore, a variety of modification strategies have been proposed for targeting treatments based on Fe3O4 MNPs. Au nanomaterials possess good properties of optical and photothermal, which enables them extensively applied in photoacoustic imaging (PI) and photothermal treatment for the ablation of tumors. Therefore, the introduction of Au NPs based on Fe3O4 MNPs could provide more possibilities in diagnosis and treatment for tumors. The combination of Fe3O4 MNPs and Au NPs is a commonly used strategy in the construction of multifunctional platform of diagnosis and treatment due to their great performance in MRI (Fe3O4 MNPs), CT (Au NPs), photoacoustic imaging (PAI, Au NPs) and photothermal therapy (Au NPs). Li et al. designed pH-responsive magnetoplasmonic nanoassembly (MPNA) assembled by Fe3O4 nanocluster and gold nanoshell, which was used in the photothermal therapy for tumors under the guidance of PAI/CT/MRI trimodal imaging (Figs. 6(b) and 6(c)) [124]. In the system of MPNA, the Fe3O4 nanocluster was coated with gelatin by the hydrothermal method, and gelatin with amino groups offered growth sites for gold seeds to form gold nanoshell. Both in vitro and in vivo assays showed that MPNA have the capacity of PAT/CT/MRI trimodal imaging and photothermal treatment. Chen et al. fabricated GSH-responsive intelligent magnetic Au nanowreaths (Au NWs) for tumor photothermal treatment under the guidance of PA/MR dual-modal imaging (Figs. 6(d) and 6(e)) [125]. Au NWs were firstly synthetized through Au nanorings seed-mediated growth method, and then the SiO2 shell was modified on Au NWs for further functionalization. Positive charged polymers containing disulfide bonds were linked in the SiO2 shell, and exceedingly small magnetic iron oxide NPs (ES-MIONs) with negative charge were conjugated to positive charged polymers through electrostatic interactions, forming a compact shell. Finally the amine-terminated PEG was linked to the surface of Au NWs through EDC/NHS-mediated amide reaction to enhance the stability of system.
Fig.6 (a) The fabrication and function of Fe3O4/MCPC. Reproduced with permission from Ref. [123]. (b) Schematic illustration of MPNA design concept. Reproduced with permission from Ref. [124]. (c) Schematic illustration of MPNA preparation. Reproduced with permission from Ref. [124]. (d) The fabrication of GSH-responsive magnetic Au NWs. Reproduced with permission from Ref. [125]. (e) The application mechanism of magnetic Au NWs. Reproduced with permission from Ref. [125].

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Conclusions and outlook

In summary, superparamagnetic property and biocompatibility of Fe3O4 MNPs enable them to be one of the most prospective nanomaterials in the application of biomedical field. With the rapid developments in nanotechnology and imaging technology, more and more composite materials based on Fe3O4 MNPs have been designed as multifunctional platform towards the diagnosis and treatment of diseases. However, the obstacles during the process of rapid developments should be emphasized, which deserve to solving for better applications prospects: 1) Large-scale preparation of Fe3O4 MNPs in laboratory is still to be researched and it is a huge problem in future industrial production as well. 2) Systematic and detailed mechanisms concerning preparation methods of Fe3O4 MNPs should be established and perfected, which could guide the research of superior contrast agent. 3) The construction of multifunctional platform based on Fe3O4 MNPs has gained great improvements in diagnosis and treatment. Several studies have been carried out at animal level and great performances have been achieved, which enhances the accuracy of diagnosis and provides feasible strategies for disease treatment. Nevertheless, there are still problems to be solved in future application in clinical, for instance, the treatment efficiency and the controllability of treatment process are still unknown. With the advancement of nanomaterials, more attention to modification strategies on nanomaterials towards diagnosis and treatment of disease should be paid in order to make considerable progress.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 11502158, 11632013 and 11802197). The support of the Shanxi Provincial Key Research and Development Project, China (Grant Nos. 201803D421060, 201903D421064 and 201803D421076), the Natural Science Foundation of Shanxi Province, China (201901D111078 and 201901D111077), and the Shanxi Scholarship Council of China (No. HGKY2019037) are also acknowledged with gratitude.
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