Introduction

Cancer diagnostics is a method that combines diagnosis and therapeutics of cancer diseases, which involves nanomaterial preparation, bioprobe targeting, molecular imaging, and minimally invasive treatment [1]. It is increasingly clear that ultrasensitive and quantitative measurement of theranostic biomarkers and efficient identification, visualization of cancer at its earliest stage with high resolution and in a quantitative manner, molecular targeting, and localized treatment will all be critical for precision treatment of cancer [2].

The traditional treatment methods for cancer include surgery, radiation therapy, and chemotherapy. The primary treatment method for cancer is surgery, but it is generally suitable only in early stages of cancer [3]. Most patients are not suitable for surgical treatment in the late stages, such as breast cancer [4] and pancreatic cancer [5]. Radiation therapy mainly uses high-energy radiation, such as X-rays and gamma-rays, to create energy directly to kill cancer cells or inhibit their growth [6]. The main limitations of traditional radiation therapy lie in the radiation that also produces radioactive doses in normal tissues, leading to persistent patient harm, and may have long-term side effects [7]. Proton therapy, a more accurate and effective radiation therapy, uses high-energy proton beams to directly kill cancer cells [8]. This method reduces the side effects of radiation therapy significantly by killing only the cancer cells with little harm to healthy cells [9]. However, the price is high because it requires high-quality treatment facilities [10]. Chemotherapy works by using cytotoxic drugs to inhibit cell proliferation [11]. Most chemotherapy drugs must be close to their maximum tolerated dose to function, which means chemotherapy is toxic to the whole body [12]. This leads to various side effects and gradually decreases the patient’s immune function [13]. Magnetic fluid hyperthermia (MFH), as a new therapeutic technology, uses high-frequency excitation to generate electromagnetic waves produced by the magnetic field, based on relaxation loss or hysteresis loss to heat the tumors to about 43 °C, to kill cancer cells through high temperature. This technology has the advantages of non-invasive, radiation-free, no disease-forming, and low treatment costs compared to the above treatment methods. It has little toxicity to the healthy tissues [14].

Hyperthermia has been widely studied in recent years. This process does not directly kill the cells but leads to the initiation of a series of pro-apoptotic and apoptotic signaling cascades [15], which finally induces cell death. Heat can slow or stop tumor growth by damaging or killing cancer cells by damaging proteins, structures, and blood vessels within the tumor [14]. The heat can induce the increase in some proteins in the lesion site, such as γ-H2AX, which can cause DNA damage or apoptosis, making cancer cells more vulnerable to radiation therapy and chemotherapy in subsequent treatments [16]. Meanwhile, the heat also modifies the blood circulation to deliver oxygen to the tumor tissue, making the tumor cells more sensitive to radiation therapy and chemotherapy [17]. Cellular responses to heat stress can also promote the expression of heat shock proteins, which can induce an organism’s immunity to tumor cells [18]. Therefore, hyperthermia is increasingly used in combination with radiotherapy [19] and chemotherapy [20] to treat solid tumors. In the conducted clinical studies by Deger [21] et al., the combination of heat therapy and radiotherapy was applied to prostate cancer. After treatment, prostate-specific antigen (PSA) was significantly lowered. Brero et al. [22] effectively demonstrated the radiosensitization of hyperthermia to pancreatic cancer cells by combining proton therapy and MFH, and the proton therapy they used was synergistically cooperative with MFH. Singh et al. [23] compared the individual effects of heat therapy and chemotherapy with the combination therapy in prostate cancer and found that the combination therapy had significant efficiency in suppressing tumor growth.

Researchers have proposed many different hyperthermia methods. A comparison of their classifications and applications is summarized in Table 1.

Table 1 A comparison of different hyperthermia methods
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A treatment method needs to be guided by the appropriate imaging mode to achieve the purpose of accurate treatment. Magnetic particle imaging (MPI) is a novel quantitative imaging technique with its advantages of high sensitivity and resolution, which uses the nonlinear magnetization behavior of magnetic nanoparticles (MNPs) [41]. In this review, we discuss MPI-guided MFH (MPI-MFH) and its application in cancer.

In the following, we briefly introduced MPI and MFH in this section, including their basic principles, features, and devices. Then, we showed some typical applications of image-guided MFH in cancer therapy, illustrating the potential of MPI-guided MFH in cancer precision therapy. The MNPs, targeted modified MNPs, and their application in MPI and MFH are then presented. Lastly, we discuss the current challenges of MPI-MFH. In addition, we look ahead to the future of MPI-MFH and other applications in precise treatment of cancer.

Introduction of MPI and MFH

MPI

MPI has been extensively used in studies including hemodynamic evaluation [42], cardiac imaging [43], cell tracing [44, 45], cancer imaging [46], perfusion imaging [47], and prediction of the MFH effect [40]. The MPI device simply consists of the selection coils or permanent magnets that generate a field-free region (FFR), the drive coils that excite the nonlinear magnetization behavior of MNPs, and the receiver coils that induce changes of the magnetization of MNPs (Fig. 1) [48]. The magnetization dynamics of MNPs are very complex and can be simplified to the Langevin theory description under the assumption that MNPs are in a constant thermal equilibrium [49].

Fig. 1
figure 1

Illustration of the principle of MPI. a M-H curve under Langevin’s model. b Exciting magnetic field. c Time-dependent magnetization. d Fourier-transformed signal

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MPI signals also hold promise for temperature imaging. Relaxation processes are temperature dependent, so it is expected to estimate the sample temperature from the magnetization response signals of MNP samples [50].

Since the first MPI scanner for small animals was proposed in 2005 [41], the development of MPI devices has made great progress, as reported in [51]. We reviewed the development of MPI devices, as shown in Fig. 2. Currently, two commercial devices have been developed, one from Bruker and the other from Magnetic Insight. In 2014, traveling wave magnetic particle imaging (TWMPI) was proposed to generate a dynamic gradient field system that can cover a larger field of view, providing a new direction for large bore device development [52]. For the development of a large bore size of MPI, Graeser et al. proposed a human-sized MPI system suitable for the detection of human heads [53]. Over the past 2 years, MPI devices have made progress in increasing the bore size and individual functions [54].

Fig. 2
figure 2

The main devices of MPI. a The device from Bruker. b The device from Magnetic Insight. c TWMPI scanner. d Human-sized interventional MPI scanner and human-sized wearable brain scanner. e Human-sized MPI for brain applications. a From http://www.bruker.com; b from http://www.magneticinsight.com; c from [52], d from [54]; e from [53]

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As a new imaging method, MPI has many advantages:

  • MPI has good penetration and signal-to-noise ratio;

  • The MPI signal has no radiation and does not harm the human body [51];

  • The MPI signal will not undergo radioactive decay over time [55];

  • MPI has real-time imaging capabilities to provide immediate feedback [56, 57];

  • MPI is expected to realize the detection of multiple parameters, such as temperature and viscosity [58, 59].

MFH

Under the induction of an AMF, MNPs generate heat through relaxation loss or hysteresis loss [60]. According to Rosensweig’s theory [61], the average volume energy dissipation rate of magnetic particles per period under the action of alternating magnetic fields is defined as follows:

$$P=f\Delta U=-f{\upmu }_{0}\oint MdH$$

where f and H are the frequency and amplitude of the applied magnetic field, respectively, M is the particle magnetic moment, and \({\mu }_{0}\) is the vacuum permeability.

The heating capacity of MNPs is defined as the specific absorption rate (SAR), expressed as the heating power (P) produced per unit mass of MNPs(\({m}_{MNP}\)):

$$SAR=\frac{P}{{m}_{MNP}}=C\left(\frac{\Delta T}{\Delta t}\right)\left(\frac{1}{m}\right)$$

where C is the sample-specific heat capacity, ΔT/Δt is the increase in temperature with time, and m is the mass concentration of MNPs [62].

From this formula, it can be seen that the heating efficiency of magnetic particles is related to the frequency of external AMF and the area enclosed by M and H curves. Theoretically, SAR will increase with the increase of magnetic field strength and frequency, as does the experimental result [63]. In addition, the properties of MNPs, including viscosity, radius, anisotropy, and collective behavior caused by surface modification, will also affect the thermal conversion efficiency [64, 65]. Table 2 lists several commercial MNP-related parameters for reference.

Table 2 Basic parameters of several commercial MNPs
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In MFH, coils are generally used as converters between electrical power and magnetic field energy (Fig. 3). Coils can be divided into solenoid shape [66], flat shape [67], Helmholtz’s coil [68], and birdcage coil according to the shape. The first clinical MFH system, MFH® 300F, was reported in 2004 [69].

Fig. 3
figure 3

MFH coils. a Traditional MFH coils. b Special thermotherapy coil in MPI. c Traditional MFH coil physical picture. a From [62]; b from [80]; c from [67]

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Although MFH has many advantages and application prospects, there are still many challenges in its clinical application:

  1. (1)

    Real-time image guidance

A good imaging guidance can identify the location of lesions and the thermal dose of MFH, allowing doctors to predict the effect of hyperthermia [70]. It is expected to eliminate the unnecessary risk of damaging healthy tissue and provide feedback and a basis for doctors to adjust the treatment process [71]. The aforementioned CT and MRI-guided hyperthermia cannot achieve real-time guidance, and they usually rely on pre-treatment images [72].

  1. (2)

    Off-target accumulation of MNPs

After systemic administration, liver and kidneys compete with tumors for MNPs, resulting in accumulation of particles in non-targeted organs [73]. At 300 kHz, all regions of the body with MNPs are heated indiscriminately [74]. Avoiding heating off-target areas can reduce collateral thermal damage to these organs, which is important in achieving precision hyperthermia [75].

  1. (3)

    Non-invasive temperature monitoring

Temperature monitoring and adjustment are important during hyperthermia [76]. It has been reported that tumor areas with hyperthermia temperatures between 41 and 45 °C are more susceptible to further damage [77]. So real-time thermal feedback can avoid temperatures that are too low or too high [78]. The existing temperature measurement technology is limited to placing a temperature sensor inside the heated tumor, which requires the sensor to be non-metallic to prevent interference with the AMF or heating during the heating process [79].

In summary, both MPI and MFH utilize the corresponding properties of MNPs for imaging and therapeutic. Now, we will compare the two methods briefly (Table 3).

Table 3 Comparison of MPI and MFH
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Image-guided MFH

CT or MRI-Guided MFH

MFH alone cannot implement precision therapy without the help of medical image guidance. The current clinical guidance methods of MFH are mainly CT and MRI [83]. In the MFH, the density of MNP-enriched tissue regions is significantly higher than those of other normal tissue regions, which can be detected by CT [84, 85]. In clinical research, Johnnsen et al. [86] used CT imaging to develop therapeutic plans to achieve the treatment of prostate cancer. This guiding method allows for higher injection precision and thus better treatment results. MRI measures relaxation time and proton density. Clinically, contrast agents enhance the relaxation rates of water molecules around the body to obtain highly contrasting MRI images [87]. The MRI-guided MFH technology has its intrinsic advantages in providing accurate guidance and expected non-invasive temperature detection [88]. Wang et al. [89] developed a multifunctional MNP to achieve MRI-guided MFH in a breast cancer mouse model, which significantly reduced the tumor volume and the number of M2-TAMs promoted in the tumor. Corresponding materials (Fe3O4@polyvinyl pyrrolidone nanotubes) for MRI-guided MFH have also been developed [90].

Compared with CT, MRI and MPI have no radiation. MRI currently uses MNPs as negative contrast agents for lymph node and liver imaging. In these areas, tissues contain a large number of phagocytes, which absorb MNPs to make the image darker [91]. This process may obscure parts of the anatomy. Other sources of endogenous contrast, such as the existence of iron deposits, may interfere with the MNP signal [92]. In addition, compared to MRI, MPI directly measures the concentration of MNPs, which are quantifiable and highly sensitive [93].

In conclusion, MPI can locate tumors more accurately, which is a significant advantage for image-guided MFH. The amount of heat deposited in the organism is directly related to the amount of MNPs, and the quantifiable nature of MPI also allows MPI to indirectly quantify the thermal dose [75].

MPI-Guided MFH

Researchers have paid attention to the combination potential of MPI and MFH. MPI and MFH work separately by utilizing the responses of MNPs to an applied AMF. Both MPI and precisely localized MFH use gradient magnetic fields. In Langevin’s theory, the selection field is divided into a magnetic FFR and saturation region. Particles in the saturation region will constrain the deflection of the dipole, thus completing the confinement of the heating region, which is expected to achieve precise positioning of hyperthermia. Based on this, MFH is expected to eliminate interference from non-targeted organs during the heating process.

In 2016, Dhavalikar et al. theoretically demonstrated the possibility of combining MPI with a high-frequency-driven AMF [94]. Bauer et al. first demonstrated that a sample in a region of interest can be selectively heated with the help of a gradient field of MPI [95]. In 2017, the first combined MPI-MFH system was reported by Hensley et al. [57], which can realize selectively heat magnetic nanoparticle samples at a distance of 3 mm in vitro (Fig. 4). An MPI-MFH treatment platform was first demonstrated by Tay et al. in 2018 [75]. The experimenters performed selective heating and histological evaluations on a double-tumor mouse model to verify the localization of the lesion and tumor treatment capabilities of the platform (Fig. 5). According to Fig. 5, it can be clearly found that any region can be positioned and heated during the heat shock process; if there is no gradient during the heat shock process, then regions with particles in the body will be heated uniformly. In 2020, Wells et al. [96] first proposed an MPI-MFH platform based on a 3D Lissajous scanning trajectory with frequencies of around 25 kHz. In recent years, great progress has been made in research focusing on MPI-MFH. In order to have a better combination of MPI and MFH, researchers still face many problems which we will discuss in the following parts.

Fig. 4
figure 4

In vitro selective heating achieved by MPI-MFH. Figure 4 is from [57]

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Fig. 5
figure 5

In vivo selective heating of mice achieved by MPI-MFH. Figure 5 is from [75]

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Targeting MPI and MFH Fusion in the Treatment of Tumors

MNPs are the only signal source for MPI visualization. The performance of MNPs is also one of the key factors to determine the quality of MPI images. In order to obtain good quality images, MNPs should have the properties of a strong response signal and slow attenuation of the signal harmonic spectrum. When MNPs are applied for MFH, they need to have a good thermal effect and temperature sensitivity. MNPs usually have magnetic core coated with a biocompatible polymer coating such as carboxyl dextran or polyethylene glycol (PEG). These outer coats have a number of functional groups that can bind to functional molecules, such as drugs or ligands. This can improve the targeting of MNPs and increase their accumulation or penetration depth in the lesion area [97, 98].

Targeted Modified MNPs

Although studies on MNPs for imaging and hyperthermia have been demonstrated, a major obstacle limiting their clinical application is the insufficient concentration of particles reaching the target area after intravenous injection, resulting in an inability to accurately image and hyperthermia [99]. It has been confirmed by a large number of researches that the radius, anisotropy, structure, doping, and surface modification of particles will have a significant influence on the imaging [100] and high-temperature results [64]. There are two main ways to obtain functionalized MNPs. One way is taking advantage of the special physiological and anatomical characteristics of tumor tissues to allow for natural differences in drug distribution in the body [101]. The other is to increase uptake of magnetic particles by cells by changing the shape or aggregation state of magnetic particles or to enhance passive targeting through EPR effects, thus accumulating in tumor tissues [102]. Surface modification of targeted molecules can confer targeting properties to MNPs to significantly affect their diagnostic and therapeutic properties [103]. Current targeting molecules include antibodies [104], peptides [105], small organic molecules [106], and other biological targeting molecules [107]. Current studies have confirmed that many tumors have specific targets, such as human epidermal growth factor receptor 2 (HER-2) and luteinizing hormone-releasing hormone (LHRH) for breast cancer [108, 109], folate receptor for ovarian and cervical cancer [110], and vascular endothelial growth factor (VEGF) for glioma [111].

In MPI, the concentration of particles can be increased by targeted modification of particles, resulting in higher MPI signal intensity and better image resolution at the lesion. Tomitaka et al. combined lactoferrin with MNPs, and the resulting particles were targeted to gliomas [112]. Zhang et al. took advantage of the properties of the plectin-1 peptide targeted to pancreatic ductal adenocarcinoma and combined plectin-1 peptide and IRDye800CW with MNPs to generate pancreatic ductal adenocarcinoma-targeted probes. Uniform distribution and in vivo residence time were all improved [113]. Wang et al. selected the breast cancer-targeted peptide CREKA to couple with MNPs, and a stronger MPI signal than the untargeted tissue could be obtained by using this particle [114].

In MFH, the targeted modification of MNPs has a similar function with MPI, which can improve the efficiency of hyperthermia. We did a table (Table 4) summarizing the use of active tumor targeting in hyperthermia.

Table 4 Application of active targeting modified particles in hyperthermia
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Applications of MPI-MFH Hyperthermia in the Treatment of Tumors

The application of MPI-MFH in tumors is relatively few because MPI itself is a new technology, and the combination of the two devices needs further research. Among them, the study of Du et al. [126] has opened a new horizon for us. Du et al. developed CREKA-modified MNPs using the theoretical basis that the pentapeptide CREKA can selectively bind to proteins overexpressed in certain breast cancer cells and stromal cells (Fig. 6). Such particles can target tumors and improve the uniformity of particle delivery within the tumor to obtain good MRI and MPI signals. The targeted modified particles can be uniformly distributed in the tumor and reach to ~ 43 °C quickly. In a mouse breast tumor model, the mice injected with the particles nearly disappeared after hyperthermia and did not return. This particle has great potential for precise imaging and efficient MFH.

Fig. 6
figure 6

CREKA-modified MNPs for bi-modal MRI/MPI-guided magnetothermal therapy. Figure 6 is from [126]

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Song et al. [127] started from MNPs and selected carbon-coated FeCo (FeCo@C-PEG) nanoparticles as the MPI tracer. When applied in a mouse model of breast cancer, it was found that FeCo@C-PEG was enriched in tumors by 4.76 times that of VivoTrax, and tumor cells also ingested significantly more FeCo@C-PEG than VivoTrax. In in vivo experiments, the temperature of tumors directly injected with FeCo@C-PEG can rise to 47 °C within 10 min, and the volume of tumors after 14 days was significantly smaller than that of the control group. This particle can improve image quality and conversion efficiency which can make MPI-guided MFH more effective.

Tay et al. [75] demonstrated a theranostic platform combining MPI and MFH. Using the self-developed MNPs, they first realized directional heating in the phantom. Then, MPI was used to guide MFH in glioma mouse models, and the gradient of MPI was used to achieve precise hyperthermia.

Challenges

Development of Hardware Equipment

After more than 20 years of development, MPI has come a long way in both theory and equipment. But at present, MPI hardware equipment still faces some problems, such as the need to develop a human-sized device [80], the balance between imaging performance and power consumption [128], and the need to combine with other imaging modalities to provide sufficient information [129].

Real-time simultaneous imaging and hyperthermia is possible, because MNPs can generate MPI signals during heating. Usually, the operating frequencies of the two are significantly different. The operating frequency of MPI is roughly 10 kHz ~ 100 kHz [130], and the operating frequency of MFH is roughly 100 kHz ~ 300 kHz [50]. There are two options for combining the two. First, the fixed operating frequency is between 20 and 40 kHz, which theoretically can achieve simultaneous imaging and hyperthermia. However, we need to give MNPs multi-dimensional excitation to achieve the same thermal effect as in high frequency [96]. We believe a better way is to work at a low frequency and high frequency in time-sharing, but the complexity of the equipment could be significantly increased.

MNP Optimization

The response of MNPs to AMF can achieve both imaging and MFH. Translating this potential into clinical applications requires the development of MNPs. Therefore, it is urgent to prepare MNPs that have excellent imaging capabilities, thermal efficiency, temperature monitoring capabilities, and biocompatibility.

SAR and PNS Limits

The AMF can affect the human body through peripheral nerve stimulation (PNS) or induction eddy current heating in vivo, and these magnetic field changes have potential risks for the human body [53]. For frequencies below 100 kHz, it should be particularly concerned by electrical stimulation risks; while for higher frequencies, the primary considerations should be thermal heating [131]. During the MPI-guided MFH process, we must consider the two limits of PNS and SAR. For the application of the thoracic body, the limit of PNS is about 3 mT μ0−1 [132], and the limit of PNS is linearly related to the magnetic directional cross-section of the body, so it is safe to apply 6 mT μ0−1 [53] to the head and 10 mTμ0−1 to the whole body. For the SAR, the spatial average SAR exposed to tissues in public and controlled environments is 2 W/kg and 10 W/kg [133]. Currently, no more specific data on MPI-guided MFH PNS and SAR advice values is available. The limiting of PNS is necessary to prevent excessive muscle and nerve stimulation, and the limiting of SAR is crucial to prevent system temperature rise [130]. However, the importance of these two limits for MPI-guided MFH is undeniable.

Prospect of Application

A significant advantage of MPI is that the signal can be quantified. On the combined MPI and MFH platform, this advantage can be translated into the evaluation of therapeutic effects. In Ohki et al.’s study, regions of interest were mapped using MPI, which was used to quantitatively compare the effects of tumor hyperthermia alone and hyperthermia combined with radiotherapy [134]. Numerous studies have shown that the combination of radiotherapy or chemotherapy with hyperthermia is more helpful in the treatment of cancer [83]. Other studies have shown that hyperthermia can be combined with gene therapy or immunotherapy [135]. Pan et al. demonstrated that combined MFH and immunotherapy have great potential in primary and metastatic tumors [136]. MPI-MFH is expected to enable quantitative assessment of the efficacy of hyperthermia alone and in combination therapy. In addition, MPI-MFH also has great potential for controlled release and targeted delivery of drugs and can be used in other non-cancer diseases.

Conclusion

MPI-MFH is expected to realize the combination of diagnosis and treatment, allowing MPI images to accurately locate the lesion and predict the magnetic thermal effect at the same time, which helps doctors to plan and adjust the magnetic thermal plan. Currently, MPI-MFH has achieved millimeter-precise guided heating which has been demonstrated in mice. However, MPI-MFH still has a long way to go. The development of MPI-MFH devices, the design of MNPs that consider both MPI and MFH performance, and the successful clinical applications in humans are all urgent problems that need to be solved. It is encouraging that more and more scholars are noticing the potential of MPI-MFH and are proposing creative solutions to these problems. We believe that in the future, MPI-MFH, combined with other therapies and technologies, will provide better options to treat cancer and even non-cancer diseases.