.4. Magnetic Hyperthermia
3.4. Magnetic Hyperthermia
Hyperthermia is a treatment with a long history. MIONs have the ability to convert the energy of an alternating magnetic field (AMF) into heat. Hyperthermia using this magnetothermal effect is called magnetic hyperthermia (MHT). As a means of in situ hyperthermia, magnetic hyperthermia can kill tumor tissues more accurately, and it is not limited by the depth of tissue penetration. It has developed many application scenarios in the field of tumor therapy
[87,88,89][57][58][59]. The improvement of the efficiency of tumor magnetic hyperthermia depends on the improvement of specific absorption rate (SAR), and SAR is directly proportional to the Ms of MIONs
[90][60]. It has been proven that the Ms of MIONs are strongly related to their size
[39][32]. SPIONs with a diameter of less than 20 nm have a SAR in the range of hundreds of W/g
[42][34]. In theory, the SAR of MIONs could be improved by increasing the size of MIONs. Paradoxically, larger–sized MIONs also exhibit ferromagnetic/ferrimagnetic properties. The existence of remanence disfavors colloidal stability of the MIONs, which in turn can decrease its SAR. In recent years, some MIONs with special magnetic domain structures have gradually shown their advantages. In one example, iron oxide nanorings of a specific size will exhibit vortex magnetic domains. The magnetic domains of this structure are closed loops connected end to end. While maintaining high ferrous hysteresis loss, the residual magnetization is kept at zero, achieving a SAR exceeding 2000 W/g while having excellent colloidal dispersion
[42][34].
3.5. Chemodynamic Therapy
In an acidic environment, Fe
2+ in MIONs can catalyze the Fenton reaction:
Fe
+ H
O
= Fe
+ HO
• + H
Due to its similar behavior to peroxidases such as horseradish peroxidase (HRP), the ability of MIONs to catalyze the Fenton reaction is also called peroxidase–like activity of a nanozyme. This reaction can generate a large amount of ROS in the tumor cells, break the redox balance of tumor cells, and then damage tumor cells
[93][61]. This phenomenon is known as chemodynamic therapy (CDT). However, since the pH in the tumor microenvironment does not meet the optimal conditions for the Fenton reaction
[94[62][63],
95], the direct application of MIONs in tumor CDT is limited. Hence, strategies to improve the Fenton reaction activity of MIONs are vital for their CDT efficacy.
4. Implementation of Magnetotheranostic Based on Magnetic Nanoplatforms
4.1. Magnetotheranostics Based on Magnetic Nanoplatforms Only
MIONs have their own therapeutic and diagnostic functions such as MRI, MPI, MHT, and CDT. Therefore, improvements on MIONs are beneficial for their magnetotheranostics performances. The Ms of MIONs received great attention from researchers at an earlier time
[34][64], because the improvement of Ms will simultaneously enhance the T2–weighted imaging performance of MIONs and the thermal conversion efficiency of MHT. Recent work in this area has become more diversified, and one direction is T1–T2 dual–modality imaging combined with treatment. Liu et al.
[90][60] synthesized wüstite Fe
0.6Mn
0.4O nanoflowers. Unlike the antiferromagnetic bulk wüstite, Fe
0.6Mn
0.4O nanoflowers exhibit ferromagnetism, which may be due to exchange coupling effect. The as–prepared nanoflowers exhibit excellent magnetic induction heating effects (SAR can reach 535 W/g), which could induce tumor regression in breast cancer through MHT. The longitudinal relaxation rate r1 and lateral relaxation rate r2 of Fe
0.6Mn
0.4O nanoflowers are as high as 4.9 and 61.2 mM
−1 [Fe]+[Mn]·s
−1, respectively. These nanoflowers showed both T1 and T2 enhancing properties in the mouse glioma model. Different from this static T1–T2 dual–modal contrast agent, another type is dynamic T1–T2 dual–modal contrast agents. They can present two states of T1 or T2 contrast, and certain events will prompt the transition between the two states. This is generally accomplished by disintegrating large particles into small particles (T2 to T1) or aggregation of small particles into large particles (T1 to T2). An example of the conversion of T2 enhancement to T1 enhancement is listed in
Section 3.2 [81][65]. In the work by Zhou et al.
[100][66], the ultrasmall SPIONs aggregated into clusters in the tumor in situ, resulting in the conversion of T1 enhancement to T2 enhancement. They used hyaluronic acid (HA) to encapsulate ultrasmall SPIONs, which showed T1 enhanced performance before penetrating into the tumor. After entering the tumor area, the surface–modified HA was degraded by the abundant hyaluronidase, which decreased the colloidal stability of ultrasmall SPIONs and caused aggregation of the nanoparticles into clusters, resulting in enhanced T2 imaging performance and weakened T1 imaging performance. Although the therapy performance of the designed ultrasmall SPIONs was not investigated in this work, its penetration–aggregation design still provided a strategy for future magnetotheranostics.
4.2. Integration of Magnetic Nanoplatforms with Phototheransotics
Similar to magnetotheranostics, comprehensive application of the optical properties of nanomaterials in therapeutic diagnostics are called phototheranostics, covering technologies such as photothermal therapy (PTT), photodynamic therapy (PDT), and photoacoustic imaging (PAI). Corresponding to the magnetic core in magnetotheranostics, the phototheranostics nanoplatform needs a photosensitizer as its core. Among the various photosensitizers, noble metal nanoparticles, especially Au nanoparticles
[103][67] can efficiently complete energy conversion through the localized surface plasmon resonance (LSPR) effect, and are often used to form a hybrid magnetoptical theranostics nanoplatform with MIONs for therapeutic diagnostics. Liu et al.
[104][68] assembled SiO
2–coated Au nanowreaths (AuNWs) with ultrasmall SPIONs through molecules containing polycystamine blocks (
Figure 53a). After sensing the GSH in the tumor cells, the disulfide bond of polycystamine was cleaved, causing the disassembly of ultrasmall SPIONs from the surface of AuNWs, and the MRI contrast performance of the ultrasmall SPIONs changed from T2 enhancement to T1 enhancement (
Figure 53b). The released AuNWs were used for photothermal therapy and photoacoustic imaging (
Figure 53c,d).
Figure 53. (
a) Schematic illustration of the synthesis of magnetic gold nanowreath. (
b) Corresponding T1–weighted images (top, disassembled; bottom, assembled) of magnetic AuNWs. Concentrations of Fe are 0.5, 0.25, 0.125, 0.0625, 0.03125, and 0.01563 mM (from left to right). (
c) Ultrasonic (US), photoacoustic imaging (PA), and merged images of tumor before injection (0 h) and at 2, 4, 24, and 48 h after intravenous injection of magnetic AuNWs upon irradiation by an 808 nm pulsed laser. (
d) Representative thermal images of U87MG tumor bearing mice after injection of magnetic AuNWs and PBS. The tumors were irradiated by an 808 nm CW laser at 0.75 W/cm
2. Reprint with permission from
[104][68]. Copyright 2018 American Chemical Society.
4.3. Integration of Magnetic Nanoplatforms with Fluorescence Imaging
Fluorescence imaging (FI) relies heavily on the penetration of light in tissue, which limits its application in the field of in vivo diagnosis and therapy. However, because fluorescent molecules can be designed to achieve highly specific responsiveness, fluorescence imaging is often used as an auxiliary imaging method for the magnetotheranostics nanoplatform to monitor its response behavior in the body. Zhou et al. [109][69] designed a nanoplatform capable of detecting tumor hypoxic environment, composed of ultrasmall SPIONs and assembly–responsive fluorescent dyes (NBD), and used nitroimidazole derivatives as hypoxia–sensitive detectors.
4.4. Integration of Magnetic Nanoplatforms with CT&PET/SPECT
Although iodine–based contrast agents for CT have been well developed, certain components of the magnetotheranostics nanoplatforms also have the ability to act as CT contrast agents. The use of CT to guide the diagnosis and therapy of the magnetic nanoplatforms has remarkable application prospects. A relatively common example is the gold–magnetic composites, wherein the high CT value of gold enables it to be traced by CT
[111][70]. Liu et al. developed an ultrasonication–triggered interfacial assembly approach (
Figure 64a,b) to synthesize magnetic Janus amphiphilic nanoparticles (MJANPs) for image–guided cancer MHT (
Figure 64c)
[16][71]. Au NPs–MIONs MJANPs made of Au NPs and MIONs could achieve MRI/CT dual–modality imaging and could be used to guide MHT (
Figure 64d). Similarly, if CuInS/ZnS NPs and MIONs were used to make CuInS/ZnS NPs–MIONs MJANPs, MRI/FI dual–modality imaging can be used to guide MHT (
Figure 64e).
Figure 64. (
a) Schematics of the ultrasonatically triggered interfacial assembly process. (
b) SIM image of the Pickering emulsion. Fluoresceinamine was used to label graphene oxide nanosheets (green), and rhodamine B isothiocyanate (RITC) was used to label Co cluster–embedded IONPs (red). (
c) Photographs of pre– and post–MHT treatment mice. (
d) In vivo T2–weighted MRI and CT images of tumor–bearing mice pre– and post–injection of Au NPs−MIONs MJANPs. Arrowheads indicate the tumor. (
e) In vivo T2–weighted MRI and fluorescence images of tumor–bearing nude mice pre– and postinjection of CuInS/ZnS−MIONs MJANPs. Arrowheads indicate the tumor. Reprint with permission from
[16][71]. Copyright 2019 American Chemical Society.
4.5. Magnetic Nanoplatforms Carrier Based Drug Delivery
The magnetotheranostic nanoplatform has become a representative delivery system due to its adjustable size, easy image tracking, and clear metabolic pathway. The delivery mechanism of MIONs can be divided into passive targeting and active targeting. Passive targeting mainly depends on the enhanced permeability and retention (EPR) effect of MIONs. Although the mechanism still needs to be further investigated [119[72][73],120], the EPR effect can indeed enhance the enrichment of nanoparticles (not just MIONs) in the tumor area [5]. In addition, the ligands of tumor characteristic markers can be employed to functionalize MIONs in order to give them the ability to actively target tumors [6], and for more efficient drug delivery. In a recent work, paclitaxel (PTX) and cisplatin (CDDP) have been loaded into the carboxymethyl dextran coating of the clinical iron supplement FMX, and actively target gliomas through HMC, which was an organic anion transport polypeptide targeting agent with near–infrared fluorescence. This system was used for MRI/FI visualized drug delivery of glioblastoma multiforme (GBM) [121][74]. Liu et al. [122][75] designed a delivery system with a Yolk–shell structure. The vesicles were composed of PEG–PPS–SS–PEG and loaded with ultrasmall SPIONs and DOX, which were encapsulated together by a polyacrylic acid coating. In tumor cells, vesicles were disintegrated under the influence of GSH. The complex of ultrasmall SPIONs and DOX was then separated, so that the drug release process could be monitored by an enhancement in T1 MRI. The complex microenvironment of the tumor tissue could limit the penetration of the nanoplatforms [123,124][76][77].