Dual-Functional Supernanoparticles with Microwave Dynamic

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Dual Functional Supernanoparticles with Microwavedynamic Therapy and Microwave Thermal Therapy Qiong Wu, Na Xia, Dan Long, Longfei Tan, Wei Rao, Jie Yu, Changhui Fu, Xiangling Ren, Hongbo Li, Li Gou, Ping Liang, Jun Ren, Laifeng Li, and Xianwei Meng Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.9b01735 • Publication Date (Web): 23 Jul 2019 Downloaded from pubs.acs.org on July 23, 2019

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Dual Functional Microwavedynamic Thermal Therapy

Supernanoparticles with Therapy and Microwave

Qiong Wu†, Na Xia‡, Dan Long†, Longfei Tan†, Wei Rao†, Jie Yu§, Changhui Fu†, Xiangling Ren†, Hongbo Li††, Li Gou‡, Ping Liang§,*, Jun Ren†, Laifeng Li†,*, and Xianwei Meng†,* †Laboratory

of Controllable Preparation and Application of Nanomaterials, CAS Key Laboratory

of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China ‡ College

§

of Materials Science and Engineering, Sichuan University, Chengdu 610065 China

Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing 100853

China ††

Beijing Key Laboratory of Construction-Tailorable Advanced Functional Materials and Green

Applications, School of Materials Science & Engineering, Beijing Institute of Technology, Beijing 10081 China

Corresponding Author Xianwei Meng ([email protected], Tel. +86 010-82543521, Fax +86 010-82543521) Laifeng Li ([email protected], Tel. +86 010-82543698, Fax +86 010-82543698) Ping Liang ([email protected], Tel. +86 010-66937981, Fax. +86 010-66939530)

ACS Paragon Plus Environment

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ABSTRACT

The cytotoxic reactive oxygen species (ROS) generated by photo-activated sensitizers are well explored in tumor therapy for nearly half century, which is known as photodynamic therapy (PDT). The poor light penetration depth severely hinders PDT as a primary or adjuvant therapy for clinical indication. While microwave (MW) is advantageous for deep penetration depth, but the MW energy is considerably lower than that required for activation of any species to induce ROS generation. Herein, we find that liquid metal (LM) supernanoparticles activated by MW irradiation can generate ROS, such as ·OH and ·O2. On this basis, we design dual functional supernanoparticles by loading LMs, and MW heating sensitizer ionic liquid (IL) into mesoporous ZrO2 nanoparticles, which can be activated by MW as sole energy source for dynamic and thermal therapy concomitantly. The microwavesensitiser opens the door to entirely novel dynamic treatment for tumor.

KEYWORDS Liquid metals, supernanoparticles, microwavedynamic therapy, microwave thermal therapy


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The photodynamic effect, which refers to the production of localized reactive oxygen species (ROS), such as singlet oxygen (1O2), superoxide (O2–), peroxide (O22–), and the hydroxyl radical (·OH), are produced by photosensitizers exposed to specific wavelengths of excitation light (UV, visible, or near infrared light).1-3 The high level of ROS usually causes oxidative damage to lipids, proteins, and DNA, resulting in the consequent of cellular dysfunction. By virtue of this effect, photodynamic therapy (PDT) can destroy biological targets, for example virus, bacteria, and pathological cell. One key matter has been discovered that tumor cells were usually killed preferentially by ROS due to their different redox states from normal cells.4 A variety of photosensitizers have been prepared for PDT of solid tumors.5-8 Compare with the conventional cancer treatment protocols, PDT possesses following main advantages.9-13 Firstly, the PDT process is in a spatiotemporally selective manner with localized therapeutic effect. Secondly, it is a minimally invasive process with minimal systemic toxicity. Finally, the side effects are significantly reduced. In spite of these advantages, there is an intrinsic problem at the core of the PDT protocol, hindering it from being recommended as a primary or adjuvant therapy for clinical indication.1416

The poor light penetration depth severely limits the effectiveness of PDT, which result in

inappropriate for not only the deep-seated tumors but also large superficial tumors.17,

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The

photodynamic effect decays exponentially with the tissue thickness. It has a therapeutic effect only to the tumor in the depth of a few millimeters even at an optimum wavelengths.19, 20


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Alternatively, microwave (MW), as an electromagnetic spectrum with the frequency lower than infrared light, has been extensively explored for tumor ablation in clinic, i.e. microwave thermal therapy (MWTT), due to its deep penetration depth in tissues, high heating efficiency, and negligible side effects.21-23 Compare with light, MW is a superior energy source to trigger the ROS generation for tumor therapy. Thus, we define microwavedynamic therapy (MDT) as a therapy which uses microwavesensitizers to generate cytotoxic ROS under MW irradiation. However, to the best of our knowledge, there is still no report on using microwavedynamic effect for tumor therapy to date, because MW energy is routinely considered insufficient for inducing free radical generation. The reason is that MW has the energy only of 10-3 eV, which is too low to cleave chemical bonds. Liquid metal (LM) refers in particular to the metal and alloy whose melting-point is near or below room temperature.24, 25 A typical LM, eutectic gallium-indium (EGaIn) alloy, has attracted increasing attentions due to its great potential for diverse areas, for instance, materials science and engineering, energy, catalysis and biomedicine.26-31 In our recent work, it is found that EGaIn supernanoparticles can generate ROS under MW irradiation, which can serve as a microwavesensitizer for revolutionizing the ROS generation techniques. In this study, we report LM supernanoparticles as microwavesensitizers with the capability of ROS generation under MW irradiation. The LMs of EGaIn alloy containing 75.5% Ga and 24.5% In by weight, and ionic liquid (IL) are uniformly loaded into mesoporous ZrO2


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nanoparticles to prepare IL-LM-ZrO2 supernanoparticles (IL-LM-ZrO2 SNPs). The synthesized IL-LM-ZrO2 SNPs have uniform size and good colloidal stability, showing highly effective combination of MDT and MWTT against cancer (Scheme 1). Microwavedynamic effect is achieved by the as-prepared supernanoparticles. LMs play crucial role in ROS generation and inducing apoptosis of tumor cells under MW irradiation. Due to the favorable MW sensitivity of IL, MW heating effect as adjuvant efficacy is concurrent with the ROS generation. These results show that MDT and MWTT can be implemented in a single supernanoparticle. Furthermore, with the PEG modification, the ideal biocompatibility of PEG-IL-LM-ZrO2 supernanoparticles (PEG-IL-LM-ZrO2 SNPs) is confirmed by toxicity study. Under the combined treatment of MDT and MWTT, the tumor inhibition rate for mice is as high as 92.2 ± 6.8% in the subcutaneous tumor models and even 40% of the tumor-bearing mice were completely cured in the orthotopic HCC mouse models. We hope that this microwavedynamic effect could improved the efficacy of dynamic treatment to deep-seated tumor in clinical studies. As shown in Figure 1, the morphology and size of supernanoparticles were characterized by SEM and TEM. The as-prepared LM-ZrO2 SNPs were substantially spherical solid nanoparticles with a diameter of 210 ± 60 nm (Figure 1a, 1b). The EDS results of LM-ZrO2 SNPs indicated that the elements of O, Zr, Ga, and In were evenly distributed across the nanospheres (Figure 1c, 1d). Uniform size distribution and good dispersibility of the as-prepared LM-ZrO2 SNPs have therefore been confirmed. Figure 1e presented the FT-IR pattern of PEG-IL-LM-ZrO2 SNPs. The


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strong and wide absorption band between 3550 and 3200 cm–1 was correspond to the O-H stretching vibration. The asymmetric stretching vibration of -CH3 in IL was identified at 2960 and 1380 cm–1. The peaks at 2925, 2850, and 1462 cm–1 could be ascribed to asymmetric stretching, symmetrical stretching and shear vibrations of -CH2-, respectively. The absorption at 1050 cm–1 was attributed to the stretching vibration of C-O characteristic absorption. The results showed that IL, LM and PEG were successfully loaded into or grafted onto the ZrO2, indicating the successful synthesis of PEG-IL-LM-ZrO2 SNPs. The zeta potential of as-synthesized LM, ZrO2, LM-ZrO2 SNPs, IL-LM-ZrO2 SNPs and PEG-IL-LM-ZrO2 SNPs was shown in Figure S1b, which further provides a basis for the synthesis and stability of supernanoparticles. The stability of PEG-IL-LM-ZrO2 SNPs in phosphate-buffered saline solutions (PBS) and normal saline was investigated and the TEM images was shown in Figure S2. The Dynamic Light Scattering (DLS) was also adopt to evaluate the stability of PEG-IL-LM-ZrO2 SNPs (Figure S3), the result shows that PEG-IL-LM-ZrO2 SNPs have certain stability under acidic and neutral physiological conditions. The above results demonstrate the successful fabrication of stable PEG-IL-LM-ZrO2 SNPs. High intracellular level of ROS can induce apoptosis and autophagy of the tumor cells, which offers an opportunity for efficient and effective anti-cancer treatment.32,

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Minimum energy

required for activating an agent to generate ROS is at the level of hundreds of m·eV. However, MW energy is generally considered to be too low to cleave chemical bonds and induce free


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radical generation. Recently, the realization of ROS generation triggered by MW irradiation has been proved in an aqueous solution with the presence of specific nanomaterials.34, 35 Quan et al. revealed that MW can activate the ROS generation in the presence of activated carbon and air supply.36 In this work, IL-LM-ZrO2 SNPs were developed for generating ROS using MW as the sole energy source for the first time. DCFH-DA is a frequently used fluorescence probe to confirm the generation of ROS and to detect the concentration of ROS. Herein, IL-LM-ZrO2 SNPs were dispersed in PBS and DCFH-DA, whose fluorescence intensity keeps a linear relation with ROS concentration. As shown in Figure 2a, 2b, the content of ROS produced by IL-LM-ZrO2 SNPs under MW irradiation was about 2.1 times as high as that of NIR irradiation, about 3.7 times as high as that of IL-LM-ZrO2 SNPs alone without MW irradiation, 4.7 times as high as PBS under MW irradiation, and 5.9 times high than that of PBS. Obviously, the ROS generation of IL-LMZrO2 SNPs is related to MW irradiation, IL-LM-ZrO2 SNPs can produce remarkably larger amount of ROS under MW irradiation. The LM-ZrO2 SNPs could also generate ROS under MW irradiation, and content of ROS was three times as much as that without MW irradiation. But the amount of ROS was lower than that of IL-LM-ZrO2 SNPs irradiated by MW, indicating that heat had certain influence on the content of ROS, but the influence was far less significant than that brought by MW irradiation. This is also consistent with the results of ROS produced by IL-LMZrO2 SNPs inconstant hot water at 45 °C. The above results indicate that IL-LM-ZrO2 SNPs can


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produce ROS under MW irradiation. As the signal in the ESR spectrum indicated (Figure 2c), IL-LM-ZrO2 SNPs did not display obvious response before MW irradiation. While triggered by the MW irradiation, significant characteristic peaks were observed and a large amount of ·OH was generated. Similarly, IL-LM-ZrO2 SNPs also generated superoxide anion free radical (·O2) under MW irradiation in solution (Figure 2d). ESR spectrum manifested that IL-LM-ZrO2 SNPs mainly produced ·OH and ·O2 under MW irradiation in solution. Next, we performed experiments to investigate ROS generation by PEG-IL-LM-ZrO2 SNPs in vitro. HepG2 cells were incubated with 100 μg mL–1 of PEG-IL-LM-ZrO2 SNPs for 12 h, and irradiated with 0.9 W MW for 5 min. Those cells were labeled by DCFH-DA and observed under fluorescence microscopy. It was found that the fluorescence of the MW-treated cells after incubation with PEG-IL-LM-ZrO2 SNPs was the brightest (Figure 2e, Figure S4). And the fluorescence of cells with or without MW irradiation could not be observed. Therefore, we suggest that a large amount of ROS was produced by PEG-IL-LM-ZrO2 SNPs in vitro under MW irradiation. The results are consistent with the measurements by ESR. In particular, our group has found that the MW irradiation can improve the peroxidase-like catalytic activity of the Mn-ZrMOF NCs, which led to a large production of ∙OH by catalyzing H2O2 decomposition.37 Unlike the materials that catalyze H2O2 to enhance ROS generation, the as-made IL-LM-ZrO2 SNPs are capable to generate ROS directly under MW irradiation, which is independent of the


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existence of substances such as H2O2. The test results and the analysis provide a compelling basis for the in vivo tumor therapy of MDT. The ROS generation mechanism is still under debate. One of the rationalities is that a portion of MW energy is concentrated into hot spots by the localized resonant coupling to point defects or weak surface bonds, which causes the generation of free radical.36 It is reasonable to deduce that ·OH generated by IL-LM-ZrO2 SNPs under MW irradiation also follows the similar mechanism. Temperatures of solution and IL-LM-ZrO2 SNPs rise at the different rates under MW irradiation because of the internal heating by MW energy, which induces IL-LM-ZrO2 SNPs to attain a higher local surface temperature than solution. The interfacial selective heating by MW energy creates “hot spots” in the mesopores of supernanoparticles.38 In the hot spots, the IL-LM-ZrO2 SNPs use the energy of MW irradiation to drive the electron transfer from Ga to the water and oxygen adsorbed in the mesopores of SNPs. Thus ·OH and·O2 are produced, involving the following equation (1), (2) and (3):

(1) (2) (3) To verify our hypothesis, IL-LM-ZrO2 SNPs with 5, 10, 15, and 20 mg were dispersed in 2 mL PBS under MW irradiation at 0.9 W for 10 min respectively, and Ga cation concentration


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was measured by IPC-MS (Figure 2f). The concentration of Ga cation increases with the concentration of IL-LM-ZrO2 SNPs increases. When the concentration of IL-LM-ZrO2 SNPs was 10 mg mL-1, the concentration of Ga cation was the highest. The concentration of Ga cation was the lowest at the concentration of IL-LM-ZrO2 SNPs was 2.5 mg mL-1. The analysis evidently proves that the concentration of Ga cation increases as the concentration of IL-LMZrO2 SNPs increases. In combination with the fact that the concentration of IL-LM-ZrO2 SNPs was related to the ROS generation in the fluorescence experiment, the correlation between the concentration of Ga cation and the ROS generation was verified from the side. Next, 5 mg mL-1 IL-LM-ZrO2 SNPs was dispersed in PBS and irradiated by MW at 0.9 W for 0, 10, 20, and 30 min. The results of IPC-MS displayed that the concentration of Ga cation increased with the time of MW irradiation increased (Figure S5a). Combined with the fluorescence experiment, the ROS generation was related to MW irradiation, which also indirectly indicated that the Ga cation was related to the ROS generation. The above results confirm that IL-LM-ZrO2 SNPs release Ga cations during ROS generating process. While under the same conditions, the concentration of Ga cation was increased very slowly with time when placed in constant hot water or under MW irradiation at nitrogen atmosphere, which was less than 30% of that under the MW irradiation (Figure S5b, S5c). These further illustrated the importance of oxygen and MW irradiation in the ROS generation of IL-LM-ZrO2 SNPs. This is consistent with our hypothesis. Similar with PDT, MDT is based on the microwavedynamic effect (a MW sensitization reaction with biological effects involved in aerobic molecules). The process can be generalized as: (1) MW irradiation


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stimulates LM nanocomposites, which drive the electron rransfer from Ga to the surrounding oxygen and water for generating ROS; (2) The ROS will lead to cytotoxicity, cell damage and even death by occurring oxidative reactions with adjacent biological macromolecules. Due to the MW sensitization effect of IL and the confinement effect of ions in an enclosed space, ZrO2 nanoparticles which loaded IL would generate a thermal effect under MW irradiation. To evaluate the MW heating effect of IL-LM-ZrO2 SNPs in vitro, IL-LM-ZrO2 SNPs were dispersed in normal saline. At the same MW power and irradiation time (0.9 W, 450 MHz, 5 min), the MW heating effect of IL-LM-ZrO2 SNPs with different concentrations (0, 5, 10, and 20 mg mL–1) was measured. The temperature change of IL-LM-ZrO2 SNPs at different MW irradiation duration was observed by using a FLIR thermal imager and the FLIR images were exhibited in Figure 3a. It is demonstrated that the MW heating effect of the IL-LM-ZrO2 SNPs have a concentration-dependent manner. The higher concentration of IL-LM-ZrO2 SNPs shows the stronger effect of temperature rising under MW irradiation. The temperature variations of ILLM-ZrO2 SNPs with concentration of 5, 10, and 20 mg mL–1 were 6.8, 10.4, and 13.8 °C higher than the control group, respectively (Figure 3b, 3c). Therefore, it is conclusive that IL-LM-ZrO2 SNPs possess the enhanced MW heating effects, which can be used as a MW sensitizer for tumor MWTT in vivo. Despite that LMs have been reported with low toxicity,39,

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the IL-LM-ZrO2 SNPs were

modified by PEG for achieving better biocompatibility. MTT assay was used to detect the


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toxicity of PEG-IL-LM-ZrO2 SNPs at the cell level. Different concentrations of PEG-IL-LMZrO2 SNPs (0, 12.5, 25, 50, 75, 100, 200, 400, 600, and 800 μg mL–1) were incubated with HepG2 cells for 24 h. Then the cell viability was evaluated. As shown in Figure S6a, although concentration of PEG-IL-LM-ZrO2 SNPs was up to 800 μg mL–1, only limited effect on the cell viability could be found and the cell viability was still higher than 80%. The results demonstrate the low toxicity and favorable biocompatibility of PEG-IL-LM-ZrO2 SNPs, which can be further used for tumor therapy in vitro and in vivo. Before the application of the PEG-IL-LM-ZrO2 SNPs in animals, the experiments at the cellular level was performed to investigate the MDT and MWTT effect of PEG-IL-LM-ZrO2 SNPs. Different materials were added into the cell for the same incubation time, and then MW irradiation with different time was performed. As shown in Figure S6b, the cell viability of control group with MW irradiation time of 0, 3, 5, and 8 min was 100 ± 5%, 95.1 ± 10%, 94 ± 9.2%, and 105 ± 8.4%, which was attributed to the fact that MW irradiation alone cannot produce enough heat to kill cells. Moreover, when the temperature was not high enough, the viability of cells increased instead. While the cell viability of PEG-IL-LM-ZrO2 SNPs group was 90.7 ± 9.9%, 70.6 ± 6.9%, 58.6 ± 3.5%, and 42.1 ± 5.3%, respectively. The results indicated that the cell viability can be reduced with the prolongation of the MW irradiation time. The viability of cells in PEG-IL-ZrO2 SNPs group (MWTT group) was lower than that of the control group under the same MW irradiation time, which shows that the MW heating effect of PEG-IL-ZrO2


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SNPs has lethal effect on cells. The thermal distribution and MW heating curves of different groups also proved this point (Figure S6c and S6d). Meanwhile, the viability of cells in PEGLM-ZrO2 SNPs group (MDT group) was lower than that of the control group, because the ROS generation from LM under MW irradiation also had lethal effect on cells. These results correspond to the in vitro results of the materials, i.e. under MW irradiation, the rapid rise of solution temperature in the presence of IL-ZrO2 SNPs leads to cancer cell death, and ROS generation in the presence of LM-ZrO2 SNPs also leads to the death of cancer cells. PEG-ILLM-ZrO2 SNPs composited IL and LM have significant inactivation effect on cells, the cell viability of PEG-IL-LM-ZrO2 SNPs group was less than 43% after MW irradiation for 8 min at 0.9 W. Furthermore, the live/dead cells staining was also conducted to assess the MDT and MWTT effect of PEG-IL-LM-ZrO2 SNPs under MW irradiation for 8 min at 0.9 W. The results was shown in Figure S7, which was consistent with the trends of cellular MW experiment, indicating the PEG-IL-LM-ZrO2 SNPs could effectively kill tumor cells under the combined effect of MDT and MWTT by using MW as the sole energy. The PEG-IL-LM-ZrO2 SNPs were proved to be biocompatible by cytotoxicity experiment and achieved combined therapy of MDT and MWTT in cellular level, which further providing hope for further biological applications in animals. Since PEG-IL-LM-ZrO2 SNPs have the combined effect of MDT and MWTTT in vitro, we wondered whether the same effect is achieved in vivo. Toxicity test was carried out first to


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evaluate the safety of the PEG-IL-LM-ZrO2 SNPs in vivo. The PEG-IL-LM-ZrO2 SNPs were injected into mice via the tail vein with different concentrations (0, 50, 100, and 150 mg kg-1) to observe the mice toxicity response. PEG-IL-LM-ZrO2 SNPs exhibited little toxicity even at high concentrations. The body weight and viability of mice injected with PEG-IL-LM-ZrO2 SNPs at the concentration up to 150 mg kg-1 were not affected within 21 days (Figure S8). The weight of the other three groups was not significantly abnormal compared to the control group, indicating the good biocompatibility of the PEG-IL-LM-ZrO2 SNPs in vivo. The blood routine and blood biochemical index of the mice approached those of the control group, and the difference was within the normal range (Figure S9). Moreover, the paraffin sections of the organs showed no obvious tissue abnormalities, indicating that the PEG-IL-LM-ZrO2 SNPs had no negative effect on organs and could be used for tumor therapy in vivo (Figure S10). All the above results have proved that the low toxicity and good biocompatibility of the PEG-IL-LM-ZrO2 SNPs. Based on the ideal results of toxicity test in vivo (Figure S8, S9, S10), the PEG-IL-LM-ZrO2 SNPs were investigated for the further application in vivo. Since the CT imaging function of ZrO2, PEG-IL-LM-ZrO2 SNPs were expected to be used to visualize the tumor treatment process. Accordingly, the CT imaging effect of the as-prepared materials was evaluated in vitro and in vivo. The CT imaging signals of IL-LM-ZrO2 SNPs with different concentrations (2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 mg mL-1) were detected in vitro (Figure S11a). The linear regression function was y = 0.18764 + 8.0052x. It could be observed that IL-LM-ZrO2 SNPs had CT


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imaging capability and the CT signal increased as the concentration increased. Due to the excellent biocompatibility of PEG-IL-LM-ZrO2 SNPs, the in vivo CT imaging capability of PEG-IL-LM-ZrO2 SNPs was tested. As shown in the Figure S11b, the CT value of the tumor was changed with the tail vein injection time and reached the highest level after 6 h of injection, indicating that the accumulation of PEG-IL-LM-ZrO2 SNPs in tumor site reached maximum at 6 h. The above results proved that the synthesized PEG-IL-LM-ZrO2 SNPs can be used for CT imaging in vivo to monitor the therapeutic effects visually in real time. Inspired by the large amount of ROS generation and outstanding MW heating effect under MW irradiation, the PEG-IL-LM-ZrO2 SNPs are encouraged for the further application in animals to inspect the MDT and MTT combined therapeutic tumor effect in vivo. The Balb/c mice bearing H22 tumor cells and the C57 mice bearing HepG 1-6 tumor cells were used as experimental subcutaneous tumor model and in situ tumor model. The PEG-IL-LM-ZrO2 SNPs reached at the peak concentration in tumor tissues at 6 h after tail vein injection by the CT imaging and ICP-MS detection (Figure S12), which provided an optimal time for tumor therapy. Tumor bearing mice were separated into six groups: PEG-IL-LM-ZrO2 SNPs + MW (MDT + MWTT), PEG-LM-ZrO2 + MW (MDT), PEG-IL-ZrO2 + MW (MWTT), MW, PEG-IL-LMZrO2 SNPs, and control group. The tumor sites of mice (PEG-IL-LM-ZrO2 SNPs + MW, PEGLM-ZrO2 + MW, PEG-IL-ZrO2 + MW and MW group) were irradiated after 6 h via tail vein injection. The heating effect was observed by the FLIR thermal imager during MW treatment of


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mice (Figure 4a and Figure 5c). For the subcutaneous tumor models, the MW irradiation was performed directly on the tumor site with a WZY-1 MW therapeutic instrument (450 MHz, continuous wave). The MW irradiation condition was 0.9 W and 5 min. The temperature in the MW group and the PEG-LM-ZrO2 + MW group could only increases to 54.5 °C and 54.3 °C, while the temperature in the PEG-IL-ZrO2 + MW group and the PEG-IL-LM-ZrO2 + MW group increased to a high level of 59.7 °C and 58.4 °C, respectively (Figure 4b). For the orthotopic HCC mouse models, MW therapy was more complex and relatively more meaningful. Similar to the establishment of the in situ tumor model, orthotopic HCC was treated by minimally invasive MW therapy. The KY-2000 microwave ablation instrument (2450 MHz, continuous wave) was used for minimally invasive treatment. The power of MW treatment was 2 W and the time was 1 min. The temperature in the MW group and the PEG-LM-ZrO2 + MW group rose to 84.5 °C and 85.3 °C, while the temperature in the PEG-IL-ZrO2 + MW group and the PEG-IL-LM-ZrO2 + MW group increased to 112.1 °C and 108.7 °C, respectively (Figure 5a and Figure S14a). The results revealed that PEG-IL-LM-ZrO2 SNPs still have favourable MW heating effect in vivo for tumor MWTT. As illustrated in Figure S13a and Figure S14b, the PEG-IL-LM-ZrO2 SNPs displayed negligible impact on the tumor growth. For the subcutaneous tumor models, the tumor recurrence of the MW group was observed at day 4 after MW irradiation. And the tumor volume curve indicated that the PEG-LM-ZrO2 + MW group had higher inhibition efficacy (70.0%)


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toward tumor growth than the MW group (56.4%) (Figure 4c), which was primarily attributed to the ROS generation (MDT). Similarly, the inhibition efficacy of the PEG-IL-ZrO2 + MW group (67.0%) was higher than that of the MW group, which basically arose from higher temperature (MWTT). Obviously, PEG-IL-LM-ZrO2 + MW group combined with MDT and MWTT displayed ideal tumor inhibition effect (92.2%), which showed distinct difference compared to PEG-IL-ZrO2 + MW group and PEG-LM-ZrO2 + MW group. Furthermore, PEG-IL-LM-ZrO2 + MW treatment group also showed higher survival rate (100%) on day 17 (Figure S13b), while the mice in both PEG-IL-LM-ZrO2 group and control group were dead on day 12. The tumor photos were demonstrated in Figure 4d, which were consistent with the above experimental results. Then the treated mice were sacrificed on day 17, no visible abnormality was found in each tissue section, indicating the good biocompatibility of the materials (Figure S15). Comparing the sections of the tumor, it can be found that the tumor cells in the PEG-IL-LMZrO2 + MW group were severely damaged, which illustrates the PEG-IL-LM-ZrO2 SNPs could combine MDT and MWTT for effective tumor treatment under MW irradiation. While for the orthotopic HCC mouse models, PEG-IL-LM-ZrO2 + MW treatment group (MDT + MWTT) also exhibited better tumor treatment effect. Except for the PEG-IL-LM-ZrO2 + MW group, mice in other groups gradually died with the increase of days from the second day after treatment (Figure 5b). It was found that the main cause of death was tumor metastasis, mainly liver metastasis and lung metastasis, which was shown in Figure S16. After 14 days of


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treatment, the PEG-IL-LM-ZrO2 + MW group (100%) showed a higher survival rate than the control group (20%), the MW group (40%), the PEG-IL-LM-ZrO2 SNPs group (40%), the PEGIL-ZrO2 +MW group (60%), and the PEG-LM-ZrO2 +MW group (60%). The tumor photos were shown in Figure 5d and Figure S17, manifesting a relatively high inhibition efficacy of PEG-ILLM-ZrO2 + MW group, and even 40% of the tumor-bearing mice were completely cured, which was consistent with the results of the subcutaneous tumor model experiments. The above results proved that the PEG-IL-LM-ZrO2 SNPs was effective in the tumor treatment (MDT + MWTT) under sole MW irradiation. Although MWTT (PEG-IL-ZrO2 +MW) has certain therapeutic effect, it is not significant enough. Only when combined with MDT (PEG-IL-LM-ZrO2 SNPs +MW, MDT + MWTT) can the ideal therapeutic effect be achieved. In conclusion, we have successfully designed and synthesized the PEG-IL-LM-ZrO2 SNPs. The combined MWTT and MDT have been achieved simultaneously for the first time by using MW as sole energy source. The IL-LM-ZrO2 SNPs can produce a large number of ·OH and ·O2 only triggered by MW irradiation. IL-LM-ZrO2 SNPs also show favorable MW heating performance. It is revealed that nanoscale liquid metals (LMs) can significantly augment ROS under MW irradiation, which may be attributed to the ‘electron transfer in hot spots’ mechanism. The PEG-IL-LM-ZrO2 SNPs combined with MDT and MWTT have significant therapeutic effects on tumor in vitro and in vivo. Furthermore, PEG-IL-LM-ZrO2 SNPs had CT imaging capability and can be used for CT imaging in vivo to monitor the therapeutic results visually in


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real time. The SNPs current strategy can effectively realize the combined treatment of MWTT and MDT without additive of H2O2, which paves a new route for the development of tumor treatment in the future.


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Figures and Tables

Scheme 1. Schematic Diagram of PEG-IL-LM-ZrO2 SNPs combined MDT with MWTT for tumors treatment. PEG-IL-LM-ZrO2 SNPs were constructed by loading liquid metals (generation source of ROS) and ionic liquid (MW heating enhancer) into ZrO2 (contrast media) nanoparticles with the PEG modification (biocompatibility raiser). Under MW irradiation, PEG-IL-LM-ZrO2 SNPs can generate ROS to induce cell apoptosis and autophagy (MDT), and rapid heating to inactivate the tumor cells (MWTT).


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Figure 1. Characterization of PEG-IL-LM-ZrO2 SNPs. a) SEM images and particle size statistics of LM-ZrO2 SNPs. b) TEM images of LM-ZrO2 SNPs. The scale bar of picture in the upper right corner is 100 nm. c) EDS traces of LM-ZrO2 SNPs. d) TEM element mapping of LM-ZrO2 SNPs. The scale bar is 100 nm. e) FT-IR spectra of PEG, IL, LM, ZrO2 and PEG-IL-LM-ZrO2 SNPs.


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Figure 2. Behavior of PEG-IL-LM-ZrO2 SNPs generating ROS under MW irradiation in vitro. a) and b) Fluorescence intensity of DCF in PBS under different treatments. c) and d) were EPR detection of IL-LMZrO2 SNPs under MW irradiation to produce ·OH and ·O2, respectively. e) Fluorescence picture of the MW-


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treated cells after incubation with PEG-IL-LM-ZrO2 SNPs. f) Ga ion concentration in solution after MW irradiation with different concentrations of IL-LM-ZrO2 SNPs by IPC-MS.

Figure 3. MW heating effect of IL-LM-ZrO2 SNPs in vitro. a) The thermal distribution on the surface of ILLM-ZrO2 SNPs solution with different concentrations (0, 5, 10 and 20 mg mL-1) at different time points (0, 60, 120, 180, 240 and 300 s) under MW irradiation was demonstrated by FLIR images. b) In vitro MW heating curves (0.9 W, 450 MHz, 5 min) of IL-LM-ZrO2 SNPs solution with different concentrations (0, 5, 10, and 20 mg mL-1). Asterisks indicate significantly differences (***P < 0.001). c) Temperature changes histogram of IL-LM-ZrO2 SNPs solution with different concentrations (0, 5, 10, and 20 mg mL-1) under the same heating condition.


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Figure 4. Results of MW therapy in vivo of subcutaneous tumor models. a) The thermal distribution of body surface in mice treated with MW irradiation. b) The temperature curve of tumor surface in MW therapy. c) Tumor volume changes of the treated mice in 17 days. Asterisks indicate significantly differences (**P < 0.01). d) Tumor images after treatment for 17 days.


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Figure 5. Results of MW therapy in vivo of orthotopic HCC mouse models. a) The temperature curve of tumor surface in MW therapy. b) Survival rate of the treated mice in each group. c) The thermal distribution of body surface in mice treated with MW irradiation. d) Images of the in situ tumor on liver after treatment for 14 days, the areas in the white circle are tumors.


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AUTHOR INFORMATION Notes: The authors declare no competing financial interest. Corresponding Author E-mail: [email protected]

ACKNOWLEDGMENT The authors acknowledge financial support from the National Natural Science Foundation of China (Project No. 91859201, 61671435 and 81630053). ASSOCIATED CONTENT

Supporting Information Available: Detailed experimental sections and Figures S1-S17 are available in the supporting information. The supporting information file is available free of charge.


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For Table of Contents Only


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Dual-Functional Supernanoparticles with Microwave Dynamic

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