Tumor microenvironment-responsive MnSiO<sub>3</sub>-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy

Tumor microenvironment-responsive MnSiO₃-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy

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Fan Jiang^a^,^b, Chunzheng Yang^a^,^b, Binbin Ding^a^,^b, Shuang Liang^a^,^b, Yajie Zhao^a^,^b, Ziyong Cheng^a^,^b, Min Liu^c, Bengang Xing^d, Ping'an Ma^a^,^b^,^*, Jun Lin^a^,^b^,^*

Chinese Chemical Letters | 2022, 33(6) : 2959 - 2964

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Chinese Chemical Letters | 2022, 33(6): 2959-2964

• Communication •

Tumor microenvironment-responsive MnSiO₃-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy

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Fan Jiang^a^,^b, Chunzheng Yang^a^,^b, Binbin Ding^a^,^b, Shuang Liang^a^,^b, Yajie Zhao^a^,^b, Ziyong Cheng^a^,^b, Min Liu^c, Bengang Xing^d, Ping'an Ma^a^,^b^,^*, Jun Lin^a^,^b^,^*

Affiliations

^aState Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China

^bSchool of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China

^cDepartment of Periodontology, Stomatological Hospital, Jilin University, Changchun 130021, China

^dSchool of Physical & Mathematical Sciences, Nanyang Technological University, Singapore 639798, Singapore

Published: 2022-06-15 doi: 10.1016/j.cclet.2021.12.096

Outline

Abstract

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Compared with traditional photodynamic therapy (PDT), ultrasound (US) triggered sonodynamic therapy (SDT) has a wide application prospect in tumor therapy because of its deeper penetration depth. Herein, a novel MnSiO₃-Pt (MP) nanocomposite composed of MnSiO₃ nanosphere and noble metallic Pt was successfully constructed. After modification with bovine serum albumin (BSA) and chlorine e6 (Ce6), the multifunctional nanoplatform MnSiO₃-Pt@BSA-Ce6 (MPBC) realized the magnetic resonance imaging (MRI)-guided synergetic SDT/chemodynamic therapy (CDT). In this nanoplatform, sonosensitizer Ce6 can generate singlet oxygen (¹O₂) to kill cancer cells under US irradiation. Meanwhile, the loaded Pt has the ability to catalyze the decomposition of overexpressed hydrogen peroxide (H₂O₂) in tumor microenvironment (TME) to produce oxygen (O₂), which can conquer tumor hypoxia and promote the SDT-induced ¹O₂ production. In addition, MP can degrade in mildly acidic and reductive TME, causing the release of Mn²⁺. The released Mn²⁺ not only can be used for MRI, but also can generate hydroxyl radical (^∙OH) for CDT by Fenton-like reaction. The multifunctional nanoplatform MPBC has high biological safety and good anticancer effect, which displays the great latent capacity in biological application.

Key words

Sonodynamic therapy / Chemodynamic therapy / Artificial enzyme / Oxygen generation / Synergetic therapy

Cite this Article

Fan Jiang, Chunzheng Yang, Binbin Ding, Shuang Liang, Yajie Zhao, Ziyong Cheng, Min Liu, Bengang Xing, Ping'an Ma, Jun Lin. Tumor microenvironment-responsive MnSiO₃-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy[J]. Chinese Chemical Letters, 2022 , 33 (6) : 2959 -2964 . DOI: 10.1016/j.cclet.2021.12.096

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In recent years, external minimally invasive or noninvasive treatment methods have attracted much attention worldwide due to its spatial/temporal controllability, tumor specificity, and low toxicity [1-3]. Among them, photodynamic therapy (PDT), a treatment method that can induce cell death by stimulating photosensitizers to produce cytotoxic reactive oxygen species (ROS) under laser irradiation, has been widely explored [4-7]. However, the low penetrating depth of light hinders the therapeutic effect. Lately, ultrasound (US) has become the research hotspot because of its non-invasiveness, low cost, and high depth of tissue penetration. It has been reported that US can activate sonosensitizers to produce toxic ROS for tumor treatment, which is termed as sonodynamic therapy (SDT) [8-11]. In the process of SDT, oxygen (O₂) is beneficial to singlet oxygen (¹O₂) generation. But the severe hypoxia in the solid tumor microenvironment (TME) and the O₂ consumption during SDT restrict the therapeutic efficacy of SDT [12-14]. Therefore, increasing the content of oxygen in TME can effectively enhance the treatment effect of SDT. Aroused by this, many efforts have been made. Some O₂ storage materials, such as metal−organic frameworks [15-17], hemoglobin [18-21], perfluorocarbon [22-24], have been reported to increase the content of O₂ in TME. In addition, some nanozymes can also be widely utilized to increase O₂ content by in situ O₂ generation, mainly including Pt [25-27], MnO₂ [28-30], CeO₂ [31-33], and so on.

Chemodynamic therapy (CDT) is considered as an attractive way for cancer treatment by generating excessive hydroxyl radicals (^∙OH) for cancer cell apoptosis [34]. Some metal (iron [35-37], copper [38-41], manganese [42-44]) ions have been reported to catalyze hydrogen peroxide (H₂O₂) in TME to produce ^∙OH. Generally, the body has the natural metal ions (i.e., Fe ion) to produce ^∙OH by catalyzing the decomposition of H₂O₂ via the Fenton reaction. However, the efficiency of Fenton reaction is decreased due to the low content of Fe ions in cancer cells. Therefore, adding additional CDT reagent is of great significance to promote the formation of toxic ^∙OH. Unfortunately, CDT alone is difficult to obtain ideal therapeutic effect. To solve this problem, CDT is usually combined with other treatment methods. Lin et al. integrated CaO₂ nanodots and Fe³⁺ co-incorporated MOF to realize the combined Radiotherapy (RT)/CDT [37]. Liang et al. synthesized platinum (IV) prodrug-conjugated albumin‐based CuO/MnO_x nanoagent for combined chemotherapy/CDT [45]. Jia et al. developed an intelligent nanoplatform by immobilizing UCNPs on FeMn-LDH nanosheets for synergistic photothermal/photodynamic/CDT [46]. Therefore, it is promising to combine CDT with other treatment modalities for cancer therapy.

Inspired by above finding, herein, we first synthesized platinum (Pt)-modified MnSiO₃ nanocomposite. After modification with bovine serum albumin (BSA) and chlorine e6 (Ce6), the multifunctional nanoplatform MnSiO₃-Pt@BSA-Ce6 (MPBC) was successfully constructed for catalysis-enhanced SDT/CDT. Under US irradiation, Ce6 can convert O₂ into ¹O₂ for SDT to kill tumor cells. MnSiO₃ is sensitive to the weak acidity and high GSH content in the TME, causing the rapid release of Mn²⁺. The released Mn²⁺ not only could generate ^∙OH for CDT by catalyzing the endogenic H₂O₂, but also displayed an excellent T₁-weighted MRI performance. Besides, the metal Pt can catalyze the H₂O₂ in TME into O₂ to overcome tumor hypoxia and accelerate the SDT-induced ROS generation. In vitro and in vivo experiments proved that the nanoplatform had a remarkable therapeutic effect, which had enormous potential in cancer treatment.

In this work, we first synthesized uniform MnSiO₃ nanosphere. Then polyvinylpyrrolidone (PVP) decorated Pt nanoparticles (NPs) were absorbed on the surface of amino-modified MnSiO₃. The formed MP was decorated with BSA to improve the biocompatibility of NPs. After conjugating sonosensitizer Ce6 with MPB through the formation of amide bonds, the multifunctional nanoplatform was successfully constructed. Scheme 1 displayed the schematic summary of the detailed synthesis procedures and therapeutic mechanism of the nanoplatform. The MnSiO₃ nanospheres with an average diameter of 120 nm were prepared based on well-dispersed mesoporous silica nanoparticles by a hydrothermal method (Figs. 1a and b). Meanwhile, the PVP coated-Pt NPs with an average diameter of 4 nm were also successfully prepared (Fig. 1c). After MnSiO₃ was modificated with 3-aminopropyltriethoxysilane (APTES), the Pt NPs were decorated onto the surface of MnSiO₃ to form MP NPs by electrostatic adsorption. Transmission electron microscope (TEM) images (Fig. 1d) and X-ray diffraction (XRD) (Fig. 1f) pattern proved the successful construction of MP NPs. The nitrogen adsorption-desorption isotherm curves were displayed in Fig. 1h. Compared with MnSiO₃ (198.9 m²/g, black), the specific surface areas of MP (142.2 m²/g, red) obviously decreased, and the corresponding pore size also decreased. These results were attributed to the blockage of MnSiO₃ channel by Pt NPs. The Energy dispersive X-ray (EDX) mapping (Fig. 1e) and X-ray photo-electron spectroscopy (XPS) (Fig. S1 in Supporting information) confirmed the elemental compositions of MP NPs. In Fig. 1g, the high resolution XPS demonstrated that the Mn 2p_3/2 was composed of Mn²⁺ (641 eV), Mn³⁺ (642 eV), and Mn⁴⁺ (644 eV). BSA was adsorbed on the surface of MP NPs to improve the biocompatibility. Fourier transform infrared (FTIR) spectra demonstrated the successful loading of BSA (Fig. S2 in Supporting information). The absorption bands of MPB around 1655 and 1532 cm⁻¹ belonged to the amide I and amide II bands of BSA, respectively [47]. Thermogravimetric analysis (TGA) showed that the content of BSA loaded on MP was 17% (Fig. 2a). Sonosensitizer molecule Ce6 was linked on the surface of MPB though the amidation reaction between the amino group of BSA and carboxyl group of Ce6. The absorption peaks of Ce6 (404 and 660 nm) were all observed in the absorption spectrum of MPBC (Fig. 2b), demonstrating the successful loading of Ce6. The loading content of Ce6 was estimated to be 20% by UV−vis absorption spectra (Fig. S3 in Supporting information). The change of zeta potential on the surface of NPs displayed the every procedure of preparation process (Fig. 2c).

Iron-triggered Fenton chemistry has been widely used to induce tumor cells apoptosis though catalyzing endogenous H₂O₂ into ^∙OH. It is reported that the Mn²⁺ also can achieve CDT by generating ^∙OH through Fenton-like reaction [48, 49]. Here, we chose methylene blue (MB), a dye that can be degraded by ^∙OH, as an indicator to verify the ^∙OH generation. As shown in Fig. 2d, bicarbonate (HCO₃⁻) plays an important role in Mn²⁺-mediated Fenton-like reaction. Meanwhile, the ^∙OH generation is proportional to the concentration of H₂O₂ (Fig. 2e). With the increase of H₂O₂ concentration, the absorbance of MB decreased, confirming more ^∙OH generation.

Metal Pt has been reported as an artificial enzyme to generate O₂ by decomposing H₂O₂. Compared with natural enzymes, artificial enzymes possess following advantages: low cost, good stability, and ease preparation [50-52]. To investigate the catalase-like activity of MP, we employed a dissolved oxygen instrument to monitor the O₂ generation. As displayed in Fig. 2f, in the absence of MP, the O₂ concentration of the solution remained stable, demonstrating that the influence of the environment on the measurement results was negligible. When adding MP into the solution, O₂ was released rapidly within a short time, confirming the excellent catalytic ability of MP. Sufficient O₂ supply is conducive to the ¹O₂ generation. Here, singlet oxygen sensor green (SOSG), a dye that is highly specific to ¹O₂, was employed to explore the ¹O₂ generation ability of MPBC under US irradiation. As shown in Fig. 2g, the fluorescent signals of the MPBC group dramatically increased with the increase of US time, proving the SDT effect of MPBC. Besides, the generation of ¹O₂ is dependent on the power density of US irradiation (Fig. 2h). More importantly, the presence of H₂O₂ could greatly promote the ¹O₂ yield induced by US irradiation (Fig. 2i), which was because the MP could generate sufficient O₂ to enhance ¹O₂ production by catalyzing H₂O₂ under US irradiation.

To explore the therapeutic mechanism in vitro, we first evaluated the intracellular uptake of MPBC by flow cytometry (FCM). As depicted in Fig. 3a, NPs could be effectively internalized by cells as the coincubation time extended. Then, the biocompatibility of MPB in vitro was evaluated by cell counting kit-8 (CCK-8) assay. As shown in Fig. S4 (Supporting information), cells treated with MPB NPs displayed 85% survival rate on fibroblast cell lines (L929) cells when the concentration of MPB was 100 ppm, indicating the excellent biocompatibility of MPB NPs. Meanwhile, the killing effect of MP NPs on human cervix cancer cells (HeLa) cells was higher than that of normal cells, which was due to the more ^∙OH production via Mn²⁺-mediated Fenton-like reaction in cancer cells [53, 54]. In addition, bis(triphenylphosphine) ruthenium(II) dicarbonyl chloride ([Ru(dpp)₃]Cl₂) was used to evaluate the catalytic O₂ production capacity of MPB. As shown in Fig. S5 (Supporting information), the fluorescence intensity of MPB group is weaker than that of control group, suggesting more O₂ generation. FCM experiment also proved the result (Fig. 3b). Then we employed 2′, 7′-dichlorofluorescein diacetate (DCFH-DA), a dye that could be rapidly oxidized to bright green fluorescence 2, 7-dichlorofluorescein (DCF) by ROS, to studied the intracellular ROS production. As shown in Fig. 3d, the MPB group showed a weak green fluorescence compared with the control and US groups, which was attributed to the Mn²⁺-mediated Fenton-like reaction. Especially, the cells treated with MPBC combined with US irradiation displayed the strongest green fluorescence, which was because Pt catalyzed the decomposition of endogenous H₂O₂ into O₂ for promoting US-triggered ROS generation. Next, we explored the synergistic effect of MPBC. The cells were divided into six groups, such as the control group, US group, MPB group, MPB + US group, MPBC group and MPBC + US group. From Fig. 3c, compared with the control group, US group showed negligible cell damage. It is noteworthy that the cell viability of MPBC + US group was lower than that of the other groups, demonstrating the good anticancer effect of combined catalysis-enhanced SDT and CDT. Furthermore, we also carried out FCM experiments to study the anticancer effect of combined CDT/SDT. In Fig. 3e, the MPBC + US group displayed the highest percentage of cell apoptosis compared with other groups. The live/dead staining assay also confirmed the extensive cell death of MPBC + US group (Fig. S6 in Supporting information). The above results demonstrate that the MPBC-based combined CDT/SDT have a good ability to kill cancer cells and possess a great potential in cancer therapy.

Motivated by the good anti-cancer effect of MPBC in vitro, the therapeutic efficacy of MPBC in vivo was then explored. We randomly divided the U14 tumor-bearing Balb/c mice into six groups: (1) control; (2) US; (3) MPB; (4) MPB + US; (5) MPBC; (6) MPBC + US. The mice were injected with NPs intratumorally. After 3 h post-injection of NPs (15 mg/kg), mice were exposed to US irradiation (1.0 MHz, 1.5 W/cm², 50% duty cycle, 5 min). The tumor sizes and weights of mice were measured every two days after treatment. As displayed in Fig. 4a and Fig. S7 (Supporting information), tumors in control group and US group grew rapidly. Mice treated with MPB, MPB + US and MPBC showed moderate tumor inhibition. Notably, the MPBC + US group displayed effective tumor growth inhibition owing to the combined effect of catalysis-enhanced SDT and CDT. The effective therapeutic effect of combined therapy was observed by the TUNEL staining of tumors (Fig. 4e). Meanwhile, we also performed hypoxia inducible factor HIF-1α (HIF-1α) and vascular endothelial growth factor (VEGF) staining assay to observe whether the MPB had the ability to relieve hypoxia within tumor. As displayed in Figs. 4f and g, the control group showed strong HIF-1α and VEGF fluorescence, suggesting the hypoxia state of the tumor. MPB group showed weak fluorescence, which was because Pt NPs could catalyze the decomposition of H₂O₂ to produce O₂. Moreover, after different treatments, no obvious damage in the main organ tissues of mice was observed by H & E staining and the body weights of mice had no loss (Fig. S8 in Supporting information and Fig. 4b). Besides, we also performed the serum biochemistry and blood hematological analysis of MPBC + US-treated mice and healthy mice. In Fig. S9 (Supporting information), all the measured parameters between MPBC + US group and healthy group remained in the normal range. Meanwhile, the hemolysis rate of nanoparticle was less than 5% at different concentrations (Fig. S10 in Supporting information). These results demonstrate that the MPBC-based synergistic therapy has good therapeutic effect and a high therapeutic biosafety, which offer an expansive prospect for cancer treatment.

It is reported that Mn-O bonds can be destroyed at faintly acidic and reducing environments [55, 56]. Enlightened by this, the release behavior of Mn from MPB at different conditions was explored (Fig. 4d). Compared with pH 7.4, the release rate in acidic (pH 6.5) or reduced (pH 7.4, GSH 10 mmol/L) solution increased significantly, which was due to the fracture of Mn-O bond and the subsequent destruction of MnSiO₃ structure. The released Mn²⁺ can be employed for T₁-weighted MRI. Therefore, we explored the potential application of MPB nanocomposites for MRI. As shown in Figs. 4c and i, the longitudinal relaxivities (r₁) of MPB in mildly acidic (pH 6.5) or reduced (pH 7.4, GSH 10 mmol/L) environment was higher than that in neutral (pH 7.4) environment, confirming the pH/GSH-activatable MRI. Moreover, the in vivo MRI of the tumor site was also performed. As displayed in Fig. 4h, after intratumoral injection of MPB, the T₁₋MR signal of the tumor enhanced. The above results confirm that the MPB is a promising potential MRI agent.

In conclusion, multifunctional MPBC nanoplatforms were constructed to achieve MRI image-guided synergistic SDT/CDT. Under US irradiation, Ce6 could generate ROS for SDT to induce cancer cells apoptosis. And the SDT effect was enhanced by the O₂ in TME generated by the catalase-like activity of the loaded Pt. The MnSiO₃ nanosphere can be degrade in TME, the released Mn²⁺ could catalyze H₂O₂ to produce ^∙OH for CDT and display an excellent potential for T₁-weighted MRI. More importantly, in vitro and in vivo data showed MPBC-based combined therapy could kill tumor safely and effectively, which supplied a new paradigm in cancer treatment.

Declaration of competing interest

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

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This work is financially supported by the National Natural Science Foundation of China (NSFC, Nos. 51720105015, 51972138, 51929201, 51922097, 51772124 and 51872282), the Science and Technology Cooperation Project between Chinese and Australian Governments (No. 2017YFE0132300), the Key Research Program of Frontier Sciences, CAS (No. YZDY-SSW-JSC018). All animals experiments in this study were performed according to a protocol approved by the Institutional Animal Care and Use Committee of Jilin University.

Supplementary materials

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Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2021.12.096

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Year 2022 volume 33 Issue 6

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doi: 10.1016/j.cclet.2021.12.096

Receive Date：2021-09-14
Online Date：2025-12-19
Published：2022-06-15

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Received：2021-09-14
Revised：2021-12-17
Accepted：2021-12-31

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^aState Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China

^bSchool of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China

^cDepartment of Periodontology, Stomatological Hospital, Jilin University, Changchun 130021, China

^dSchool of Physical & Mathematical Sciences, Nanyang Technological University, Singapore 639798, Singapore

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Scheme 1 (a) Schematic illustration for the synthesis steps of MPBC nanoplatform. Mesoporoussilica was treated by hydrothermaltreatment to produce MnSiO₃. PtNPs were absorbed on the surface of amino-modified MnSiO₃. BSA was modified to improve the biocompatibility of NPs. Then sonosensitizer Ce6 was conjugated with MPB through the formation of amide bond. (b) The antitumor mechanism of MPBC nanoplatform. Under USirradiation, Ce6 could generate ROS for SDT. And the O₂ in TME generated by the catalase-like activity of the loaded Pt could improve the SDT effect. Meanwhile, the released Mn²⁺ by degradation of NPs could catalyze H₂O₂ to produce ^∙OH for CDT, causing the good synergistic therapeutic effects of SDT and CDT.

Fig. 1 TEM images of (a) Mesoporoussilica, (b) MnSiO₃ spheres, (c) PVP-Pt NPs, and (d) MP NPs. (e) The EDS and elemental mappings of MP. (f) XRD spectra of MnSiO₃ and MP. (g) High-resolution Mn 2p XPS spectra of MP. (h) N₂ adsorption-desorption isotherm and poresizedistribution (inset image) of MnSiO₃ (black) and MP (red).

Fig. 2 (a) TGA of MP and MPB. (b) UV–vis–NIR absorption spectra of MPB, free Ce6, and MPBC. (c) Zetapotential of NPs in each synthesis step. (d) The absorption spectra of MB in different solutions (25 mmol/L NaHCO₃/5% CO₂ buffer solution, 10 µg/mL MB, 8 mmol/L H₂O₂, and 0.5 mmol/L MnCl₂). (e) The absorption spectra of MB in different H₂O₂ concentrations. (f) The O₂ production in H₂O₂ solution (1 mmol/L). (g) The fluorescenceintensities of SOSG in MPBC solution under USirradiation. (h) The fluorescence intensities of SOSG in MPBC solution under different US irradiation densities for 5 min. (i) The production of ¹O₂ in MPBC solution at different conditions.

Fig. 3 (a) Cellular uptake of MPBC by HeLa cells at different time points by FCM. (b) Intracellular O₂ change after different treatments probed with O₂ probe [Ru(dpp)₃]Cl₂ by FCM. (c) Cellviabilities of HeLa cells after treated with different materials (100 ppm) upon USirradiation (1.0 MHz, 1.5 W/cm², 50% duty cycle, 1 min). (d) Intracellular ROS detection of HeLa cells after treated with different conditions. Scale bar is 10 µm. (e) Apoptosis assay of HeLa cells after different treatments by FCM.

Fig. 4 (a) Tumor-volume curves and (b) body-weight curves of mice after different treatments. (c) Plots of 1/T₁ vs. Mn concentration. (d) The release of Mn in different environments. (e) TUNEL staining in the tumor site of mice after different treatments. (f) HIF-1α and (g) VEGF immunofluorescence images of tumor slices in control and MPB groups. (h) In vivo T₁-weighted MRI after the intratumoral injection of MPB. (i) In vitro T₁-weighted MRI with different concentrations of MPB (15.625, 31.25, 62.5, 125, 250, 500 ppm) in different environment. Scale bar is 50 µm.

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