br X ray di raction XRD
X-ray diﬀraction (XRD) analysis displayed that all MCDIONs had the typical diﬀraction peaks of ION and MnCO3 (Fig. 2A), implying that MnCO3 was successfully integrated into IONs. The compositions of IONs and MCDIONs were investigated by Fourier transform infrared (FT-IR) spectroscopy. As shown in Fig. S3A, all samples had similar curves. The peaks at 586 cm−1 could be attributed to typical Fe-O stretching vi-bration. The peaks at 1048 and 1638 cm−1 were assigned to -C-N stretching vibration and -N-H bending vibration, demonstrating the existence of PEI chains in these particles . For MCDIONs, a new peak appeared at 880 cm−1 assigned to MnCO3, indicating that Mn Gap 26 successfully coated into ION. In addition, the thermogravi-metric analysis (TGA) curves demonstrated the content of PEI in these particles (Fig. 2B). MCDION-1 had a significantly higher PEI content than that of the other samples, implying that MCDION-1 had more active groups.
The M-T curves showed that all MCDIONs below 300 K are classical ferromagnets, indicating that the magnetic core might eﬀectively dis-turb the T1 imaging eﬀect of Mn ions (Fig. 2D–H). Subsequently, the M-H curves further confirmed the magnetic properties of MCDIONs. Fig. 2I showed that no MCDIONs had any remanence or coercivity at 300 K, suggesting that these particles were soft ferromagnets. In addition, the saturated magnetization of MCDIONs gradually decreased with Mn content increasing, which might be attributed to the existence of non-magnetic MnCO3. Based on the above analysis, these MCDIONs might be good candidates for the fabrication of eﬀective pH-responsive MRI agent, in which the release behavior of Mn2+ ions from MCDIONs plays a key role. As shown in Fig. 2C and S3B-C, Mn release could be eﬀec-tively triggered by pH, and the amount of released Mn2+ ions drama-tically increased with pH decreasing. Interestingly, MCDION-1 released the most Mn2+ ions in comparison with other MCDIONs under acidic conditions and possessed the best response ability to pH, implying that MCDION-1 might have better pH-sensitive MRI contrast ability.
Subsequently, we explored the pH-responsive contrast ability of these MCDIONs using a 9.4 T MRI scanner. As shown in Fig. S4, the T1 images slightly brightened with increasing MCDION concentration under neutral conditions. Nevertheless, with decreasing pH, the T1 images of MCDIONs dramatically brightened, suggesting that all MCDIONs had a pH-responsive contrast ability. In addition, the brightness of MCDION-1 in the T1 images showed a large variation in comparison with that of the other MCDIONs, implying that MCDION-1
Scheme 1. (A) Illustration of the synthetic process of MCDION-Se. (I) Se activates SOD, which catalyzes SOAR into H2O2, and then ION and Mn2+ ions catalyze H2O2 into highly toxic ·OH via the Fenton-like reaction. (II) Mn2+ ions and nano-Se eﬀectively inhibit the generation of ATP in cells. (B) The cascade reaction of MCDION-Se in the intracellular environment.
had the strongest response to pH in T1 contrast. In addition, MCDIONs displayed a low T1 relaxation rate under neutral conditions (Fig. 3A–E), which could be attributed to the T1 quenching eﬀect of the magnetic core. Interestingly, the T1 relaxivity of MCDIONs continually increased with decreasing pH (Fig. 3F) because many of the Mn2+ ions released from MCDIONs were away from the magnetic core, and the corre-sponding quenching eﬀect was decreased (Fig. S5). Moreover, the T1 relaxivity of MCDION-1 dramatically increased from 2.7 to 7.1 mM−1s−1 and presented the highest variation among all groups, suggesting that MCDION-1 could be an eﬀective pH-responsive MRI CA. Therefore, in the following study, MCDION-1 was further modified in the fabrication of an eﬀective drug-free theranostic agent.
As previously reported [42,43], nano-Se had a good cancer inhibi-tion eﬀect and a low side-eﬀect in the body. Therefore, nano-Se was integrated into MCDION-1 to promote synergistic cancer treatment. As shown in Fig. 4A and Fig. S6B, the surface of MCDION-1 had significant bumps and the corresponding energy dispersive spectrometer (EDS) data confirmed the existence of Se, suggesting that Se compound suc-cessfully grew in the MCDION-1. The chemical state of Se in MCDION-1 was determined according to the X-ray photoelectron spectroscopy (XPS) spectra (Fig. 4B and C). The peaks at 161.4 eV could be attributed to the existence of Se with a zero valent state, implying that nano-Se was successfully coated onto MCDION-1. Besides, the XRD pattern of MCDION-Se presented the same peaks as that of MCDION-1, suggesting that nano-Se was amorphous (Fig. S6D). The hydrodynamic size dis-tribution of MCDION-Se showed a narrow peak and the size slightly increased, (Fig. S6A). Meanwhile, the surface potential of MCDION-Se signifcantly decreased, further confirming that MCDION-1 successfully