br In addition clinical imaging technology is critical
In addition, clinical imaging technology is critical for observing the details of the tumor in vivo [30–32]. Among clinical imaging technol-ogies, magnetic resonance imaging (MRI) is one of the most commonly used techniques for cancer diagnosis because it can acquire high-re-solution 3D tomographic images with excellent soft-tissue contrast. Commonly, the clinical imaging process requires contrast agents (CAs) to obtain high-quality cancer images [33–38]. Currently, the clinical CAs are mainly small molecules that are passively distributed into the interstitial space of tissues and organs, making the observation of cancer tissue be diﬃcult. To overcome this shortcoming, it was neces-sary to construct CAs that responded to the microenvironment of the tumor (i.e. pH). These CAs could be also used to monitor in real time the information of tumor treated with CDT agents.
Based on the above analysis, herein, a pH-responsive MRI ther-anostic platform that integrated CDT with limotherapy was developed via nano-Se-coated manganese carbonate-deposited iron oxide nano-particles (MCDION-Se). As illustrated by Scheme 1B, the manganese carbonate in MCDION-Se could be dissolved in the weakly acidic en-vironment of tumor tissues and release abundant of Mn2+ ions, en-dowing MCDION-Se with a specific MR contrast ability for cancer tis-sues. Additionally, the released Mn2+ ions not only catalyzed H2O2 to form toxic ·OH in cancer cells via a Fenton-like reaction, but also in-hibited the generation of X-press Tag and then starved cancer cells. Besides, nano-Se coated onto MCDION-Se eﬀec-tively activated SOD and promoted the generation of SOARs in vivo, enhancing the content of H2O2 in cancer cells based on the reaction of SOD and SOAR (scheme 1A I). Subsequently, the generated H2O2 would be further catalyzed into ·OH via Mn2+ ions and iron oxide nano-particles (IONs), causing the apoptosis of cancer cells. Interestingly, nano-Se also acted as an ATP inhibitor and blocked the energy re-quirement for cancer cells (scheme 1A II), further resulting in cancer cell apoptosis and improving the cancer treatment eﬀect. By integrating CDT with limotherapy and tumor-specific MRI, this system could be a good replacement for traditional chemotherapeutics and a promising candidate for the visualization therapy of tumors by MRI.
2. Results and discussion
As illustrated by scheme 1A, MCDION could be synthesized by solvent-thermal decomposition using iron (III) acetylacetonate (Fe (acac)3) and manganese acetylacetonate (Mn(acac)2) as precursors and Biomaterials 216 (2019) 119254
polyethyleneimine (PEI) as a surfactant. Subsequently, PEI was used to further modify MCDION for obtaining a highly positive charge, making nano-selenium with negative charge eﬀectively coated on MCDION to form MCDION-Se. Transmission electron microscopy (TEM) images showed that IONs were monodisperse and consisted of many tiny na-nocrystals (Fig. 1A). In addition, MCDIONs presented a similar mor-phology as that of IONs (Fig. 1B–F). The high-resolution TEM (HRTEM) displayed that MCDIONs had two types of the interplanar spacing, and was respectively 0.211 nm and 0.237 nm (Fig. S1), which could be at-tributed to the (400) plane in IONs (JCPDS No. 75–0449) and the (110) plane in MnCO3 (JCPDS No. 86–0173) [39,40]. The elemental mapping and surface scanning analysis of MCDIONs showed significant signals of Mn, Fe, and O and demonst rated the uniform distribution of Mn in MCDIONs (Fig. 1G–P), confirming that manganese carbonate was suc-cessfully embedded into IONs. Subsequently, the Mn content in MCDION could be adjusted by controlling the additive amount of Mn precursors. MCDIONs with diﬀerent MnCO3 contents were synthesized and then the Mn contents of samples measured using inductively cou-pled plasma mass spectrometry (ICP-MS) were 39.7% (designated as MCDION-1), 21.2% (designated as MCDION-2), 20.0% (designated as MCDION-3), 15.9% (designated as MCDION-4) and 12.2% (designated as MCDION-5). The size of MCDION in the TEM images gradually in-creased with increasing Mn content. Additionally, the hydrodynamic size of these particles was investigated using a dynamic light scattering (DLS) detector, and was similar to that observed by TEM (Figs. S2A and B).