Novel multifunctional nanoplatform for tumor-specific therapy

Recently, the team of Professor Wang Leyu of Beijing University of Chemical Technology and the team of Professor Tony D. James of the University of Bath in the United Kingdom developed a 19F MRI functional nanoprobe with tumor microenvironment response, through the rational design of the nanoprobe structure, under the regulation of the tumor microenvironment, it can simultaneously activate the 19F MRI signal and enhance its chemokinetic treatment ability, so as to realize the integration of diagnosis and treatment of liver cancer in situ. The study, titled “Nanoplatforms with synergistic redox cycles and rich defects for activatable image-guided tumor-specific therapy,” was published in the journal Chem.

Due to the lack of obvious lesion location and the difficulty of identifying early lesion characteristics, the accurate diagnosis and efficient treatment of tumors in deep tissues is a major problem in tumor diagnosis and treatment. Magnetic resonance imaging (MRI) technology is safe and non-invasive, penetrates deeply, and provides rich physiological information, and has been widely used in clinical tumor diagnosis. However, due to the abundance of protons in healthy tissues and pathological tissues and the small difference in proton relaxation time, the imaging contrast of lesion tissues based on 1H magnetic resonance imaging is poor, which is easy to lead to missed diagnosis and misdiagnosis in clinical diagnosis. Currently, MRI contrast agents are usually introduced to enhance MRI contrast changes in lesion location and normal tissue. In addition, other nuclei such as 13C, 19F, 23Na, 31P and 129Xe are also used in magnetic resonance imaging. Among these nuclei, the 19F nucleus has a natural abundance of 100% and a sensitivity comparable to the hydrogen nucleus (about 83%), the chemical shift range is large, which can realize the imaging of multiple signals, and because the fluorine element in living organisms is mainly present in bones and teeth, the background noise in the soft tissue of the 19F nucleus is almost zero, which makes the real-time tracking and quantification application of the 19F nucleus in magnetic resonance imaging possible. Professor Wang Leyu’s team has been committed to the design and application of new multifunctional 19F magnetic resonance imaging (19F MRI) nanoprobes in recent years, and has achieved a series of results. In order to further improve the sensitivity of 19F MRI probes, recently, the team of Professor Wang Leyu of Beijing University of Chemical Technology and the team of Professor Tony D. James of the University of Bath in the United Kingdom developed a 19F MRI functional nanoprobe with tumor microenvironment response, through rational design of nanoprobe structure, under the regulation of tumor microenvironment, can simultaneously activate 19F MRI signal and enhance its chemokinetic treatment ability, to achieve the integration of diagnosis and treatment of liver cancer in situ.

The main research content of this work is the design and preparation of a multifunctional nanoplatform based on copper/manganese bimetallic sulfide nanoflowers (CMC NFs) that can be used for tumor microenvironment-specific activation of 19F MRI-guided chemokinetic and photothermal combination therapy, which can act as a dual regulator in the tumor microenvironment (slightly acidic/overexpressed glutathione), on the one hand, it can be used as an enhancer for chemokinetic therapy, with the help of double redox pairs (Cuox/Cured, Mnox/Mnred) and abundant sulfur defects, which can be efficiently converted into hydrogen peroxide by adjusting the electron density distribution of the active site to produce reactive oxygen species for specific tumor treatment; On the other hand, by compounding the fluorinated small molecule perfluorocrown ether with this nanoplatform, since CMC NFs are easily dissociated in the tumor microenvironment, thereby weakening the paramagnetic relaxation enhancement effect of paramagnetic manganese ions on 19F, the specific imaging and chemokinetic enhancement therapy of living tumors (subcutaneous tumors/hepatic in situ tumors) activated by the tumor microenvironment can be realized.

Figure 1. Schematic diagram of the preparation of an intelligent nanoplatform for activated 19F NMR imaging and the mechanism of signal activation and ROS enhancement

Firstly, the structural characteristics of copper/manganese bimetallic sulfide nanoflowers were systematically investigated, and a series of characterization results showed that the material had double redox pairs and abundant sulfur defects, which greatly promoted the catalysis of H2O2 and the generation of ROS. By systematically comparing the catalytic performance of copper sulfide alone, manganese sulfide and copper/manganese bimetallic sulfide nanoflower, it can be found that only CMCF NCs show the best reactive oxygen species production performance in the simulated tumor environment, and CMCF has the ability to consume GSH, therefore, the material has great potential in breaking the redox balance in cancer cells and enhancing the therapeutic effect of chemokinetics.

Figure 2.Study of nanozyme activity of nanoplatforms

When the same amount of CMCF NCs were injected into the tumor and normal subcutaneous tissue of mice, it was clear from 19F magnetic resonance imaging that the signal at the tumor site was significantly higher than the signal intensity in normal tissue (Figures 3A-3B), indicating that the signal of CMCF NCs has the property of activating the tumor microenvironment. Further, by injecting CMCF NCs into a mouse model of hepatocarcinoma in situ, the tumor site of the liver was clearly seen in the 19F magnetic resonance imaging map 8 h after injection (Figure 3C), indicating that CMCF NCs can be applied to in vivo in situ specific identification of tumors in deep tissues. In addition, copper/manganese bimetallic sulfide nanoflowers also have near-infrared secondary photothermal effects, which can potentially be used for photothermal therapy.

Figure 3. In vivo magnetic resonance imaging and photothermal performance studies

Figure 4.Therapeutic performance of nanoplatforms for living tumors

Finally, the authors constructed a 4T1-bearing mouse model and randomly divided into different groups, during the treatment, there was no significant change in the body weight of mice in all groups, while only the group injected intravenously with CMCF NCs showed the best tumor suppression efficiency, indicating that near-infrared illumination and the use of CMCF NCs were not systematically biotoxic to mice, and at the same time, the nanoplatform showed excellent effect of inhibiting tumor growth.

The intelligent nanoplatform in this work has broad application prospects in the diagnosis and treatment of living drug tracing and deep tumors by specifically generating reactive oxygen species and activating imaging signals at tumor sites. (Source: Science Network)

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