Due
to the complexity of multifactorial diseases, single-target
drugs do not always exhibit satisfactory efficacy. Recently, increasing
evidence indicates that simultaneous modulation of multiple targets
may improve both therapeutic safety and efficacy, compared with single-target
drugs. However, few multitarget drugs are on market or in clinical
trials, despite the best efforts of medicinal chemists. This article
discusses the systematic establishment of target combination, lead
generation, and optimization of multitarget-directed ligands (MTDLs).
Moreover, we analyze some MTDLs research cases for several complex
diseases in recent years and the physicochemical properties of 117
clinical multitarget drugs, with the aim to reveal the trends and
insights of the potential use of MTDLs.
Na-doped Ni-rich LiNi0.5Co0.2Mn0.3O2 cathode material, Li0.97Na0.03Ni0.5Co0.2Mn0.3O2, is synthesized by a hydroxide co-precipitation route. The structural characterization reveals that the substitution of Na for Li results in a more ordered α-NaFeO2 structure, enlarges Li layer spacing, and reduces the degree of cation mixing. The Li0.97Na0.03Ni0.5Co0.2Mn0.3O2 material has a high tap density of 2.17 g cm(-3) that meets the commercial requirement in lithium ion batteries (LIBs). The galvanostatic charge/discharge results show that the electrochemical performance of the Li0.97Na0.03Ni0.5Co0.2Mn0.3O2 is significantly improved. At 0.2, 1, 10, 30 and 50 C, the specific capacities of the Li0.97Na0.03Ni0.5Co0.2Mn0.3O2 are 228.43, 163.12, 121.43, 95.56 and 60.09 mA h g(-1), respectively, which are superior to those of the undoped LiNi0.5Co0.2Mn0.3O2 due to the enlargement of Li layer spacing, the decreased degree of cation mixing, and the rapid diffusion of Li-ion in the bulk lattice after the substitution of Na for Li. Therefore, the Na-doped Ni-rich LiNi0.5Co0.2Mn0.3O2 material is a promising cathode candidate for the next generation of LIBs.
Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst.Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies.Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment.Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas.
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