Since disulfiram (DSF) can inhibit the activity of alcohol dehydrogenase without causing any side effects, it has been widely used as an effective drug in the treatment of alcohol addiction. Recently, researchers found that DSF can be rapidly converted to diethyldithiocarbamate (DTC), which can be incorporated with Cu2+ to generate the (N, N-diethyldiethyldiocarbamate) copper(II) complex (Cu(DTC)2), a compound that blocks the normal degradation of intracellular proteins and leads to the accumulation of toxic proteins, which in turn promotes apoptosis of tumor cells. However, the content of Cu2+ in cells is very low, and the DSF is difficult to dissolve in water, which limits the application of DSF in tumor therapy.
Based on previous research, Zhang and coworkers designed a dual gate-controlled intelligent nanoreactor HDHF which used HCuS as a nano-carriers to transport FePtMn and DSF into cells. Meanwhile, the HCuS has high efficiency of photothermal conversion and can promote chemokinetic therapy (CDT). When exposed to an 808 nm laser, HCuS would collapse and release the loaded DSF and FePtMn. The released FePtMn nanocrystals could sustainably release Fe2+, catalyzing H2O2 to highly cytotoxic •OH, thus triggering CDT. Meanwhile, this process also releases a large amount of Cu2+, which can bind to DTC to form a complex, and then promote the apoptosis of tumor cells. Moreover, to achieve specific recognition of tumor cells by HDHF, the surface of nanoparticles was modified with hyaluronic acid. In the presence of hyaluronidase in the tumor microenvironment, HDHF can release FePtMn and DSF. Besides, FePtMn NPs can effectively improve the load capacity and prevent premature DSF leakage.
Fig.1 In vivo antitumor evaluation of the nanomaterials. (Zhang, 2022)
After synthesizing the required material, they tested its biocompatibility in vitro. Subsequently, they evaluated the antitumor efficacy of the nanomaterials in vivo by administering five intravenous injections of nanomaterials over 14-days in female Balb/ C mice. As shown in Figure 1, compared with the control group, the treatment effect of HDHF and HDHF + laser irradiation group was significant. The tumor inhibition rate of HDHF + laser group was as high as 95.27%, which was much higher than that of other groups, indicating that photothermal therapy, CDT and DSF-based chemotherapy had a high synergistic anti-tumor effect. Furthermore, the HIF-1α levels of FePtMn involved groups decreased significantly, indicating that FePtMn has the catalytic capacity to produce oxygen. No weight loss was observed in all tested mice, which proved the good biocompatibility of the nanotherapy proposed in this study.
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