Lysosome-targeted ROS-responsive graphene oxide-based drug delivery system to overcome tumor DOX resistance

The lysosomes of drug-resistant tumor cells transport doxorubicin (DOX) and its nanocarriers into lysosomes through a sequestration mechanism, making it difficult for DOX to reach the therapeutic concentration. In this study, a nanodrug delivery system (Dp/DGPP) capable of overcoming tumor lysosomal resistance was developed. The system consists of three parts: graphene oxide (GO)-Se-Se-DOX, polyethyleneimine-pluronic F127 (PEI-PF127) for improved biocompatibility, and Dp44mT for amplifying reactive oxygen species (ROS) and disrupting lysosomes. After entering MCF-7/ADR tumor cells, loading Dp44mT can reduce the permeability of lysosomal membranes by increasing the level of ROS. DOX subsequently escapes from lysosomes and breaks the diselenide bond to complete its release. The experiment proved that Dp/DGPP exhibited a significant ROS-dependent response to the release of DOX. Compared with the other groups, it had greater cytotoxicity, and the IC50 value of DOX against MCF-7/ADR cells was as low as 6.71 μM. Compared with the DOX group, the Dp/DGPP group exhibited greater DOX accumulation in MCF-7/ADR cells, with 1.5-fold greater fluorescence at 4 h. Meanwhile, Dp/DGPP can cause lysosomal dysfunction by reducing lysosomal membrane permeability. Western blot results revealed that the expression of Pgp protein decreased in the Dp/DGPP group, whereas the expression of autophagy related LC3-II and P62 protein increased, which confirmed that autophagic flux was blocked. This reduces potential drug resistance and promotes cell death. In addition, the Dp/DGPP group achieved a 70 % inhibition rate in MCF-7/ADR tumors in vivo. This nanodrug delivery system provides a potential strategy to overcome tumor DOX resistance via lysosomes.