# The Exploitation of Lysosomes in Cancer Therapy with Graphene-Based Nanomaterials
## 5 The Role of Lysosomes in GNM-Based Cancer Therapy
Therefore, the ATPase continuously pumps protons into the endosome/lysosome, which is followed by an influx of chloride ions, water osmosis, increased pressure, and, finally, lysosomal rupture. In the umbrella effect, protonation of amines leads also to charge repulsion and nanoparticle expansion, which causes endosomal/lysosomal rupture. By inducing membrane stress and internal membrane tension, nanoparticles can lead to the formation of pores on the endosome/lysosome membrane. In photochemical disruption, a light-irradiated (blue wavy arrows) photosensitizer (yellow circles) attached to a GNM-containing nanocarrier generates ROS (yellow stars), which destroys the integrity of the endosomal/lysosomal membrane. and loaded it with DOX and ICG. The formed ICG/DOX/GO-PPF68 was internalized into multidrug-resistant (MDR) MCF-7/ADR human breast cancer cells by endocytosis, where PPF68 protected the drugs from leakage and degradation. ROS, which was generated by NIR-irradiated ICG, triggered the cleavage of the diselenide bond in the complex, resulting in the release of DOX. The proton sponge effect of PAMAM and ROS induced LMP and allowed the lysosomal escape of DOX. Upon NIR irradiation, the ROS and heat generated by ICG, the heat generated by GO, and the antiproliferative effect of DOX decreased the viability of tumor cells. Notably, the intravenously injected composite accumulated in the tumor tissues of MCF-7/ADR tumor-bearing mice due to the EPR effect and greatly reduced the tumor growth of the animals upon NIR irradiation [15]. [PERSON] et al. loaded DOX on GO-wrapped gold nanorods, which enabled complex detection by Surface-enhanced Raman spectroscopy (SERS). At the beginning of treatment with DOX@GO@AuNR complex, the SERS signals from GO and DOX overlapped near HeLa cells. Later, the \(\pi\)-\(\pi\) DOX/GO interaction was broken at low lysosomal pH, as evidenced by a decrease in DOX signals compared to GO SERS signals, indicating the appropriate time to irradiate the cells. The photothermal effect of NIR-irradiated GO and antiproliferative effects DOX reduced cell viability. The antitumor effect of DOX@GO@AuNR was confirmed in NIR-irradiated HeLa-bearing mice [63]. [PERSON] et al. developed a GO-based nanocarrier and loaded it with DOX and Ag nanoparticles as SERS substrates. The Ag-GO/DOX complex was endocytosed by Ca Ski human cervical carcinoma cells, and the low lysosomal pH disrupted the \(\pi\)-\(\pi\) interaction between DOX and GO surface, resulting in the release of DOX. SERS tracking confirmed that DOX escaped from the lysosomes into the cytoplasm and entered the nucleus, while GO remained in the cytoplasm [59]. [PERSON] and colleagues utilized both \(\pi\)-\(\pi\) stacking and hydrophobic interactions to load DOX onto nanographene oxide (NGO). They then co-coated the formed hydrophobic NGO/DOX with a biomimetic membrane made of soy phosphatidylcholine (SPC) and modified it with a PEGylated lipid-FA (where FA stands for folic acid). The resulting NGO/DOX@SPC-FA complex demonstrated long-term blood circulation in HeLa cervical tumor-bearing mice and preferential entry into the tumor tissue due to the EPR effect. The FA moiety facilitated the binding of the complex to the FA receptor on cancer cells, followed by clathrin-dependent endocytosis. DOX was released from NGO in the acidic lysosomal environment due to the protonation effect, escaped from the lysosomes, and entered the nucleus to exert its anticancer effect [60]. [PERSON] et al. prepared a complex of NGO, PEG, positively charged poly(allylamine hydrochloride), and 2,3-dimethylmaleic anhydride (DA) with pH-dependent charge reversibility, and then loaded it with DOX. The formed NGO-PEG-DA/DOX was negatively charged at a physiological pH of 7.4, whereas it was positively charged in the tumor microenvironment (pH = 6.8) due to the cleavage of DA. This enhanced its uptake in MCF-7 cells and provided tumor-specific cytotoxicity. At a lysosomal pH of 5, DOX was released from the complex due to its protonation-induced hydrophilicity/solubility.