# The Exploitation of Lysosomes in Cancer Therapy with Graphene-Based Nanomaterials
## 5 The Role of Lysosomes in GNM-Based Cancer Therapy
In lysosomes, cathepsin B cleaved the peptide, releasing Ce6 from GO. Upon red light irradiation, Ce6 induced the formation of singlet oxygen \({}^{1}\)O\({}_{2}\), which triggered the release of cathepsin B from lysosomes to cytosol and led to LCD [16]. [PERSON] and colleagues attached a PEG-modified Ru(II)-polypyridyl complex to rGO through \(\pi\)-\(\pi\) stacking and hydrophobic interactions. Upon internalization, the rGO-Ru-PEG complex was detected in lysosomes of A549 cells. Low pH and the heat produced by \begin{table}
\begin{tabular}{c c c c} \hline \hline
**GNMs/Graphene-Based DDSs** & **Cell Type** & **Mechanism of LMP Induction** & **Ref** \\ \hline GNSs & RBL2H3 & Sharp edges and rough surface of GNSs + \(\downarrow\) mitochondrial & [67] \\  & & electron transport chain \(\rightarrow\) ROS & \\ \hline DSPE-PEG2000-FA + Ce6-Pep + GO & HeLa & Light \(\rightarrow\) Ce6 \(\rightarrow\)\({}^{1}\)O\({}_{2}\)\(\rightarrow\) cathepsin B release & [16] \\ \hline rGO-Ru-PEG & A549 & Light \(\rightarrow\) Ru \(\rightarrow\) ROS \(\rightarrow\) cathepsin B release & [17] \\ \hline DHA-GO-Tf & EMT6 & Low pH \(\rightarrow\) release of Fe\({}^{+3}\) from the Tf \(\rightarrow\) Fe\({}^{+3}\) reduced to & [33] \\  & & Fe\({}^{+2}\)\(\rightarrow\) Fe\({}^{+2}\) + DHA \(\rightarrow\) ROS \(\rightarrow\) lysosomal damage & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: GNMs and graphene-based DDSs induce LMP. \(\rightarrow\) denotes causal connection; \(\downarrow\) denotes decrease/inhibition. ROS—reactive oxygen species. Abbreviations for GNNs/graphene-based DDSs in order of appearance: GNSs, graphene nanosheets; DSPE-PEG2000-FA, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate(polyethylene glycol)-2000]; Ce6, Chlorin e6; GO, graphene oxide; rGO-Ru-PEG, reduced graphene oxide loaded with Ru(II)-polypyridyl complex modified with polyethylene glycol; DHA, dihydroartemisinin; Tf, transferrin. NIR irradiated-rGO caused the release of Ru-PEG from the rGO surface. The irradiation of cells with NIR for PTT and blue light for PDT resulted in the synergistic induction of apoptosis through the generation of ROS and the release of cathepsin B from lysosomes into the cytosol. Notably, treatment with rGO-Ru-PEG and irradiation with both NIR and blue light significantly reduced tumor growth in A549 tumor-bearing mice [17]. [PERSON] et al. developed DHA-GO-Tf by combining the anti-malarial drug dihydroartemisinin (DHA), nanoscale GO, and transferrin (Tf), an iron transporter that can target tumor cells expressing Tf receptors. DHA-GO-Tf was endocytosed in EMT6 cells. In the acidic environment of lysosomes, iron (Fe\({}^{+3}\)) was released from Tf and reduced to Fe\({}^{+2}\) by lysosomal ferrireductase. The reaction between DHA and Fe\({}^{2+}\) generated ROS, leading to oxidative damage of lysosomes and cytotoxicity. DHA-GO-Tf was found to preferentially accumulate in the tumor tissue of EMT6-bearing mice and induce complete tumor regression [33]. In above-mentioned studies, LMP appears to be only one of the steps leading to tumor cell death. Considering the huge instability of cancer lysosomes, the ability of using LCD in GNM-based tumor therapy should be investigated in more detail. It is useful to determine whether there is a relationship between the size and charge of GNMs and their capacity to destabilize lysosomes. The ability of GNMs to induce LMP could be stimulated by their modification with amine-modified polystyrene, as this has been shown to be successful with other nanoparticles [72]. In addition, loading GNM with anticancer drugs that can themselves induce LMP, such as vincristine, vinblastine, paclitaxel, cisplatin, and doxorubicin [73], could be used for this purpose.