# The Exploitation of Lysosomes in Cancer Therapy with Graphene-Based Nanomaterials
## 5 The Role of Lysosomes in GNM-Based Cancer Therapy
Abbreviations for graphene-based DDSs in order of appearance: GPCP/miR-2 li/ICG, poly(l-lysine)-modified graphene conjugated with citraconine and polyamidoamine loaded with indocyanine green and miR-2 li; ICG/GPP, graphene oxide modified with poloxamer 188-modified polyamidoamine-dendrimer; GO/AuNS-PEG/Ce6, PEGylated graphene/gold nanostar hybrid loaded with Chlorin e6; FPS, fluorinated GO modified with PEI and sericin; FPS-Cur, FPS loaded with curcumin; ICG/DOX/GO-PPF68, graphene oxide conjugated with polyamidoamine-pluronic F68 loaded with doxorubicin and indocyanine green; DOX@-GO@AuNR, gold nanorods wrapped in graphene oxide and loaded with doxorubicin; Ag-GO/DOX, graphene oxide loaded with doxorubicin and AG; NGO/DOX@SPC-FA, nanographene oxide loaded with doxorubicin, co-coated with soy phosphatidylcholine and modified with a PEGylated folic acid; NGO-PEG-DA/DOX, nanographene oxide conjugated with polyethylene glycol and poly(allylamine hydrochloride), modified with 2,3-dimethylmaleic anhydride and loaded with doxorubicin; PKSE7(PEI-GO), poly(ethylene imine) coated with poly(ethylene imine)-poly(l-lysine)-poly(l-glutamic acid) and conjugated with reduced graphene oxide; GPC-NP, graphene oxide transformed into 3D in the presence of cisplatin and loaded with prokaryotic; GDC-NP, graphene oxide transformed into 3D in the presence of cisplatin and loaded with doxorubicin; GT/IR820/DP-CpG, 1,2-distearoyl-3-phosphatidylylethanolamine and polyethylene glycol conjugated with alkyl triphenylphosphonium and graphene oxide, loaded with diphenylmethylsilane-substituted CPG and photosensitizer IR820. Theranostics is a term used to describe the simultaneous diagnosis and treatment of a disease. In a study by [PERSON] et al., a graphene/gold nanostar hybrid was stabilized by PEGylation in a GO/AuNS-PEG complex. PEGylation is a widely used method to improve the hydrophilicity and biocompatibility of nanocomplexes [65]. The photosensitizer Chlorin e6 (Ce6) was loaded onto the GO/AuNS-PEG complex through \(\pi\)-\(\pi\) stacking. The resulting photothermalzo/AuNS-PEG/Ce6 was endocytosed into the lysosomes of EMT6 mouse breast cancer cells. Upon NIR irradiation, the lysosomal membrane was ruptured by the heat and ROS generated by GO/AuNS-PEG and Ce6, respectively. This facilitated the release of the complex from the lysosomes and its targeting of the mitochondria, ultimately inducing cell death. Treatment of EMT6 tumor-bearing mice with GO/AuNS-PEG/Ce6 and NIR irradiation enabled in-vivo photothermal imaging by an infrared camera and strongly reduced tumor growth [62]. [PERSON] and co-workers modified fluorinated GO with two molecules with pH-dependent charge reversal properties, PEI and sericin from silkworm, to form nanocarriers named FPS. FPS was loaded with the hydrophobic natural antitumor drug curcumin. Formed FPS-Cur contained two different pH-sensitive amide linkages that were negatively charged at blood pH (\(\approx\)7.4), resulting in a prolonged circulation time. At mildly acidic conditions (pH \(\approx\) 6.5 for tumor extracellular matrix and pH \(\approx\) 5.5 for endosomes/lysosomes), the amide linkages in FPS-Cur underwent hydrolysis, causing the complex to switch its charge from negative to positive. The induced electrostatic repulsion led to the opening of the complex's structure, allowing for the release of curcumin. Curcumin then entered the nucleus, triggering apoptosis and necrosis of HeLa cervical cancer cells [14]. The hydrophobic antitumor drug and DNA synthesis inhibitor doxorubicin (DOX) binds to graphene and its derivatives through both hydrophobic and \(\pi\)-\(\pi\) stacking interactions. [PERSON] et al. conjugated GO with PAMAM-Pluronic F68 (PPF68) via a diselenide bond  
Figure 3: The possible mechanisms of endosomal/lysosomal escape of anticancer drugs (red circles) released from GNMs. In the proton sponge effect, GNM-bound molecules containing amine groups with buffering capacity absorb protons.