The Exploitation of Lysosomes in Cancer Therapy with Graphene-Based Nanomaterials

Abstract

Graphene-based nanomaterials (GNMs), including graphene, graphene oxide, reduced graphene oxide, and graphene quantum dots, may have direct anticancer activity or be used as nanocarriers for antitumor drugs. GNMs usually enter tumor cells by endocytosis and can accumulate in lysosomes. This accumulation prevents drugs bound to GNMs from reaching their targets, suppressing their anticancer effects. A number of chemical modifications are made to GNMs to facilitate the separation of anticancer drugs from GNMs at low lysosomal pH and to enable the lysosomal escape of drugs. Lysosomal escape may be associated with oxidative stress, permeabilization of the unstable membrane of cancer cell lysosomes, release of lysosomal enzymes into the cytoplasm, and cell death. GNMs can prevent or stimulate tumor cell death by inducing protective autophagy or suppressing autolysosomal degradation, respectively. Furthermore, because GNMs prevent bound fluorescent agents from emitting light, their separation in lysosomes may enable tumor cell identification and therapy monitoring. In this review, we explain how the characteristics of the lysosomal microenvironment and the unique features of tumor cell lysosomes can be exploited for GNM-based cancer therapy.

Keywords: cancer; endosomal/lysosomal escape; graphene-based drug delivery systems; graphene-based nanomaterials; lysosomal cell death; lysosomes.

Figure 1

The structure of GNMs and graphene-based DDSs.

Figure 2

The entry of GNMs and graphene-based DDSs into cells. In phagocytosis, large GO are engulfed in a phagosome, which fuses with the lysosome. In clathrin-mediated endocytosis, small GO nanosheets and GQDs are bound to cell surface receptors and internalized into clathrin-coated vesicles that mature into late endosomes and eventually fuse with the lysosome. Small hydrophobic graphene sheets and flakes enter the cytoplasm directly by penetrating the plasma membrane and can become entrapped in autophagosomes, which subsequently fuse with lysosomes in the process of autophagy. GQDs can also cross cell membranes by caveolae-mediated endocytosis, which occurs through the formation of caveolae vesicles, which may fuse with endosomes.

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. 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.