Abstract
The restriction of a tumor’s energy supply is proven to be an effective means of treatment. Glucose oxidase (GOx), an enzyme that catalyzes the conversion of glucose to glucolactone, producing oxygen and hydrogen peroxide in the process, has proved useful in this regard. However, hypoxia, which is implicated in tumor growth, has been found to mediate resistance to this type of tumor starvation. Here, we describe the design and testing of a platelet membrane mimetic, PMS, consisting of mesoporous silica nanoparticles (MSNs) loaded with metformin (MET) as an inner layer and platelet membranes (PM) as an outer layer that inhibits oxygen consumption by the tumor cells’ respiratory pathways and enhances the effectiveness of GOx. MET directly inhibits the activity of complex I in mitochondrial electron transport and is thus a potent inhibitor of cell respiration. PMS target tumor tissue effectively and, once internalized, MET can inhibit respiration. When oxygen is plentiful, GOx promotes glucose consumption, allowing amplification of its effects on tumor starvation. This combination of respiratory suppression by PMS and starvation therapy by GOx has been found to be effective in both targeting tumors and inhibiting their growth. It is hoped that this strategy will shed light on the development of next-generation tumor starvation treatments.
Highlights
Increased proliferation places extensive demands on tumor cells’ metabolic processes compared to their normal somatic cell counterparts
Tumor cells characteristically make use of aerobic glycolysis in addition to mitochondrial oxidative phosphorylation to meet their energy demands (Liberti and Locasale, 2016; Gao and Wei, 2017), Changes and rearrangements of tumor cells’ metabolic pathways occur to accommodate these higher energy requirements (Vander Heiden et al, 2009; Tennant et al, 2010). This is known as the Warburg effect (Gatenby and Gillies, 2004; Kim and Dang, 2006; Koppenol et al, 2011), This shift to aerobic glycolysis renders the cells more vulnerable to alterations in the cellular glucose supply. This is the principle behind the proposed cancer starvation therapy, Starvation Therapy Against Hypoxic Tumor which effectively starves the cells by depleting their glucose supply (Kim and Dang, 2006; Li et al, 2018)
The MET-loaded mesoporous silica nanoparticles (MSNs) were shown by transmission electron microscopy (TEM) imaging to measure ∼100 nm in diameter with a gray 5 nm- thick membranous outer shell (Figure 1A)
Summary
Increased proliferation places extensive demands on tumor cells’ metabolic processes compared to their normal somatic cell counterparts. Tumor cells characteristically make use of aerobic glycolysis in addition to mitochondrial oxidative phosphorylation to meet their energy demands (Liberti and Locasale, 2016; Gao and Wei, 2017), Changes and rearrangements of tumor cells’ metabolic pathways occur to accommodate these higher energy requirements (Vander Heiden et al, 2009; Tennant et al, 2010). This is known as the Warburg effect (Gatenby and Gillies, 2004; Kim and Dang, 2006; Koppenol et al, 2011), This shift to aerobic glycolysis renders the cells more vulnerable to alterations in the cellular glucose supply. This approach has stimulated much interest (Fu et al, 2018; Yu et al, 2018; Xie et al, 2019) and the glucose oxidase GOx has attracted attention (Fu et al, 2019; Yang et al, 2019; Gao et al, 2020; Ren et al, 2020) for its role in the oxidation of glucose to gluconic acid, a reaction that can be harnessed to restrict the glucose supply to tumor cells (Jain, 2014; Gao et al, 2020)
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