Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice

Abstract

The encapsulated 2-deoxy-D-glucose in poly(lactic-coglycolic acid) nanoparticles showed antitumor immunity and cytotoxicity in liver tumors in mice. These 2-deoxy-Dglucose in poly(lactic-co-glycolic acid) nanoparticles not only amplified antitumor effects induced by sorafenib or anti-programmed death-1 antibody, but also suppressed anti-programmed death-1-resistant tumors. BACKGROUND & AIMS: Immune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg effect recently has gained attention as a cancer immune-resistance mechanism. Considering glycolysis inhibitors as therapeutic agents, their specific delivery to cancer cells is critical not to induce adverse effects. Thus, we investigated antitumor effects of a glycolysis inhibitor, consisting of 2-deoxy-D-glucose (2DG)encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-NPs), against hepatocellular carcinoma in mice. METHODS: The antitumor effects of 2DG-PLGA-NPs were examined using hepatoma cell lines, xenograft tumors, and hepatocarcinogenic and syngeneic mouse models. RESULTS: The 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T-cell trafficking. In addition, 2DG-PLGA-NPs induced decreased lactate production and increased interferon-g-positive T cells in liver tumors. Human CD8 þ T cells cocultured with 2DG-PLGA-NP-treated Huh7 cells showed their increased interferon-g production and glucose uptake compared with the CD8 þ T cells co-cultured with PLGA-NP-treated Huh7 cells. Chemotaxis of CD8 þ T cells was suppressed by lactate and enhanced by glucose. Interferong enhanced CD8 þ T-cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9/CXCL10) production in liver tumors via interferon-g-Janus kinase-signal transducers and activator of transcription pathway and AMP Q6-activated protein kinase-mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by sorafenib or an anti-programmed death-1 antibody, but also suppressed anti-programmed death-1-resistant tumors. CONCLUSIONS: The newly developed 2DG-PLGA-NPs showed antitumor immunity and cytotoxicity in liver tumors in mice, suggesting the potential of 2DG-PLGA-NPs for future clinical applications.

Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19

“…This mode of action makes 2-DG a possibly useful drug for inhibition of metabolic reprograming which also occurs in cancer, resulting in decreased glucose consumption and inhibition of the glycolytic pathway in cancer cells (Woodward and Cramer, 1952). Studies carried out in vitro and in murine models showed that 2-DG may induce antitumor CD8 + T cellmediated cytotoxicity and increased production of IFN-g (Sasaki et al, 2021). In addition, 2-DG in association with radiotherapy also has other immune effects by increasing cell membrane expression of molecules that are relevant to antigen presentation (MHC II and CD86) by dendritic cells and reducing production of the pro-inflammatory cytokine TNFα (Farooque et al, 2014).…”

CD26/DPP4 as a Therapeutic Target in Nonalcoholic Steatohepatitis Associated Hepatocellular Carcinoma

“…Considering the potential role of DPP4 inhibitors as additional therapeutic agents in current HCC treatment, it should also be noted that the combination of a DPP4 inhibitor (sitagliptin) and an anti-PD1 antibody improved anti-tumor immunity in immunocompetent mice [ 33 ]. We recently demonstrated that 2-deoxy-D-glucose (2-DG)-encapsulated poly[lactic-co-glycolic acid] (PLGA) nanoparticles (2-DG-PLGA-NPs) augmented chemokine (CXCL9/CXCL10) production in liver tumors via the interferon-γ-Janus kinase-signal transducer and activator of transcription pathway and 5′ adenosine monophosphate-activated protein kinase-mediated suppression of histone H3 lysine 27 trimethylation (H3K27me3) [ 54 ]. Although this type of chemokine induction is totally different from that induced by DPP4 inhibitors, 2-DG-PLGA-NPs also enhance CD8 + T cell infiltration into liver tumors, and not only amplified the anti-tumor effects induced by the anti-PD1 antibody but also suppressed anti-PD1-resistant tumors [ 54 ].…”

Drug delivery systems as immunomodulators for therapy of infectious disease: Relevance to COVID-19

“…The therapeutic utility of 2-DG is low due to the compound having poor accumulation in targeted organs and a short half-life as it is rapidly metabolised. However, nanoformulations of 2-DG exist [203] , [204] , [205] and may be considered as therapeutic in COVID-19 due to the improved biodistribution of 2-DG. In addition, authors [176] showed that inhibiting HIF-1α via BAY87-2243 also reduced replication of SARS-CoV-2.…”