Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.
In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.
As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.
But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.
“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”
The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.
After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.
Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.
Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.
Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.
According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.
“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.
Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.
“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.
PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.
“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.
The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.
