The formimidoyltransferase cyclodeaminase (FTCD) gene encodes an enzyme required for the catabolism of histidine and tetrahydrofolate (THF). Previous studies showed that FTCD plays a role as a tumour suppressor gene in hepatocellular carcinoma (HCC). It is unknown whether the restoration of functional FTCD may exhibit an anti-tumour effect on HCC. This study constructed a delivery system based on hollow mesoporous organosilica nanotheranostics (HMON) capable of efficiently loading Mn ions and FTCD plasmids. This study showed that the Mn-doped and FTCD-loaded nanoparticles (HMON@Mn-PEI@FTCD) could efficiently induce the expression of FTCD and achieve enhanced magnetic resonance imaging. In vitro results demonstrated that the upregulation of FTCD induced by HMON@Mn-PEI@FTCD nanoparticles dramatically reduced intracellular THF levels, inhibited of NADPH/NADP+ and GSH/GSSG ratios, and induced reactive oxygen species generation and mitochondrial oxidative stress. As a result, cytochrome c release increased with the opening of the mitochondrial permeability transition pore, which finally activated the caspase-dependent cell apoptosis pathway. Therefore, our designed HMON@Mn-PEI@FTCD could induce apoptosis by activating the mitochondria-mediated apoptosis signalling pathway, and finally significantly suppressed the proliferation of HCC both in vitro and in vivo, which provides an effective strategy for the treatment of HCC.
Keywords: FTCD plasmid; Hepatocellular carcinoma (HCC); Hollow mesoporous organosilica nanoparticles (HMON); Mitochondrial damage; tetrahydrofolate (THF).
Copyright © 2021 Elsevier B.V. All rights reserved.