Ceramide-Graphene Oxide Nanoparticles Enhance Cytotoxicity and Decrease HCC Xenograft Development: A Novel Approach...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Hepatocellular carcinoma (HCC) treatment faces challenges with drug effectiveness and specificity.
• C6-ceramide shows anti-cancer potential but is limited by poor water-solubility.
• Novel drug delivery systems are needed to improve ceramide's therapeutic application in HCC.

Purpose of the Study:

• To develop and evaluate a novel nano-drug delivery system (NGO-PEG-PEI/Cer) for HCC treatment.
• To assess the in vitro and in vivo antitumor efficacy of NGO-PEG-PEI/Cer, alone and in combination with sorafenib.
• To investigate the mechanisms underlying NGO-PEG-PEI/Cer's effects on HCC cells, including drug resistance.

Main Methods:

• Synthesis of polyethylene glycol (PEG) and polyethylenimine (PEI) co-conjugated ultra-small nano-graphene oxide (NGO-PEG-PEI) loaded with C6-ceramide.
• In vitro assessment of cellular uptake and mechanism (clathrin-mediated endocytosis).
• In vitro and in vivo evaluation of antitumor efficacy and synergistic effects with sorafenib in HCC models, including drug-resistant xenografts.

Main Results:

• NGO-PEG-PEI significantly enhanced C6-ceramide cellular uptake via clathrin-mediated endocytosis.
• The combination of NGO-PEG-PEI/Cer and sorafenib demonstrated synergistic antitumor effects.
• NGO-PEG-PEI/Cer potentially overcomes multidrug resistance (MDR) by inactivating MDR and Akt signaling pathways.
• Significant tumor growth inhibition and improved survival rates were observed in vivo, including in drug-resistant models.

Conclusions:

• NGO-PEG-PEI serves as an effective nano-platform for delivering C6-ceramide in HCC treatment.
• The developed nanocomposite exhibits potent cancer cell-killing capabilities.
• The combination therapy of NGO-PEG-PEI/Cer and sorafenib presents a promising strategy for treating drug-resistant HCC.