Trimethyl chitosan–cysteine-based nanoparticles as an effective delivery system for portulacerebroside A in the management of hepatocellular carcinoma cells in vitro and in vivo

Abstract

Portulacerebroside A (PCA), a cerebroside compound extracted from Portulaca oleracea L., has been shown to suppress hepatocellular carcinoma (HCC) cells. This study aims to investigate the effectiveness of trimethyl chitosan–cysteine (TMC-Cys) nanocarrier in delivering PCA for HCC management and to elucidate the molecular mechanisms behind PCA’s function. TMC-Cys nanocarriers notably augmented PCA’s function, diminishing the proliferation, migration, and invasiveness of HCC cells in vitro, reducing hepatocellular tumorigenesis in immunocompetent mice, and impeding metastasis of xenograft tumours in nude mice. Comprehensive bioinformatics analyses, incorporating Super-PRED systems alongside pathway enrichment analysis, pinpointed toll-like receptor 4 (TLR4) and epidermal growth factor receptor (EGFR) as two promising targets of PCA, enriched in immune checkpoint pathway. PCA/nanocarrier (PCA) reduced levels of TLR4 and EGFR and their downstream proteins, including programmed cell death ligand 1, thereby increasing populations and activity of T cells co-cultured with HCC cells in vitro or in primary HCC tumours in mice. However, these effects were counteracted by additional artificial activation of TLR4 and EGFR. In conclusion, this study provides novel evidence of PCA’s function in immunomodulation in addition to its direct tumour suppressive effect. TMC-Cys nanocarriers significantly enhance PCA efficacy, indicating promising application as a drug delivery system.

Keywords:

• Portulacerebroside A
• TMC-Cys nanocarrier
• TLR4
• EGFR
• T cell activity
• hepatocellular carcinoma

Authors’ contributions

RZ contributed to study design and revised the entire work. RZ and YHH conducted experiments. CCQ directed experimental methods and techniques. XP analysed the data and wrote the manuscript. ZPH, DL and YYW contributed to language modification and editing. All authors have read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The analysed data sets generated during the present study are available from the corresponding author on reasonable request.

Additional information

Funding

Financial support was provided by the Key R&D in Hainan Province [No. ZDYF2022SHFZ118], Hainan Province ‘Nanhai Xinxing’ Medical and Health Talent Platform Project and Research Fund of Hainan Cancer Hospital [No. 2023ZD05].