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Background <p>Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, largely due to multidrug resistance (MDR). Pioglitazone (PIO) and simvastatin (STAT), originally used for metabolic disorders, also modulate oncogenic pathways. This study evaluated a nanotechnology-based co-delivery approach to improve their therapeutic efficacy against chemoresistant HCC.</p> Methods and results <p>Lipid nanoparticles (LNPs) encapsulating PIO and STAT (PSLNPs) were fabricated and functionalized with chitosan (CPSLNPs) or folate-conjugated chitosan (FCPSLNPs). Physicochemical properties (size, zeta potential, polydispersity) were characterized. Hemolysis and MTT assays assessed safety and cytotoxicity in HepG2 cells. qPCR quantified IL-1β, IL-6, BCL2, and BAX expression. Molecular docking examined drug interactions with key proteins involved in proliferation, ferroptosis, inflammation, and MDR. All formulations exhibited nanoscale size and uniform dispersion. Chitosan modification increased zeta potential, and stability studies confirmed consistent physicochemical properties. Hemolysis assays demonstrated biocompatibility. Compared with free drugs, PSLNPs and their functionalized forms significantly enhanced cytotoxicity in HepG2 cells. Gene expression analysis showed downregulation of IL-1β, IL-6, and BCL2, with upregulation of BAX, indicating enhanced apoptosis. Docking studies revealed STAT strongly interacted with SDH, GST, HDAC1, and JNK3, while PIO showed higher affinity for COX-2, GPX4, HO-1, and MMP-9, supporting complementary multi-target effects.</p> Conclusion <p>Functionalized PSLNPs improved the delivery and efficacy of PIO and STAT, overcoming MDR by modulating multiple oncogenic pathways. These results highlight their promise as a multi-targeted nanotherapeutic strategy for HCC treatment.</p>

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Folate- and chitosan-functionalized lipid nanoparticles for co-delivery of pioglitazone and simvastatin to enhance hepatic cancer therapy: effects on IL-1β, IL-6, BCL2/BAX gene expression, and GPX4, COX-2, and MMP-9 activities

  • 期刊论文

  • 发表日期：

    2025年9月19日

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  • Riyadh F. Alzahrani,
  • Muteb S. Almuqati,
  • Sultan A. AlAli,
  • Khalid A. Alamer,
  • Sayed Rabbani,
  • Mohammed S. Alqahtani,
  • Ahmed H. Bakheit,
  • Hanadi H. Asiri,
  • Gamaleldin I. Harisa

摘要

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, largely due to multidrug resistance (MDR). Pioglitazone (PIO) and simvastatin (STAT), originally used for metabolic disorders, also modulate oncogenic pathways. This study evaluated a nanotechnology-based co-delivery approach to improve their therapeutic efficacy against chemoresistant HCC.

Methods and results

Lipid nanoparticles (LNPs) encapsulating PIO and STAT (PSLNPs) were fabricated and functionalized with chitosan (CPSLNPs) or folate-conjugated chitosan (FCPSLNPs). Physicochemical properties (size, zeta potential, polydispersity) were characterized. Hemolysis and MTT assays assessed safety and cytotoxicity in HepG2 cells. qPCR quantified IL-1β, IL-6, BCL2, and BAX expression. Molecular docking examined drug interactions with key proteins involved in proliferation, ferroptosis, inflammation, and MDR. All formulations exhibited nanoscale size and uniform dispersion. Chitosan modification increased zeta potential, and stability studies confirmed consistent physicochemical properties. Hemolysis assays demonstrated biocompatibility. Compared with free drugs, PSLNPs and their functionalized forms significantly enhanced cytotoxicity in HepG2 cells. Gene expression analysis showed downregulation of IL-1β, IL-6, and BCL2, with upregulation of BAX, indicating enhanced apoptosis. Docking studies revealed STAT strongly interacted with SDH, GST, HDAC1, and JNK3, while PIO showed higher affinity for COX-2, GPX4, HO-1, and MMP-9, supporting complementary multi-target effects.

Conclusion

Functionalized PSLNPs improved the delivery and efficacy of PIO and STAT, overcoming MDR by modulating multiple oncogenic pathways. These results highlight their promise as a multi-targeted nanotherapeutic strategy for HCC treatment.