用于将吡格列酮和辛伐他汀共递送以增强肝癌治疗的叶酸和壳聚糖功能化脂质纳米颗粒：对白细胞介素-1β、白细胞介素-6、BCL2/BAX基因表达以及谷胱甘肽过氧化物酶4、环氧合酶-2和基质金属蛋白酶-9活性的影响

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.

作者信息

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

机构信息

Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.

出版信息

Mol Biol Rep. 2025 Sep 19;52(1):926. doi: 10.1007/s11033-025-11011-2.

DOI:10.1007/s11033-025-11011-2

PMID:40971053

Abstract

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.

摘要

背景

肝细胞癌（HCC）是癌症死亡的主要原因之一，这在很大程度上归因于多药耐药性（MDR）。吡格列酮（PIO）和辛伐他汀（STAT）最初用于治疗代谢紊乱，也可调节致癌途径。本研究评估了一种基于纳米技术的共递送方法，以提高它们对化疗耐药性HCC的治疗效果。

方法与结果

制备了包裹PIO和STAT的脂质纳米颗粒（LNPs），并用壳聚糖（CPSLNPs）或叶酸偶联壳聚糖（FCPSLNPs）进行功能化修饰。对其物理化学性质（尺寸、zeta电位、多分散性）进行了表征。通过溶血和MTT试验评估了其在HepG2细胞中的安全性和细胞毒性。qPCR定量分析了IL-1β、IL-6、BCL2和BAX的表达。分子对接研究了药物与参与增殖、铁死亡、炎症和MDR的关键蛋白之间的相互作用。所有制剂均呈现纳米级尺寸和均匀分散性。壳聚糖修饰提高了zeta电位，稳定性研究证实了其物理化学性质的一致性。溶血试验证明了其生物相容性。与游离药物相比，PSLNPs及其功能化形式显著增强了对HepG2细胞的细胞毒性。基因表达分析显示IL-1β、IL-6和BCL2下调，BAX上调，表明细胞凋亡增强。对接研究表明，STAT与SDH、GST、HDAC1和JNK3强烈相互作用，而PIO对COX-2、GPX4、HO-1和MMP-9具有更高的亲和力，支持互补的多靶点效应。