Therapeutic potential of miRNA-26a-encapsulated nanoparticles against hepatocellular carcinoma in a murine model

Abstract

Background and aims: Hepatocellular carcinoma (HCC) treatment options are limited due to the lack of effective curative therapies, and conventional chemotherapy has often demonstrated limited effectiveness and may be associated with significant toxicity. Therefore, innovative therapeutics for HCC are urgently needed. Here, we aimed to evaluate the effectiveness of microRNA (miRNA)-26a-encapsulated nanoparticles in HCC treatment.

Methods: Span-Oleylamine-chondroitin sulfate were prepared and eighty male BALB/c mice were divided into four groups: (i) negative control group (saline injection), (ii) HCC group (intraperitoneal injection of diethylnitrosamine (DEN), at 50 mg/kg/week for 18 weeks), (iii) miRNA-26a-treated HCC group (intrahepatical injection of 100 nmol free miRNA-26a once weekly for four weeks), and (iv) miRNA-26a-loaded nanoparticles-treated HCC group (intrahepatic injection of miRNA-26a-loaded nanoparticles once weekly for 4 weeks, starting from Week 14 of DEN induction). Then, all mice were subjected to biochemical, genetic, histopathological, and immunohistochemical examinations.

Results: The HCC group showed elevated serum levels of alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha), along with upregulated hepatic expression of P70S6K, transforming growth factor-beta, DNA methyltransferase 3 beta (DNMT3b), and Caspase-3 genes, as well as HepPar 1, Ki67, cyclin D1, and arginase 1 proteins (all P < 0.001). miRNA-26a treatment attenuated these changes; moreover, the miRNA-26a-encapsulated nanoparticles caused a more dramatic decrease of these markers, resulting in almost complete restoration of the normal hepatic architecture.

Conclusions: Administration of miRNA-26a-encapsulated nanoparticles induced nearly total regression of HCC, suppression of cancer cell growth and angiogenesis, and induction of tumor necrosis. This study demonstrates the therapeutic efficacy of restoring the imbalanced expression of miRNA in the liver. Therefore, the clinical translation of this miRNA-based strategy warrants further investigation.

Keywords

Hepatocellular carcinoma (HCC) / microRNA-26a / Nanoparticles / Diethylnitrosamine / Animal model

Authors’ contributions

Marwa Hassan: Writing - review & editing, Writing - original draft, Visualization, Methodology, Formal analysis, Data curation, Conceptualization. Inés Fernández-Piñeiro: Writing - review & editing, Writing - original draft, Visualization, Methodology, Formal analysis, Data curation, Conceptualization. Iker Badiola: Writing - review & editing, Writing - original draft, Supervision, Methodology, Funding acquisition, Formal analysis, Data curation, Conceptualization. Mohamed Elzallat: Writing - review & editing, Writing - original draft, Visualization, Methodology, Formal anal-ysis, Data curation, Conceptualization. Alejandro Sánchez: Writing - review & editing, Supervision, Methodology, Formal analysis, Data curation, Conceptualization. Tarek Aboushousha: Writing - review & editing, Writing - original draft, Visualization, Methodology, Formal analysis, Data curation, Conceptualization. Ehab Hafiz: Visualization, Methodology, Data curation. Eman El-Ahwany: Writing - review & editing, Writing - original draft, Su-pervision, Project administration, Methodology, Funding acquisi-tion, Formal analysis, Data curation, Conceptualization.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was funded in part by the Science and Technology Development Fund (STDF) project No: 25901, Egypt and Faculty of Medicine and Nursery, University of Basque Country, UPV/EHU, Leioa, Spain.

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