A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice

Chun Hung Liu, Guann Jen Chern, Fu Fei Hsu, Kuan Wei Huang, Yun Chieh Sung, Hsi Chien Huang, Jiantai Timothy Qiu, Sheng Kai Wang, Chu Chi Lin, Chien Hsun Wu, Han Chung Wu, Jia Yu Liu, Yunching Chen

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16 Citations (Scopus)

Abstract

The anticancer efficacy of TNF-related apoptosis-inducing ligand (TRAIL)-based therapy is limited because of systemic toxicity, poor bioavailability, and development of TRAIL resistance. We developed a tumor-targeted LCPP (lipid/calcium/phosphate/protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells in a mouse model of HCC. TRAIL pDNA was encapsulated in a pH stimuli-responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, intracellular release of Ca2+ from the CaP core overcame TRAIL resistance by calcium influx-dependent DR5 up-regulation. TRAIL expression also attenuated fibrosis in liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. Conclusion: TRAIL pDNA delivered by HCC-targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL-based cancer therapy that could be developed for clinical applications. (Hepatology 2018;67:899–913).

Original languageEnglish
Pages (from-to)899-913
Number of pages15
JournalHepatology
Volume67
Issue number3
DOIs
Publication statusPublished - Mar 2018
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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  • Cite this

    Liu, C. H., Chern, G. J., Hsu, F. F., Huang, K. W., Sung, Y. C., Huang, H. C., Qiu, J. T., Wang, S. K., Lin, C. C., Wu, C. H., Wu, H. C., Liu, J. Y., & Chen, Y. (2018). A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice. Hepatology, 67(3), 899-913. https://doi.org/10.1002/hep.29513