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

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).

• Authors: 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
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 67 Issue 3 Pg. 899-913 (03 2018) ISSN: 1527-3350 [Electronic] United States
• PMID: 28885731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the American Association for the Study of Liver Diseases.

Chemical References

• TNF-Related Apoptosis-Inducing Ligand

Topics

• Animals
• Apoptosis
• Carcinoma, Hepatocellular (pathology, therapy)
• Cell Line, Tumor
• Disease Models, Animal
• Genetic Therapy (methods)
• Liver Neoplasms (pathology, therapy)
• Male
• Mice
• Molecular Targeted Therapy (methods)
• Nanoparticles (administration & dosage)
• TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)