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

doi:10.1002/hep.29513

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

Research output: Contribution to journal › Article › peer-review

50 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 language	English
Pages (from-to)	899-913
Number of pages	15
Journal	Hepatology
Volume	67
Issue number	3
DOIs	https://doi.org/10.1002/hep.29513
Publication status	Published - Mar 2018
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Hepatology

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10.1002/hep.29513

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@article{88bae91eb4984796892dfa9d4eea46e5,

title = "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).",

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

note = "Publisher Copyright: {\textcopyright} 2017 by the American Association for the Study of Liver Diseases.",

year = "2018",

month = mar,

doi = "10.1002/hep.29513",

language = "English",

volume = "67",

pages = "899--913",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

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TY - JOUR

T1 - A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice

AU - Liu, Chun Hung

AU - Chern, Guann Jen

AU - Hsu, Fu Fei

AU - Huang, Kuan Wei

AU - Sung, Yun Chieh

AU - Huang, Hsi Chien

AU - Qiu, Jiantai Timothy

AU - Wang, Sheng Kai

AU - Lin, Chu Chi

AU - Wu, Chien Hsun

AU - Wu, Han Chung

AU - Liu, Jia Yu

AU - Chen, Yunching

PY - 2018/3

Y1 - 2018/3

N2 - 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).

AB - 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).

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U2 - 10.1002/hep.29513

DO - 10.1002/hep.29513

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ER -

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

Abstract

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