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

36 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

ASJC Scopus subject areas

Hepatology

UN SDGs

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

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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 = "Funding Information: Received February 7, 2017; accepted September 1, 2017. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29513/suppinfo. Supported by Ministry of Science and Technology (MOST; 104-2628-B-007-001-MY3, 105-2628-E-007-007-MY3), by Chang Gung Memorial Hospital-National Tsing Hua University Joint Research Grant (104N2744E1), by Chang Gung Memorial Hospital (CMRPG3E1281~2, CORPG3F0141~2, CMRPG3F0181) and by the National Institute for Health Research (NHRI-EX106-10609BC). *These authors contributed equally to this work. Copyright VC 2017 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29513 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 = "John Wiley and Sons Ltd",

number = "3",

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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

N1 - Funding Information: Received February 7, 2017; accepted September 1, 2017. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29513/suppinfo. Supported by Ministry of Science and Technology (MOST; 104-2628-B-007-001-MY3, 105-2628-E-007-007-MY3), by Chang Gung Memorial Hospital-National Tsing Hua University Joint Research Grant (104N2744E1), by Chang Gung Memorial Hospital (CMRPG3E1281~2, CORPG3F0141~2, CMRPG3F0181) and by the National Institute for Health Research (NHRI-EX106-10609BC). *These authors contributed equally to this work. Copyright VC 2017 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29513 Publisher Copyright: © 2017 by the American Association for the Study of Liver Diseases.

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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DO - 10.1002/hep.29513

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SN - 0270-9139

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JO - Hepatology

JF - Hepatology

IS - 3

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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