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Published on: July 31, 2015
A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with
Chun-Hung Liu1, Guann-Jen Chern1, Fu-Fei Hsu2
1Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
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).
Insights
Researchers developed targeted nanoparticles to deliver therapeutic DNA for liver cancer, overcoming treatment resistance and reducing liver fibrosis. This novel approach shows promise for effective clinical applications in hepatocellular carcinoma therapy.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Nanotechnology
Background:
- TNF-related apoptosis-inducing ligand (TRAIL)-based therapies face challenges including toxicity, poor bioavailability, and resistance.
- Hepatocellular carcinoma (HCC) requires innovative treatment strategies to improve efficacy and overcome resistance mechanisms.
Purpose of the Study:
- To develop and evaluate a tumor-targeted lipid/calcium/phosphate/protamine (LCPP) nanoparticle (NP) system for delivering TRAIL plasmid DNA (pDNA) to HCC cells.
- To investigate the potential of this LCPP-NP system to overcome TRAIL resistance and reduce liver fibrosis in a mouse model of HCC.
Main Methods:
- Encapsulation of TRAIL pDNA within a pH-responsive calcium phosphate (CaP) core within LCPP NPs.
- Utilizing protamine for enhanced nuclear delivery of pDNA.
- Assessing the therapeutic effects of LCPP-NP delivered TRAIL pDNA, alone and in combination with sorafenib, on HCC progression and liver fibrosis in a mouse model.
Main Results:
- The LCPP NPs successfully delivered TRAIL pDNA into HCC cells, with intracellular Ca2+ release up-regulating DR5 and overcoming TRAIL resistance.
- TRAIL expression attenuated liver fibrosis by modulating activated hepatic stellate cells (HSCs).
- Combination therapy with LCPP-NP delivered TRAIL pDNA and sorafenib effectively attenuated HCC progression and liver fibrosis.
Conclusions:
- The developed HCC-targeted LCPP NPs offer an effective platform for TRAIL-based cancer therapy.
- This novel approach demonstrates potential for clinical application in treating hepatocellular carcinoma and associated liver fibrosis.
