Chun-Hung Liu1, Guann-Jen Chern1, Fu-Fei Hsu2, Kuan-Wei Huang1, Yun-Chieh Sung1, Hsi-Chien Huang1, Jiantai Timothy Qiu3,4,5, Sheng-Kai Wang6, Chu-Chi Lin5, Chien-Hsun Wu7, Han-Chung Wu7, Jia-Yu Liu1, Yunching Chen1. 1. Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan. 2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. 3. School of Medicine, Chang Gung University, Taoyuan, Taiwan. 4. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 5. Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan. 6. Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan. 7. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, 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).
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: Cheng Yu; Long Li; Pei Hu; Yan Yang; Wei Wei; Xin Deng; Lu Wang; Franklin R Tay; Jingzhi Ma Journal: Adv Sci (Weinh) Date: 2021-05-16 Impact factor: 16.806