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)

中文翻译：

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一种多功能纳米载体，用于有效的基于 TRAIL 的基因治疗对抗结缔组织增生的肝细胞癌

由于全身毒性、生物利用度差和 TRAIL 耐药性的发展，基于 TNF 相关凋亡诱导配体 (TRAIL) 的疗法的抗癌功效有限。我们开发了一种靶向肿瘤的 LCPP（脂质/钙/磷酸盐/鱼精蛋白）纳米颗粒 (NP)，以将 TRAIL 质粒 DNA (pDNA) 递送到 HCC 小鼠模型中的肝细胞癌 (HCC) 细胞中。TRAIL pDNA 被封装在 pH 刺激响应性磷酸钙 (CaP) 核心中，并添加鱼精蛋白以促进 pDNA 的核传递。此外，CaP 核心的 Ca2+ 细胞内释放通过钙流入依赖性 DR5 上调克服了 TRAIL 抗性。TRAIL 表达还通过将活化的肝星状细胞 (HSC) 恢复到静止状态或通过直接诱导活化的 HSC 细胞凋亡来减轻 HCC 周围肝组织中的纤维化。结论：由靶向 HCC 的 LCPP NPs 递送的 TRAIL pDNA 结合常规索拉非尼治疗可减缓 HCC 进展以及肝纤维化。总的来说，我们的研究提出了一种有效的基于 TRAIL 的癌症疗法，可以开发用于临床应用。（肝病学 2018 年；67：899-913）