Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland; Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, V6T 1Z3 Vancouver, British Columbia, Canada.
Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
J Control Release. 2021 Jun 10;334:138-152. doi: 10.1016/j.jconrel.2021.04.023. Epub 2021 Apr 22.
Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling the expression of the parvovirus-derived oncotoxic protein NS1 in HCC. This anticancer protein interacts with different cellular kinases mediating a multimodal host-cell death. Lipoplexes (LPX) designed to deliver a DNA expression plasmid encoding NS1 are characterized using a comprehensive set of in vitro assays. The mechanisms of cell death induction are assessed and phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential predictive biomarker for a NS1-LPX-based gene therapy. In an HCC xenograft mouse model, NS1-LPX therapeutic approach results in a significant reduction in tumor growth and extended survival. Data provide convincing evidence for future studies using a targeted NS1 gene therapy for PDK1 overexpressing HCC.
肝细胞癌（HCC）的发病率不断上升，且临床预后较差，这主要是由于缺乏有效的治疗选择和新兴的耐药机制。本研究旨在利用一种非病毒基因疗法，使细小病毒来源的致癌蛋白 NS1 在 HCC 中表达。这种抗癌蛋白与不同的细胞激酶相互作用，介导多种宿主细胞死亡。采用一系列体外检测方法对设计用于递送编码 NS1 的 DNA 表达质粒的脂质体（LPX）进行了表征。评估了细胞死亡诱导的机制，并鉴定出磷酸肌醇依赖性激酶 1（PDK1）是基于 NS1-LPX 的基因治疗的潜在预测性生物标志物。在 HCC 异种移植小鼠模型中，NS1-LPX 治疗方法可显著抑制肿瘤生长并延长生存期。这些数据为未来使用针对 PDK1 过表达 HCC 的靶向 NS1 基因治疗进行研究提供了令人信服的证据。
