Gene therapy is an efficient and promising approach to treat malignant tumors. However, protecting the nucleic acid from degradation in vivo and efficient delivering it into tumor cells remain challenges that require to be addressed before gene therapy could be applied in clinic. In this study, we prepared novel polyethyleneimine-RRRRRRRR(R8)-heparin (HPR) nanogel as an efficient gene delivery system, which consists of heparin and cell penetrating peptide R8 grafted low-molecule-weight polyethyleneimine (PEI). Due to the shielding effect of heparin, crosslinking PEI-R8 with heparin was designed to diminish the toxicity of the gene delivery system. Meanwhile, a partial of R8 peptide which located on the surface of HPR nanogel could significantly enhance the cellular uptake. The formed HPR/pDNA complex exhibited effective endolysosomal escape, resulting in a high-efficiency transfection. Furthermore, the HPR could deliver the plasmid which could transcribe human TNF-related apoptosis inducing ligand (phTRAIL), into HCT-116 cells and induce significant cell apoptosis. In addition, HPR/phTRAIL complex showed satisfactory antitumor activity in abdominal metastatic colon carcinoma model. Finally, the antitumor mechanism of HPR/phTRAIL was also explored by western blot and histological analysis. The above results suggested that the HPR nanogel could serve as a promising gene delivery system.

中文翻译：

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新型聚乙烯亚胺-R8-肝素纳米凝胶，可在体内外高效传递基因。

基因治疗是治疗恶性肿瘤的有效方法。然而，保护核酸免于体内降解并有效地将其递送至肿瘤细胞仍然是在将基因疗法应用于临床之前需要解决的挑战。在这项研究中，我们准备了一种新型的聚乙烯亚胺-RRRRRRRR（R8）-肝素（HPR）纳米凝胶作为一种有效的基因传递系统，该系统由肝素和细胞穿透肽R8接枝的低分子量聚乙烯亚胺（PEI）组成。由于肝素的屏蔽作用，设计PEI-R8与肝素交联可减少基因传递系统的毒性。同时，位于HPR纳米凝胶表面的部分R8肽可以显着增强细胞摄取。形成的HPR / pDNA复合物表现出有效的溶酶体逃逸，导致高效转染。此外，HPR可以将可转录人类TNF相关凋亡诱导配体（phTRAIL）的质粒传递到HCT-116细胞中，并诱导明显的细胞凋亡。此外，HPR / phTRAIL复合物在腹部转移性结肠癌模型中显示出令人满意的抗肿瘤活性。最后，还通过蛋白质印迹和组织学分析探讨了HPR / phTRAIL的抗肿瘤机制。以上结果表明，HPR纳米凝胶可以作为有前途的基因传递系统。HPR / phTRAIL复合物在腹部转移性结肠癌模型中显示出令人满意的抗肿瘤活性。最后，还通过蛋白质印迹和组织学分析探讨了HPR / phTRAIL的抗肿瘤机制。以上结果表明，HPR纳米凝胶可以作为有前途的基因传递系统。HPR / phTRAIL复合物在腹部转移性结肠癌模型中显示出令人满意的抗肿瘤活性。最后，还通过蛋白质印迹和组织学分析探讨了HPR / phTRAIL的抗肿瘤机制。以上结果表明，HPR纳米凝胶可以作为有前途的基因传递系统。