Novel polyethyleneimine-R8-heparin nanogel for high-efficiency gene delivery in vitro and in vivo

Linjiang Song,Xiuqi Liang,Suleixin Yang,Ning Wang,Tao He,Yan Wang,Lan Zhang,Qinjie Wu,Changyang Gong

doi:10.1080/10717544.2017.1417512

Abstract

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.

Highlights

Increasing attention has been focused on gene therapy, because it provides a promising approach to treat many diseases including cancers by delivering genetic drugs into target cells and tissues (Yang et al, 2007; Wang et al, 2012)
Reacting the carboxylic groups of heparin which activated by EDCI/NHS system with amine groups of PEI-R8 to form a HPR nanogel
Compared with the PEI, new signals at 1.5 ppm, 2.8 ppm and 4.2 ppm were observed in the spectrum of PEIR8, which correspond to the R8 peptide

Summary

Introduction

Increasing attention has been focused on gene therapy, because it provides a promising approach to treat many diseases including cancers by delivering genetic drugs into target cells and tissues (Yang et al, 2007; Wang et al, 2012). A suitable gene delivery system that could protect nucleic acid from degradation and selectively deliver them into target cells is needed. Nonviral vectors have attracted more attention in gene therapy. Nonviral vectors, such as cationic polymers, dendrimers, lipids and peptides, are characterized by low immunogenicity and facile fabrication and used as promising gene delivery system (Elsabahy et al, 2011; Yin et al, 2014; Jeong et al, 2016)

Methods

Results

Conclusion