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

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.

Thermoresponsive Nanogels Based on Different Polymeric Moieties for Biomedical Applications

“…The two main characteristics of nanogels are their small size (up to 1000 nm) and high swelling ratio or water content [ 46 ]. Due to these properties, nanogels have become an excellent platform in many medical applications, including photo-imaging [ 47 ], tissue regeneration [ 48 ], cancer therapy [ 49 ] and gene delivery [ 50 ]. This is based on their remarkable characteristics, such as their high capacity for drug entrapment and release [ 51 ], tailorable size [ 52 ], tuneable toxicity [ 53 ], high stability, controlled and sustained drug release [ 54 ], precise targeted delivery [ 55 ], and high biodegradability [ 56 ].…”

Polyethylenimine‐Based Nanogels for Biomedical Applications

“…b) Schematic drawing of HPR/phTRAIL NGs formation, in vivo apoptosis evaluation and antitumor effect. Reproduced under the terms of the Creative Commons License 4.0 . Copyright 2018, The Authors.…”

“…For targeted gene delivery application, PEI can be modified with targeting ligands before the preparation of NGs. Recently, Song et al developed an efficient gene delivery system based on PEI‐RRRRRRRR(R8)‐heparin (HPR) NGs, which contains heparin and cell peptide R8‐modified low molecular weight PEI . In this case, heparin can shield R8‐grafted PEI to diminish its toxicity, while a partial of R8 peptide modification enabled effective endolysosomal escape and specific cellular uptake for enhanced gene delivery.…”

Nanogel Functionalization: A Versatile Approach To Meet the Challenges of Drug and Gene Delivery

“…56−59 On the other hand, nanogels obtained by linking of polymer precursors are generally made of self-assembling amphiphilic or triblock copolymers or composed of polymers having different types of reactive sites that can be directly used in the formation of covalent bonds. This chemical cross-linking strategy includes a wide range of experimental pathways based on the principles of click chemistry, 60,61 thiol−disulfide exchange, 62−64 Schiff base reaction, 65,66 photo-or thermally induced cross-linking, 67,68 amide bond formation, 69,70 enzymemediated cross-linking, 71,72 catalyzed coupling, 73 and the chemistry of ketones, aldehydes, epoxides, or other groups. 74 Moreover, they can be used for the preparation of core−shell structures or micelles by tuning of the spatial organization of the molecules and the consequent interaction with external biomolecules.…”