A novel PH1/pE27HGFK1 nanoparticles for orthotopic glioblastoma therapy

Abstract

Abstract Background The therapeutic resistance to ionizing radiation (IR) and angiogenesis inhibitors is a great challenge for clinicians in the treatment of glioblastoma, which is associated with Hepatocyte growth factor (HGF)/MET, VEGF/VEGFR signaling pathway, and the crosstalk between them. In this study, we developed a novel recombinant fusion protein, rE27HGFK1, via HGFK1 tandem with 27 N-terminal residues of Endostatin (E27) and produced a polymeric nanoparticle formed by the co-polymer of PEGylated H1 cationic polymer (PH1) with a plasmid encoding the secreted rE27HGFK1 protein (PH1/pE27HGFK1). We further investigated the anti-tumor effects of rE27HGFK1 and PH1/pE27HGFK1 nanoparticles both in vivo and in vitro. Methods We expressed and purified the rE27HGFK1 protein via E. coli. Then, we performed cellular experiments to determine the antitumoral effects and IR radio-sensitivities of the rE27HGFK1 protein in vitro. Finally, we performed animal studies to determine the tumor-targeted abilities and antitumoral activities of the polymeric nanoparticles, PH1/pE27HGFK1, in an orthotopic U118-Luc-bearing xenografted mouse model. Results We showed that rE27HGFK1 inhibited the proliferation and the angiogenesis and enhanced the senescence and radiosensitivity of GBM via both MET and VEFGR2 signaling mediated-p16 over-expression and the down-regulation of cyclin D1-CDK4-Rb axis activities in vitro. Next, we displayed that systemic administration of the PEGylated H1 cationic polymer (PH1) effectively delivered the reporter genes to the brain tumor of an orthotopic U118-bearing xenografted mouse model. Finally, we showed that PH1/pE27HGFK1 significantly produced antitumor effects with radiosensitivity in the orthotopic U118-Luc-bearing xenografted Blab/c mouse model through inhibiting angiogenesis and tumor cell proliferation, as well as inducing the necrosis of tumor cells in vivo. Conclusions The PH1/pE27HGFK1 nano-drug combined with radiotherapy can be used as a potentially effective therapeutic strategy for Glioblastoma multiforme.

Keywords

• Glioblastoma
• Angiogenesis
• Radiosensitivity
• Blood–brain barrier permeability
• Cationic polymer
• Gene delivery