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- Title
A novel PH1/pE27HGFK1 nanoparticles for orthotopic glioblastoma therapy.
- Authors
zhang, Jian; Li, Tao; Liu, Ling; Chen, Zhenpu; Li, Li; Yao, Xiaoxuan; Cheng, Jiaxing; Hu, Xiaoyuan; Guo, Jiyin; Li, Ruilei; Ge, Chunlei; Ling, Eng-Ang; Yao, Hong
- 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.
- Subjects
CATIONIC polymers; HEPATOCYTE growth factor; RECOMBINANT proteins; CHIMERIC proteins; GLIOBLASTOMA multiforme; ESCHERICHIA coli; NANOMEDICINE; REPORTER genes
- Publication
Cancer Nanotechnology (1868-6958), 2024, Vol 15, Issue 1, p1
- ISSN
1868-6958
- Publication type
Article
- DOI
10.1186/s12645-024-00267-1