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A Novel Blood–Brain Barrier-Penetrating and Vascular-Targeting Chimeric Peptide Inhibits Glioma Angiogenesis.
- Source :
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International Journal of Molecular Sciences . May2023, Vol. 24 Issue 10, p8753. 18p. - Publication Year :
- 2023
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Abstract
- The high vascularization of glioma highlights the potential value of anti-angiogenic therapeutics for glioma treatment. Previously, we designed a novel vascular-targeting and blood–brain barrier (BBB)-penetrating peptide, TAT-AT7, by attaching the cell-penetrating peptide TAT to a vascular-targeting peptide AT7, and we demonstrated that TAT-AT7 could target binding to the vascular endothelial growth factor receptor 2 (VEGFR-2) and Neuropilin-1 (NRP-1), which are both highly expressed in endothelial cells. TAT-AT7 has been proven to be a good targeting peptide which could effectively deliver the secretory endostatin gene to treat glioma via the TAT-AT7-modified polyethyleneimine (PEI) nanocomplex. In the current study, we further explored the molecular binding mechanisms of TAT-AT7 to VEGFR-2 and NRP-1 and its anti-glioma effects. Accordingly, TAT-AT7 was proven to competitively bind to VEGFR-2 and NRP-1 and prevent VEGF-A165 binding to the receptors by the surface plasmon resonance (SPR) assay. TAT-AT7 inhibited endothelial cells' proliferation, migration, invasion, and tubule formation, as well as promoted endothelial cells' apoptosis in vitro. Further research revealed that TAT-AT7 inhibited the phosphorylation of VEGFR-2 and its downstream PLC-γ, ERK1/2, SRC, AKT, and FAK kinases. Additionally, TAT-AT7 significantly inhibited angiogenesis of zebrafish embryo. Moreover, TAT-AT7 had a better penetrating ability and could penetrate the BBB into glioma tissue and target glioma neovascularization in an orthotopic U87-glioma-bearing nude mice model, and exhibited the effect of inhibiting glioma growth and angiogenesis. Taken together, the binding and function mechanisms of TAT-AT7 were firstly revealed, and TAT-AT7 was proven to be an effective and promising peptide for the development of anti-angiogenic drugs for targeted treatment of glioma. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 16616596
- Volume :
- 24
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- International Journal of Molecular Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 163966418
- Full Text :
- https://doi.org/10.3390/ijms24108753