Vascular Endothelial Growth Factor Receptor 1 Targeting Fusion Polypeptides with Stimuli-Responsiveness for Anti-angiogenesis

• Published in: ACS applied materials & interfaces 2023-07, Vol.15 (27), p.32201-32214
• Main Authors: Kang, Min Jeong, Roh, Kug-Hwan, Lee, Jae Sang, Lee, Jae Hee, Park, SaeGwang, Lim, Dong Woo
• Format: Article
• Language: English
• Subjects: Animals; Biological and Medical Applications of Materials and Interfaces; Choroidal Neovascularization; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Mice; Peptides - chemistry; Peptides - pharmacology; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factors
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.3c03989

Genetically engineered fusion polypeptides have been investigated to introduce unique bio-functionality and improve some therapeutic activity for anti-angiogenesis. We report herein that stimuli-responsive, vascular endothelial growth factor receptor 1 (VEGFR1) targeting fusion polypeptides composed of a VEGFR1 (fms-like tyrosine kinase-1 (Flt1)) antagonist, an anti-Flt1 peptide, and a thermally responsive elastin-based polypeptide (EBP) were rationally designed at the genetic level, biosynthesized, and purified by inverse transition cycling to develop potential anti-angiogenic fusion polypeptides to treat neovascular diseases. A series of hydrophilic EBPs with different block lengths were fused with an anti-Flt1 peptide, forming anti-Flt1-EBPs, and the effect of EBP block length on their physicochemical properties was examined. While the anti-Flt1 peptide decreased phase-transition temperatures of anti-Flt1-EBPs, compared with EBP blocks, anti-Flt1-EBPs were soluble under physiological conditions. The anti-Flt1-EBPs dose dependently inhibited the binding of VEGFR1 against vascular endothelial growth factor (VEGF) as well as tube-like network formation of human umbilical vein endothelial cells under VEGF-triggered angiogenesis in vitro because of the specific binding between anti-Flt1-EBPs and VEGFR1. Furthermore, the anti-Flt1-EBPs suppressed laser-induced choroidal neovascularization in a wet age-related macular degeneration mouse model in vivo. Our results indicate that anti-Flt1-EBPs as VEGFR1-targeting fusion polypeptides have great potential for efficacious anti-angiogenesis to treat retinal-, corneal-, and choroidal neovascularization.