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

Area of Science:

• Biotechnology
• Biochemistry
• Ophthalmology

Background:

• Angiogenesis, the formation of new blood vessels, is crucial for development but also drives neovascular diseases.
• Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) plays a key role in regulating angiogenesis.
• Current anti-angiogenic therapies face challenges in specificity and efficacy.

Purpose of the Study:

• To design and synthesize novel stimuli-responsive, VEGFR1-targeting fusion polypeptides for anti-angiogenesis.
• To evaluate the physicochemical properties and anti-angiogenic potential of these fusion polypeptides.
• To assess the in vitro and in vivo efficacy of the fusion polypeptides in preclinical models.

Main Methods:

• Rational design and genetic engineering of fusion polypeptides combining an anti-VEGFR1 peptide with elastin-based polypeptides (EBPs).
• Biosynthesis and purification using inverse transition cycling.
• In vitro assays assessing VEGFR1 binding, VEGF-induced angiogenesis, and endothelial cell network formation.
• In vivo studies using a laser-induced choroidal neovascularization mouse model.

Main Results:

• Fusion polypeptides (anti-Flt1-EBPs) were successfully synthesized and exhibited solubility under physiological conditions.
• Anti-Flt1-EBPs dose-dependently inhibited VEGFR1 binding to VEGF and endothelial cell tube formation in vitro.
• The fusion polypeptides demonstrated significant suppression of choroidal neovascularization in a mouse model of wet age-related macular degeneration.

Conclusions:

• Stimuli-responsive, VEGFR1-targeting fusion polypeptides are effective anti-angiogenic agents.
• These fusion polypeptides hold significant potential for treating various neovascular diseases, including retinal, corneal, and choroidal neovascularization.