Immunometric and functional measurement of endogenous vasoinhibin in human sera

VIAN-c4551 is a cyclic antiangiogenic peptide that stands as a potent and stable inhibitor of vascular endothelial cell growth factor (VEGF), the major vasopermeability and angiogenic factor in diabetic macular edema and diabetic retinopathy. Intravitreal injections of inhibitors of VEGF are a first-line therapy, but the invasiveness, risk, and low adherence of frequent intravitreal injections interfere with the needed long-term treatments and successful outcomes. Eye drops are non-invasive and favor compliance. Here, we evaluated the preclinical efficacy, permeability, and ocular pharmacokinetics of VIAN-c4551 delivered in eye drops. VIAN-c4551 demonstrated high potency (IC50= 137 pM) to inhibit the permeability of human umbilical vein endothelial cell monolayers induced by VEGF. VIAN-c4551 eye drops potently (0.005% minimum effective dose) prevented the retinal vascular leakage induced by VEGF injected intravitreally for up to 24 hours and reversed the increase in retinal vascular permeability due to streptozotocin-induced diabetes in rats and mice. VIAN-c4551 exhibited high permeability across MDCK epithelium and, after a single topical ocular instillation in rabbits, reached the retina-choroid in micromolar concentrations several orders of magnitude above its IC50(Cmax= 51 µM at 6 hours) that lasted at least 24 hours. In conclusion, VIAN-c4551 eye drops reach the back of the eye at therapeutic concentrations, providing a potential, once-a-day, non-invasive intervention for preventing and reversing retinal vascular leakage in diabetic macular edema, diabetic retinopathy, and other vascular retinopathies and preserving sight.

show abstract

The antiangiogenic peptide VIAN-c4551 inhibits lung melanoma metastasis in mice by reducing pulmonary vascular permeability

Perez,

Zamora,

Bahena

et al. 2024

Preprint

View full text Add to dashboard Cite

Introduction: Cancer cells drive the increase in vascular permeability mediating tumor cell extravasation and metastatic seeding. VIAN-c4551, an antiangiogenic peptide analog of vasoinhibin, inhibits the growth and vascularization of melanoma tumors in mice. Because VIAN-c4551 is a potent inhibitor of vascular permeability, we evaluated whether its antitumor action extended to a reduction in metastasis generation. Methods: Circulating levels of vascular endothelial growth factor (VEGF), lung vascular permeability, melanoma cell extravasation, and melanoma pulmonary nodules were assessed in C57BL/6J mice intravenously inoculated with murine melanoma B16-F10 cells after acute treatment with VIAN-c4551. VEGF levels, transendothelial electrical resistance, and transendothelial migration in cocultures of B16-F10 cells and endothelial cell monolayers supported the findings. Results: B16-F10 cells increased circulating VEGF levels and elevated lung vascular permeability 2 hours after inoculation. VIAN-c4551 prevented enhanced vascular permeability and reduced melanoma cell extravasation after 2 hours and the number and size of macroscopic and microscopic melanoma tumors in lungs after 17 days. In vitro, VIAN-c4551 suppressed the B16-F10 cell-induced and VEGF mediated increase in endothelial cell monolayer permeability and the transendothelial migration of B16-F10 cells. Conclusions: These findings support the inhibition of distant vascular permeability for the prevention of tumor metastasis and unveil the anti-vascular permeability factor VIAN-c4551 as a potential therapeutic drug able to prevent metastasis generation by lowering the extravasation of melanoma cells.

show abstract

Immunometric and functional measurement of endogenous vasoinhibin in human sera

Cited by 3 publications

References 50 publications

Cathepsin-D and outcomes in peripartum cardiomyopathy: Results from IPAC

Cathepsin-D and outcomes in peripartum cardiomyopathy: Results from IPAC

Topical Ophthalmic Administration of VIAN-c4551 Antiangiogenic Peptide for Diabetic Macular Edema: Preclinical Efficacy and Ocular Pharmacokinetics

The antiangiogenic peptide VIAN-c4551 inhibits lung melanoma metastasis in mice by reducing pulmonary vascular permeability

Contact Info

Product

Resources

About