High Density Display of an Anti-Angiogenic Peptide on Micelle Surfaces Enhances Their Inhibition of αvβ3 Integrin-Mediated Neovascularization In Vitro

Abstract

Diabetic retinopathy (DR), Retinopathy of Pre-maturity (ROP), and Age-related Macular Degeneration (AMD) are multifactorial manifestations associated with abnormal growth of blood vessels in the retina. These three diseases account for 5% of the total blindness and vision impairment in the US alone. The current treatment options involve heavily invasive techniques such as frequent intravitreal administration of anti-VEGF (vascular endothelial growth factor) antibodies, which pose serious risks of endophthalmitis, retinal detachment and a multitude of adverse effects stemming from the diverse physiological processes that involve VEGF. To overcome these limitations, this current study utilizes a micellar delivery vehicle (MC) decorated with an anti-angiogenic peptide (aANGP) that inhibits αvβ3 mediated neovascularization using primary endothelial cells (HUVEC). Stable incorporation of the peptide into the micelles (aANGP-MCs) for high valency surface display was achieved with a lipidated peptide construct. After 24 h of treatment, aANGP-MCs showed significantly higher inhibition of proliferation and migration compared to free from aANGP peptide. A tube formation assay clearly demonstrated a dose-dependent angiogenic inhibitory effect of aANGP-MCs with a maximum inhibition at 4 μg/mL, a 1000-fold lower concentration than that required for free from aANGP to display a biological effect. These results demonstrate valency-dependent enhancement in the therapeutic efficacy of a bioactive peptide following conjugation to nanoparticle surfaces and present a possible treatment alternative to anti-VEGF antibody therapy with decreased side effects and more versatile options for controlled delivery.

Endothelial Cell Adhesion Molecules- (un)Attainable Targets for Nanomedicines

“…Besides cancer therapy, DDS targeting α v β 5 via RGD-peptide have demonstrated therapeutic antiangiogenic efficacy for the treatment of choroidal neovascularization ( 168 ). Recent in vitro results confirm the contribution of a multivalent ligand presentation for the inhibition of angiogenesis, using drug-free antiangiogenic peptide GHSDVHK-decorated micelles ( 165 ).…”

Diabetic eye: associated diseases, drugs in clinic, and role of self-assembled carriers in topical treatment

“…Prevention of abnormal growth of blood vessels in retina can be achieved by means of poly(ethylene glycol)-b-poly (propylene sulfide) micelles decorated with the antiangiogenic peptide aANGP. The aANGP-micelles showed potent angiogenic inhibitory effect at 1000-fold lower concentration than the free peptide in cell cultures [131].…”

The role of integrins in inflammation and angiogenesis

“…Specifically, a humanized anti-α4 antibody (Natalizumab) works to reduction of inflammation in multiple sclerosis by blocking the α 4 β 1 -VCAM interaction or the α 4 β 7 -mucosal addressin cell adhesion molecule interaction on mucosal endothelium, and blocking leukocyte trafficking across the blood-brain barrier (99). In another study, a micellar delivery vehicle decorated with an anti-angiogenic peptide has been shown to inhibit α v β 3 mediated neovascularization in endothelial cells (100). Several anti-cancer drugs have also been developed against integrin ligands or by using integrintargeted encapsulated nanoparticles as vehicles to unload drugs into the vasculature of several tumors (101).…”