Intravitreal Delivery of VEGF-A₁₆₅-loaded PLGA Microparticles Reduces Retinal Vaso-Obliteration in anIn VivoMouse Model of Retinopathy of Prematurity

Abstract

Purpose: Retinopathy of prematurity (ROP) is a condition of abnormal retinal vascularization with reduced levels of vascular endothelial growth factor (VEGF) causing vaso-obliteration (Phase I), followed by abnormal neovascularization from increased VEGF (Phase II). We hypothesized that intravitreal proangiogenic VEGF-A in microparticle form would promote earlier retinal revascularization in an oxygeninduced ischemic retinopathy (OIR) mouse model. Materials and Methods: Wildtype mice (39) were exposed to 77% oxygen from postnatal day 7 (P7) to P12. VEGF-A 165-loaded poly(lactic-co-glycolic acid) (PLGA) (n = 15) or empty PLGA (n = 14) microparticles were fabricated using a water-in-oil-in-water double emulsion method, and injected intravitreally at P13 into mice right eyes (RE). Left eyes (LE) were untreated. At P20, after retinal fluorescein angiography, vascular parameters were quantified. Retinal VEGF levels at P13 and flatmounts at P20 were performed separately. Results: VEGF-A 165-loaded microparticles had a mean diameter of 4.2 μm. with a loading level of 8.6 weight.%. Retinal avascular area was reduced in VEGF-treated RE (39.5 ± 9.0%) compared to untreated LE (52.6 ± 6.1%, p < 0.0001) or empty microparticle-treated RE (p < 0.001) and untreated LEs (p = 0.001). Retinal arteries in VEGF-treated RE were less tortuous than untreated LE (1.08 ± 0.05 vs. 1.18 ± 0.08, p < 0.001) or empty-microparticles-treated RE (p = 0.02). Retinal arterial tortuosity was similar in the LE of VEGF and empty microparticle-treated mice (P > 0.05). Retinal vein width was similar in VEGF-treated and empty microparticle-treated RE (P > 0.9), which were each less dilated than their contralateral LE (p < 0.01). VEGF levels were higher in P13 OIR mice than RA mice (p < 0.0001). Retinal flatmounts showed vaso-obliteration and neovascularization. Conclusions: Endogenous retinal VEGF is suppressed in OIR mice. Exogenous intravitreal VEGF-A 165loaded microparticles in OIR mice reduced retinal vaso-obliteration and accelerated recovery from vein dilation and arterial tortuosity. This may be beneficial in preventing Phase II ROP without systemic effects.

Optimal Efficacy and Safety of Humanized Anti-Scg3 Antibody to Alleviate Oxygen-Induced Retinopathy

“…Anti-VEGF drugs have been extensively investigated in various animal models of ROP and were reported to increase, decrease, or have no effects on the avascular area by different groups [ 4 , 5 , 13 , 19 , 20 , 21 ]. These conflicting results of VEGF inhibition on vaso-obliteration may result from differences in animal species, strains, OIR models, drug delivery schedule, different anti-VEGF agents, and injection techniques, and they are yet to be reconciled.…”

The role of integrins in inflammation and angiogenesis

“…The The retinal tissue has one of the body's highest metabolic demands, placing it at risk of injury from oxidative stress, metabolic derangements, and consequent pathologic neovascularization seen in retinopathy of prematurity (ROP) and other proliferative retinal vitreoretinopathies. ROP is a bi-phasic disease of retinal vascular development due to dysregulation of VEGF (82,83). In phase 1, VEGF is downregulated during exposure to hyperoxia, while in phase 2, VEGF is upregulated in relative/true hypoxia.…”

Integrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases

“…Retinopathy of prematurity (ROP), a two-phase disease of retinal vascular development, is caused by VEGF deregulation [ 77 , 78 ]. VEGF is downregulated in infants exposed to hyperoxia in phase 1, whereas in phase 2, VEGF is upregulated in relative/true hypoxia.…”