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Adah Almutairi, Viet Anh Nguyen Huu, Jing Luo, Sherrina Patel, Caroline de Gracia Lux, Kang Zhang; ROS-responsive nanoparticles to extend the lifetime of anti-angiogenic drugs. Invest. Ophthalmol. Vis. Sci. 2014;55(13):469.
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Treatment of macular degeneration and proliferative diabetic retinopathy with anti-angiogenic drugs currently requires repeated injections. As the pathophysiology of these diseases involves oxidative stress (ROS), we are examining whether delivering VEGF-Trap in nanoparticles that degrade and release cargo in response to reactive oxygen species lengthen its lifetime in the eye. This approach should tailor the amount of drug released to the progression of the disease.
The efficacy and pharmacokinetics of VEGF-Trap in the following formulations are being compared in mice with oxygen-induced retinopathy (OIR) and rats with laser-induced choroidal neovascularization (CNV): in ROS-responsive particles (composed of a polyester bearing boronic ester groups), in slowly-degrading particles (poly(lactic-co-glycolic acid) (PLGA)), and free drug. Efficacy is measured by lectin staining and fluorescein angiography, and pharmacokinetics by ELISA of the vitreous and serum. To assess lifetime, we will examine whether VEGF-Trap delivered up to three months prior to laser induction protects against CNV.
ROS-responsive particles are compatible with intravitreal administration, as they do not trigger noticeable inflammation and do not affect expression of inflammatory cytokines. VEGF-Trap is effective in preventing neovascularization in OIR when administered as a free drug (40 µg) or in ROS-responsive particles (0.4 µg VEGF-Trap), but not in PLGA (1 µg).
VEGF-Trap retains activity upon formulation in particles by nanoemulsion. ROS-responsive particles allow greater release of VEGF-Trap in eyes affected by neovascularization than PLGA particles, suggesting potential for use in formulation of anti-angiogenics.
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