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Jennifer J Kang-Mieler, Soohyun Kim, Zhe Wang, Wenqiang Liu, Glenn Yiu, William F Mieler, Sara M Thomasy; Aflibercept-loaded Microsphere-hydrogel Drug Delivery System in a Nonhuman Primate Model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3265. doi: https://doi.org/.
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Extended delivery of anti-vascular endothelial growth factors (anti-VEGFs) will significantly improve upon current repeated intravitreal therapy. Recently, we have demonstrated that our microsphere-hydrogel drug delivery system (DDS) can release bioactive anti-VEGF in a sustained manner for ~200 days in a rodent model. The purpose of this study is to evaluate the efficacy and safety of the released aflibercept from the aflibercept-DDS in a nonhuman primate model.
Biodegradable poly(lactic-co-glycolic acid) microspheres were synthesized using a modified double emulsion technique. Aflibercept-loaded microspheres (15 mg) were suspended within 1 mL of a poly(N-isopropylacrylamide)-based thermoresponsive hydrogel. Six healthy rhesus macaques were used in ocular pharmacokinetic (PK) study and three rhesus macaques were used in biocompatibility study. One eye received a sterile 50 µl intravitreal injection of aflibercept-DDS and the other eye served as a control. For the PK study, the eyes were obtained monthly to measure aflibercept level via ELISA analysis. For the safety study, intraocular pressure (IOP), fundus photography, spectral-domain optical coherence tomography (OCT) and electroretinogram (ERG) were performed monthly. At the endpoint, the eyes were harvested for histology.
IOP levels were remained in a normal range (12-21 mmHg) after the injection. Injected DDS can be visualized during clinical examination. External eyes, corneas and anterior chamber examination (including aqueous cell) were normal. There was a small amount of vitreous cells in some animals, but the overall vitreous examination was normal. The intraocular PK of aflibercept, on average, was 0.372 µg/day. There were no changes in the retinal thickness (269±2.3 µV DDS and 267±2.6 µV control). Both dark- and light-adapted ERG responses showed no changes. For example, in response to a flash intensity of 10 cd s/m2, the average dark-adapted a-wave amplitude was -139±14 µV (vs. -130±20 µV control) and the average b-wave amplitude was 245±20 µV (vs. 226±7 µV control).
There was no significant adverse effect due to the DDS injection. The aflibercept was released at a sustained manner and remained bioactive. Our DDS will be a practical and effective method to deliver bioactive anti-VEGF agents by reducing the frequency of injections and providing benefits of sustained treatment.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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