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Mark W Tibbitt, Eric A Appel, Ashwath Jayagopal, Robert Langer; Sustained Intravitreal Drug Delivery with Injectable Polymer-Nanoparticle Hydrogels. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3651.
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Approaches for the controlled release of therapeutics inhibiting neovascularization are needed to improve the clinical management of age-related macular degeneration (AMD). Currently, AMD is managed by monthly intravitreal injections of solutions of anti-angiogenesis biotherapeutics, creating a significant burden on both patient and clinician. The goal of this study was to develop a new platform for sustained release of small molecule drugs and biotherapeutics over the course of 6 months following intravitreal injection for the treatment of AMD.
Polymer-nanoparticle (PNP) hydrogels were engineered for facile intravitreal injection through narrow gauge needles owing to the high-degree of shear-thinning observed in these materials. The PNP gels were designed to form a drug delivery depot in the vitreous on account of the rapid self-healing following injection. Small molecule drugs (e.g., corticosteroids) were encapsulated into the nanoparticles using nanoprecipitation prior to PNP hydrogel fabrication. Additionally, bio-therapeutics (e.g., model IgG and Fab antibodies) were entrapped within the aqueous phase of the PNP hydrogels upon gel fabrication. The PNP hydrogels were engineered to release both classes of drugs over the course of 6 months, with independently tunable release rates. Drug loading and release was measured in vitro and in vivo with HPLC, electro-retinography, and confocal imaging of tissue sections. PNP hydrogel stability, ocular tolerability via histopathology, toxicity, and drug release were evaluated in tissue culture and animal models (rat and rabbit).
PNP gels comprised an intravitreal drug delivery depot following administration through narrow gauge needles allowing for tunable sustained delivery of both small molecules and bio-therapeutics in vitro and in vivo. The release of model IgG was observed at a therapeutic level for bevacizumab (8 µg/mL) in vitro over the course of 6 months. Moreover, the delivery depots demonstrated in vivo tolerability as assessed by histopathology.
Drug-loaded PNP hydrogels provide a promising platform for the management of AMD via intravitreal depots that sustain release for months to a year. On account of their biocompatibility and controlled release of therapeutics, PNP hydrogels can be used for mitigating the burden of monthly intravitreal injections in the management of AMD, improving adherence and clinical outcome.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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