Peer-Reviewed Journal Details
Mandatory Fields
Galvin, O,Srivastava, A,Carroll, O,Kulkarni, R,Dykes, S,Vickers, S,Dickinson, K,Reynolds, AL,Kilty, C,Redmond, G,Jones, R,Cheetham, S,Pandit, A,Kennedy, BN
2016
July
J Control Release
A sustained release formulation of novel quininib-hyaluronan microneedles inhibits angiogenesis and retinal vascular permeability in vivo
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Blindness Angiogenesis Vascular permeability Novel drug therapy OXYGEN-INDUCED RETINOPATHY MACULAR DEGENERATION DIABETIC-RETINOPATHY DRUG-DELIVERY SUPRAMOLECULAR ORGANIZATION CYSTEINYL LEUKOTRIENES BARRIER BREAKDOWN MOUSE MODEL NANOPARTICLES MICROSPHERES
233
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Pathologic neovascularisation and ocular permeability are hallmarks of proliferative diabetic retinopathy and age-related macular degeneration. Current pharmacologic interventions targeting VEGF are effective in only 30-60% of patients and require multiple intraocular injections associated with iatrogenic infection. Thus, our goal is to develop novel small molecule drugs that are VEGF-independent are amenable to sustained ocular-release, and which reduce retinal angiogenesis and retinal vascular permeability. Here, the anti-angiogenic drug quininib was formulated into hyaluronan (HA) microneedles whose safety and efficacy was evaluated in vivo. Quininib-HA microneedles were formulated via desolvation from quininib-HA solution and subsequent cross-linking with 4-arm-PEG-amine prior to freeze-drying. Scanning electron microscopy revealed hollow needle-shaped particle ultrastructure, with a zeta potential of -35.5 mV determined by electrophoretic light scattering. The incorporation efficiency and pharmacokinetic profile of quininib released in vitro from the microneedles was quantified by HPLC. Quininib incorporation into these microneedles was 90%. In vitro, 20% quininib was released over 4 months; or in the presence of increasing concentrations of hyaluronidase, 60% incorporated quininib was released over 4 months. Zebrafish hyaloid vasculature assays demonstrated quininib released from these microneedles significantly (p < 0.0001) inhibited ocular developmental angiogenesis compared to control. Sustained amelioration of retinal vascular permeability (RVP) was demonstrated using a bespoke cysteinyl leukotriene induced rodent model. Quininib-HA microparticles significantly inhibited RVP in Brown Norway rats one month after administration compared to neat quininib control (p = 0.0071). In summary, quininib-HA microneedles allow for sustained release of quininib; are safe in vivo and quininib released from these microneedles effectively inhibits angiogenesis and RVP in vivo. (C) 2016 Elsevier B.V. All rights reserved.
10.1016/j.jconrel.2016.04.004
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