Journal
JOURNAL OF CONTROLLED RELEASE
Volume 233, Issue -, Pages 198-207Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2016.04.004
Keywords
Blindness; Angiogenesis; Vascular permeability; Novel drug therapy
Funding
- Science Foundation Ireland and Technology Innovation and Development Award [13/TIDA/B2678]
- European Regional Development Fund [13/RC/2073]
- Marie Curie Industry-Academia Partnerships and Pathways (IAPP) grant [612218/3D-NET]
- Science Foundation Ireland (SFI) [13/TIDA/B2678] Funding Source: Science Foundation Ireland (SFI)
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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.
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