title: A sustained release formulation of novel quininib-hyaluronan microneedles inhibits angiogenesis and retinal vascular permeability in vivo.
abstract: 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 -35.5mV 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 4months; or in the presence of increasing concentrations of hyaluronidase, 60% incorporated quininib was released over 4months. 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.
authors.affiliation: UCD School of Biomolecular & Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Galvin
authors.affiliation: Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway, Ireland.
authors.forename: Akshay
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway, Ireland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Carroll
authors.affiliation: RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kulkarni
authors.affiliation: RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Dykes
authors.affiliation: RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Vickers
authors.affiliation: RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Dickinson
authors.affiliation: UCD School of Biomolecular & Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Reynolds
authors.affiliation: UCD School of Biomolecular & Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Kilty
authors.affiliation: UCD School of Chemistry, University College Dublin, Dublin 4, Ireland.
authors.forename: Gareth
authors.initials: G
authors.lastname: Redmond
authors.affiliation: RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Jones
authors.affiliation: RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Cheetham
authors.affiliation: Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Galway, Ireland.
authors.forename: Abhay
authors.initials: A
authors.lastname: Pandit
authors.affiliation: UCD School of Biomolecular & Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland. Electronic address: brendan.kennedy@ucd.ie.
authors.forename: Breandán N
authors.initials: BN
authors.lastname: Kennedy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D030801:Animals, Genetically Modified; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000627:therapeutic use; D016503:Drug Delivery Systems; D049452:Green Fluorescent Proteins / Q000235:genetics; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000627:therapeutic use; D058449:Intravitreal Injections; D007814:Larva; D008297:Male; D010539:Permeability / Q000187:drug effects; D010636:Phenols / Q000008:administration & dosage* / Q000627:therapeutic use; D011804:Quinolines / Q000008:administration & dosage* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D003692:Delayed-Action Preparations; D010636:Phenols; D011804:Quinolines; C485184:enhanced green fluorescent protein; C000620980:quininib; D049452:Green Fluorescent Proteins; D006820:Hyaluronic Acid
keywords: Angiogenesis; Blindness; Novel drug therapy; Vascular permeability