title: Suprachoroidal delivery in a rabbit ex vivo eye model: influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes.
abstract: OBJECTIVE
  First, to determine the influence of drug lipophilicity (using eight beta-blockers) and molecular weight (using 4 kDa and 40 kDa fluoroscein isothiocyanate [FITC]-dextrans) on suprachoroidal delivery to the posterior segment of the eye by using a rabbit ex vivo eye model. Second, to determine whether drug distribution differs between the dosed and undosed side of the eye following suprachoroidal delivery. Third, to compare the suprachoroidal delivery of sodium fluorescein (NaF) with the intracameral and intravitreal routes by using noninvasive fluorophotometry.
  
  
  METHODS
  Using a small hypodermic 26G needle (3/8") with a short bevel (250 µm), location of the suprachoroidal injection in an ex vivo New Zealand white rabbit eye model was confirmed with India ink. Ocular tissue distribution of NaF (25 µl of 1.5 µg/ml) at 37 °C was monitored noninvasively using the Fluorotron Master(TM) at 0, 1, and 3 h following suprachoroidal, intravitreal, or intracameral injections in ex vivo rabbit eyes. For assessing the influence of lipophilicity and molecular size, 25 µl of a mixture of eight beta-blockers (250 µg/ml each) or FITC-dextran (4 kDa and 40 kDa, 30 mg/ml) was injected into the suprachoroidal space of excised rabbit eyes and incubated at 37 °C. Eyes were incubated for 1 and 3 h, and frozen at the end of incubation. Ocular tissues were isolated in frozen condition. Beta-blocker and FITC-dextran levels in excised ocular tissue were measured by liquid chromatography-tandem mass spectrometry and spectrofluorometry, respectively.
  
  
  RESULTS
  Histological sections of India ink-injected albino rabbit eye showed the localization of dye as a black line in the suprachoroidal space. Suprachoroidal injection of NaF showed signal localization to the choroid and retina at 1 and 3 h post injection when compared with intravitreal and intracameral injections. Drug delivery to the vitreous after suprachoroidal injection decreased with an increase in solute lipophilicity and molecular weight. With an increase in drug lipophilicity, drug levels in the choroid-retinal pigment epithelium (RPE) and retina generally increased with some exceptions. Beta-blockers and FITC-dextrans were localized more to the dosed side when compared to the opposite side of the sclera, choroid-RPE, retina, and vitreous. These differences were greater for FITC-dextrans as compared to the beta-blockers.
  
  
  CONCLUSIONS
  The suprachoroidal route of injection allows localized delivery to the choroid-RPE and retina for small as well as large molecules. Suprachoroidal drug delivery to the vitreous declines with an increase in drug lipophilicity and molecular weight. Drug delivery differs between the dosed and opposite sides following suprachoroidal injection, at least up to 3 h.
authors.affiliation: Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Kadam
authors.forename: Jason
authors.initials: J
authors.lastname: Williams
authors.forename: Puneet
authors.initials: P
authors.lastname: Tyagi
authors.forename: Henry F
authors.initials: HF
authors.lastname: Edelhauser
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D002244:Carbon / Q000494:pharmacology; D002829:Choroid / Q000187:drug effects*; D003911:Dextrans / Q000493:pharmacokinetics; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D019793:Fluorescein / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015590:Fluorophotometry; D066298:In Vitro Techniques; D058449:Intravitreal Injections; D023421:Models, Animal; D011817:Rabbits; D012160:Retina / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D003911:Dextrans; C028433:chinese ink; C015219:fluorescein isothiocyanate dextran; D002244:Carbon; D016650:Fluorescein-5-isothiocyanate; D019793:Fluorescein