title: Intravitreal drug delivery in retinal disease: are we out of our depth?
abstract: BACKGROUND
  With the ever-increasing global burden of retinal disease, there is an urgent need to vastly improve formulation strategies that enhance posterior eye delivery of therapeutics. Despite intravitreal administration having demonstrated notable superiority over other routes in enhancing retinal drug availability, there still exist various significant physical/biochemical barriers preventing optimal drug delivery into the retina. A further complication lies with an inability to reliably translate laboratory-based retinal models into a clinical setting. Several formulation approaches have recently been evaluated to improve intravitreal therapeutic outcomes, and our aim in this review is to highlight strategies that hold the most promise.
  
  
  METHODS
  We discuss the complex barriers faced by the intravitreal route and examine how formulation strategies including implants, nanoparticulate carriers, viral vectors and sonotherapy have been utilized to attain both sustained delivery and enhanced penetration through to the retina. We conclude by highlighting the advances and limitations of current in vitro, ex vivo and in vivo retinal models in use by researchers globally.
  
  
  CONCLUSIONS
  Various nanoparticle compositions have demonstrated the ability to overcome the retinal barriers successfully; however, their utility is limited to the laboratory setting. Optimization of these formulations and the development of more robust experimental retinal models are necessary to translate success in the laboratory into clinically efficacious outcomes.
authors.affiliation: The University of Queensland, School of Pharmacy, Pharmacy Australia Centre of Excellence , 20 Cornwall Street, Woolloongabba, Brisbane, QLD, 4102 , Australia.
authors.forename: Sachin S
authors.initials: SS
authors.lastname: Thakur
authors.forename: Nigel L
authors.initials: NL
authors.lastname: Barnett
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Donaldson
authors.forename: Harendra S
authors.initials: HS
authors.lastname: Parekh
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier; D016503:Drug Delivery Systems; D006801:Humans; D058449:Intravitreal Injections; D009883:Ophthalmic Solutions / Q000008:administration & dosage*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012164:Retinal Diseases / Q000188:drug therapy*
chemical_list: D009883:Ophthalmic Solutions; D004364:Pharmaceutical Preparations
keywords: drug delivery; intravitreal delivery; nanoparticles; retina; retinal barriers; retinal models