Topical Delivery of Avastin to the Posterior Segment of the Eye In Vivo Using Annexin A5‐associated Liposomes

Abstract

Effective delivery to the retina is presently one of the most challenging areas in drug development in ophthalmology, due to anatomical barriers preventing entry of therapeutic substances. Intraocular injection is presently the only route of administration for large protein therapeutics, including the anti-Vascular Endothelial Growth Factors Lucentis (ranibizumab) and Avastin (bevacizumab). Anti-VEGFs have revolutionised the management of age-related macular degeneration and have increasing indications for use as sight-saving therapies in diabetes and retinal vascular disease. Considerable resources have been allocated to develop non-invasive ocular drug delivery systems. It has been suggested that the anionic phospholipid binding protein annexin A5, may have a role in drug delivery. In the present study we demonstrate, using a combination of in vitro and in vivo assays, that the presence of annexin A5 can significantly enhance uptake and transcytosis of liposomal drug carrier systems across corneal epithelial barriers. This system is employed to deliver physiologically significant concentrations of Avastin to the posterior of the rat eye (127 ng/g) and rabbit retina (18 ng/g) after topical application. Our observations provide evidence to suggest annexin A5 mediated endocytosis can enhance the delivery of associated lipidic drug delivery vehicles across biological barriers, which may have therapeutic implications.

Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions

“…Similarly, bevacizumab delivery from a thermosensitive, biodegradable and biocompatible intravitreal hydrogel revealed no significant improvement over controls [88]. This emphasizes the challenge and the opportunity: local, sustained delivery of anti-angiongenic factors remains a fertile area for strategic investment.…”

Delivery of therapeutics for deep-seated ocular conditions – status quo

“…In situ gels are a drug delivery system which when administered in a liquid form phase shift into a gel or solid form once reaching the conjunctival cul-de-sac. [39] Despite typically being administered [1,4] ) 2 Ability to modify the rate of release of drug [1,4] 3 Ability to provide a stimuli-sensitive drug release mechanism [1,4] 1 Allow sustained release of drug [35,36] 2 Prolonged therapeutic duration at site of action [35,36] 3 Can overcome limitation of eye drops where drug wastage is an issue [35,36] 1 No blurred vision or irritation with administration [39,40] 2 Prolonged drug retention at desired tissue in the eye [39,41] 3 Decreased frequency of dosing [40,41] 1 Both hydrophilic or lipophilic drugs can be used [32] 2 Increase drug penetration across conjunctival and corneal epithelium [32] 3 Display ability to provide sustained released [32,46] 4 Decreased frequency of dosing [46] Cons 1 Low reproducibility [4,48] 2 Instability of the macromolecules during production stage [4,48] 3 Variable size distribution [4,48] 4 Expensive [4,48] 1 May increase intraocular pressure and induce local systemic adverse effects [38] 2 Inconvenient administration for patient [38] 3 Risk of tissue damage if administered incorrectly [38] 1 Lack of cell specificity [41] 2 Requires intravitreal administration due to poor penetration & specificity [40] 3 Expensive …”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Coating diclofenac-loaded liposomes with hydrophobic PVA enhanced diclofenac delivery to the retina-choroid after topical instillation in rabbits (Fujisawa et al 2012). Annexin A5-functionalized liposomes enhanced delivery of bevacizumab to the vitreous humor and retina following topical instillation to rats and rabbits (Davis et al 2014). While these studies are promising, more confirmatory studies and mechanistic studies are needed to establish the therapeutic potential of liposomes in achieving macromolecule efficacy in the back of the eye.…”