Transscleral Protein Delivery

Because of the invasiveness of intravitreous injections, subconjunctival administration of proteins has gained increasing attention. Subconjunctival injections can be given in outpatient clinics, but intravitreal injection requires operation room setup, because there is the risk of vision-threatening endophthalmitis that must be minimized. After subconjunctival administration, the drug must diffuse through sclera, chorioidea, and RPE to reach a retinal target. Some fraction of the drug will likely be eliminated from the subconjunctival space to the blood circulation before entering the sclera (1).

The sclera is a membrane about 0.5 mm thick that is composed of interspersed collagen fibrils and water channels. Drug permeability across the sclera is not dependent on the lipophilicity (27) but is dependent on molecular weight. Macromolecules have reasonable permeability in the sclera (range: 0.2-1.0 x 10~7 cm/sec) (23). Permeation across the sclera has been widely investigated, but, in fact, the sclera is not the rate-limiting barrier in many cases. Recent investigations show that the sclera and RPE are approximately equal barriers for lipophilic small compounds, but for macromolecules and hydrophilic solutes, the RPE is tighter than the sclera (23). Although the difference appears to be approximately an order of magnitude, there is surprisingly sparse data in the literature on the permeability of RPE. In addition to the sclera and RPE, the drug should pass the chorioidea. This layer has rich blood flow, with vessels fenes-trated to allow rapid movement between the blood and choroidal tissue. It has been known for a long time that the blood vessel capillaries allow take-up of plasma proteins from tissues that have escaped from the vasculature. Therefore, it is expected that protein and peptides delivered to the choroidal tissue can transfer to blood vessels, although there is very limited data about this process. Bill determined the systemic absorption of carboxyfluorescein, albumin, and IgG from the chorioidea (28). All compounds were absorbed, but the higher-molecular-weight molecules showed decreased rates of absorption. The influence of choroidal clearance on drug permeation to the retina is not known. This is determined by the blood flow and the extraction ratio. Even at low extraction ratio values, the rate of elimination from the choroid to the blood flow is very rapid. Further studies will clarify the roles of each layer.

Subconjunctival and sub-Tenon administration of pigment epithelium-derived factor (PEDF) was investigated recently. The protein was incorporated into the polymer matrix of poly (lactide-glycolide) (PLGA) that released the drug in controlled manner, with adequate delivery into the retina being achieved over a prolonged period (29). Other investigators have also demonstrated significant drug distribution from the subconjunctival site to the retina, although the clinical utility of this method of administration remains to be seen. In addition, iontophoresis has been used to deliver drugs via transscleral route into the retina (30). The iontophoresis is used to facilitate the drug permeation into the sclera and further to the deeper tissues. This approach has been used mostly for small molecules, but recent report shows that even nanoparticles can be delivered by iontophoresis across the sclera (31). Therefore, it may be possible to use this method also for protein delivery.

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