Scleral Permeability of a Small, Single-Stranded Oligonucleotide

Abstract

Developing more effective ocular drug delivery systems is essential to improving the treatment of posterior segment eye disease. The large target area provided by the sclera and potentially less vision threatening complications are advantages of transscleral administration compared to more traditional modalities of drug delivery to the posterior segment. We aimed to determine the permeability coefficient for the in vitro diffusion of a small, single-stranded, oligonucleotide across human sclera. Transscleral permeability was measured by placing 100 microL of 2.96 x 10(-4) mol single-stranded, fluorescein-labeled oligonucleotide (MW = 7998.3) on the episcleral surface of sclera mounted in a perfusion chamber. Fractions of choroidal perfusate were collected hourly for 24 hours. The permeability constant or K(trans) for the transscleral diffusion of the naked, single-stranded, fluorescein-labeled oligonucleotide was 7.67 +/- 1.8 x 10(-7) cm/s (mean +/- SEM, N = 7). The permeability constant or K(trans) after intrascleral injection of the same fluorescein-labeled oligonucleotide was 1.32 +/- 0.42 x 10(-7) (mean +/- SEM, N = 4). This analysis demonstrates that diffusion of a naked, 24-base, single-stranded, fluorescein-labeled oligonucleotide can be accomplished by both of the described methods. The ability to deliver single-stranded oligonucleotides across the sclera may prove to be advantageous given the development of several novel therapeutic strategies that use similar molecules.

Ultrasound-Mediated Transscleral Delivery of Macromolecules to the Posterior Segment of Rabbit Eye In Vivo

“…3,5,27 Although protein and DNA are permeable across sclera-the outmost hydrophilic barrier in the transscleral route-the diffusivity is relatively low. 19,28 This property on top of the dynamic clearance makes it challenging for macromolecules topically applied on the sclera to be transported to the posterior segment. 29 This is consistent with our observation in the control experiment with the macromolecular probe, FITC-dextran of 70 kDa.…”

Transport Barriers in Transscleral Drug Delivery for Retinal Diseases

“…The permeability for a number of molecules has been measured including dextrans [30] and polyethylene glycol molecules [31] of various molecular weights, antibiotics [32] , oligonucleotides [33] , retinal anti-angiogenic molecules [34] , and lipophilic compounds [35,36] . Several factors influence the scleral permeability of molecules.…”

A Cationic Peptide, TAT-Cd0, Inhibits Herpes Simplex Virus Type 1 Ocular Infection In Vivo

“…A number of groups have identified peptides and other small molecules with therapeutic activity when topically applied to the cornea, showing that with some modification to delivery vehicle or formulation, many types of compounds can be effective in treating corneal disease. 17,27,28,[31][32][33][34][35] A synthetic retrocyclin, RC-2, is a cationic, synthetic hdefensin (molecular weight: 2041 daltons [Da]) that functions as an inhibitor of HSV infection. 36 h-Defensins are circular octadecapeptides consisting of two antiparallel b-sheets with six cysteines connecting the b-sheets to each other, forming a ladder-like array, and certain h-defensins have shown activity against multiple viruses in cell culture.…”