Intracameral Delivery of Layer‐by‐Layer Coated siRNA Nanoparticles for Glaucoma Therapy

Abstract

Glaucoma is the second leading cause of blindness worldwide, often associated with elevated intraocular pressure. Connective tissue growth factor (CTGF) is a mediator of pathological effects in the trabecular meshwork (TM) and Schlemm’s canal (SC). A novel, causative therapeutic concept which involves the intracameral delivery of small interfering RNA against CTGF is proposed. Layer-by-layer coated nanoparticles of 200–260 nm with a final layer of hyaluronan (HA) are developed. The HA-coating should provide the nanoparticles sufficient mobility in the extracellular matrix and allow for binding to TM and SC cells via CD44. By screening primary TM and SC cells in vitro, in vivo, and ex vivo, the validity of the concept is confirmed. CD44 expression is elevated in glaucomatous versus healthy cells by about two-to sixfold. CD44 is significantly involved in the cellular uptake of HA-coated nanoparticles. Ex vivo organ culture of porcine, murine, and human eyes demonstrates up to threefold higher accumulation of HA compared to control nanoparticles and much better penetration into the target tissue. Gene silencing in primary human TM cells results in a significant reduction of CTGF expression. Thus, HA-coated nanoparticles combined with RNA interference may provide a potential strategy for glaucoma therapy.

siRNA targeting Schlemm’s canal endothelial tight junctions enhances outflow facility and reduces IOP in a steroid-induced OHT rodent model

“…10 Should repeated administration be required to reduce IOP appropriately, a minimally invasive approach has been reported for periodic retrograde introduction of low-molecular-weight compounds into SC via the episcleral veins, and this could be used for non-invasive delivery of siRNA without adaptation (Retroject, Chapel Hill, NC, USA). Moreover, Dillinger et al 19 have recently shown that coating nanoparticles with hyaluronan more efficiently targets siRNA to TM and SC endothelial cells in view of the fact that such particles bind to the cell surface antigen CD44, present in greater quantities on cells of the outflow tissues. In conclusion, this study demonstrates in a well-characterized model of steroid-induced OHT a proof of concept of an siRNA-based therapeutic approach for IOP reduction.…”

Current Medical Therapy and Future Trends in the Management of Glaucoma Treatment

“…Inhibiting CTGF-induced extracellular matrix production does not interfere with TGF β -2 pleiotropic effects, therefore targeting CTGF may prove beneficial and safer in the treatment of glaucoma. Recently, the intracameral delivery of anti-CTGF small interfering RNA (siRNA) by using nanoparticles coated by hyaluronan succeeded to penetrate deeply in the outflow region and showed binding of hyaluronan to the CD44 receptors, which were overexpressed in glaucomatous eyes [ 60 ]. Hyaluronan-coated nanoparticles combined with RNA interference may provide a potential strategy for glaucoma therapy.…”

Promising Approach in the Treatment of Glaucoma Using Nanotechnology and Nanomedicine-Based Systems

“…Dillinger et al [16] proposed a novel, causative therapeutic idea which involves delivering small interfering RNA against CTGF via the intracameral route. A final layer of hyaluronan (HA) with layer-by-layer coated nanoparticles of 200–260 nm were synthesized.…”

“…The injection of nanoparticles is done through the anterior chamber and is perceived to follow the normal trabecular drainage pathway. Reproduced from ref [15,16] with permission from WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim.…”

“…An important pathological risk for primary open-angle glaucoma is the degree of the intraocular pressure (IOP) [14]. The IOP is generated within the eye’s anterior chamber by resisting aqueous humor evacuation from the trabecular meshwork (TM) and the inner wall of the Schlemm’s canal (SC) (Figure 1) [15,16].…”