No 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.

No abstract

No abstract

Purpose Decisive events of primary open angle glaucoma (POAG) onset and progression are located in the anterior chamber of the eye. Here, the outflow of aqueous humor through the trabecular meshwork (TM) and Schlemm´s canal (SC) is severely impeded.1 Conventional therapy suffers from poor compliance, low bioavailability of drugs, and does not treat the root cause of the disease. In the past few years, targets molecules and structures were identified that are associated with pathological changes of POAG and that could potentially be exploited for causative treatment.2 To efficiently address these novel targets and bring dug molecules to the TM and SC, the development of innovative and tailor‐made drug delivery systems is a prerequisite. Therefore, the goal of this study to exploit nanoparticles of different size and surface modification regarding their efficacy to accumulate in the TM after intracameral injection. Methods Polymer nanoparticles decorated with either hyaluronan or poly(ethylene imine) (PEI; about 250 nm) or gold nanoparticles of 5 nm were injected into the anterior chamber of enucleated porcine eyes. After 5 hr the anterior chamber was dissected and the iris, cornea, lens, the ciliary body and trabecular meshwork were analyzed either by fluorescence microscopy for polymer nanoparticles or inductively coupled plasma mass spectroscopy (ICP‐MS) for gold content. Results Nanoparticles decorated with hyaluronan demonstrated a favorable mobility in the extracellular matrix and excellent accumulation in the TM.3 Gold nanoparticles of 5 nm were detected in the TM at higher amounts compared to other tissues of the anterior chamber. Conclusion Nanoparticles depending on their size and surface modification are promising carriers for therapy of POAG to deliver drugs with high specificity to the TM and SC.