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Intracameral Delivery of Layer‐by‐Layer Coated siRNA Nanoparticles for Glaucoma Therapy
Author(s) -
Dillinger Andrea E.,
Guter Michaela,
Froemel Franziska,
Weber Gregor R.,
Perkumas Kristin,
Stamer W. Daniel,
Ohlmann Andreas,
Fuchshofer Rudolf,
Breunig Miriam
Publication year - 2018
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.201803239
Subject(s) - ctgf , ex vivo , trabecular meshwork , glaucoma , gene silencing , extracellular matrix , in vivo , small interfering rna , cd44 , rna interference , intraocular pressure , microbiology and biotechnology , materials science , biophysics , chemistry , in vitro , transfection , cell culture , growth factor , biology , medicine , ophthalmology , rna , biochemistry , genetics , receptor , gene
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.