Abstract
Rho-associated protein kinase (ROCK) inhibitors allow for causative glaucoma therapy. Unfortunately, topically applied ROCK inhibitors suffer from high incidence of hyperemia and low intraocular bioavailability. Therefore, we propose the use of poly (lactide-co-glycolide) (PLGA) microspheres as a depot formulation for intravitreal injection to supply outflow tissues with the ROCK inhibitor fasudil over a prolonged time. Fasudil-loaded microspheres were prepared by double emulsion solvent evaporation technique. The chemical integrity of released fasudil was confirmed by mass spectrometry. The biological activity was measured in cell-based assays using trabecular meshwork cells (TM cells), Schlemm’s canal cells (SC cells), fibroblasts and adult retinal pigment epithelium cells (ARPE-19). Cellular response to fasudil after its diffusion through vitreous humor was investigated by electric cell-substrate impedance sensing. Microspheres ranged in size from 3 to 67 µm. The release of fasudil from microspheres was controllable and sustained for up to 45 days. Released fasudil reduced actin stress fibers in TM cells, SC cells and fibroblasts. Decreased collagen gel contraction provoked by fasudil was detected in TM cells (~2.4-fold), SC cells (~1.4-fold) and fibroblasts (~1.3-fold). In addition, fasudil readily diffused through vitreous humor reaching its target compartment and eliciting effects on TM cells. No negative effects on ARPE-19 cells were observed. Since fasudil readily diffuses through the vitreous humor, we suggest that an intravitreal drug depot of ROCK inhibitors could significantly improve current glaucoma therapy particularly for patients with comorbid retinal diseases.
Highlights
With the advent of rho-associated protein kinase (ROCK) inhibitors netarsudil (RhopressaTM) and ripasudil (GlanatecTM), a promising new class of drugs has been introduced for glaucoma management [1,2]
Since fasudil readily diffuses through the vitreous humor, we suggest that an intravitreal drug depot of Rho-associated protein kinase (ROCK) inhibitors could significantly improve current glaucoma therapy for patients with comorbid retinal diseases
All three microsphere types were spherical in shape as evaluated by scanning electron microscopy (SEM) (Figure 1)
Summary
With the advent of rho-associated protein kinase (ROCK) inhibitors netarsudil (RhopressaTM) and ripasudil (GlanatecTM), a promising new class of drugs has been introduced for glaucoma management [1,2]. In contrast to standard treatment with prostaglandin analogs or β-blockers that reduce the intraocular pressure (IOP) but fail to tackle the root cause of IOP elevation, ROCK inhibitors target cells in the conventional outflow pathway [3]. They increase the outflow facility by acting on cells of the trabecular meshwork (TM) and Schlemm’s canal (SC). ROCK inhibitors are applied as eye drops and are associated with high incidence of conjunctival hyperemia and possibly subconjunctival hemorrhage [3]. An application frequency of up to two times a day is associated with poor compliance; about 20% of patients discontinue therapy with eye drops after three years [4,7,8]
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