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  • 1
    Online Resource
    Online Resource
    PLGA microspheres loaded with a ROCK inhibitor as an intravitreally injectable drug delivery system for the management of glaucoma
    Wiley ; 2019
    In:  Acta Ophthalmologica Vol. 97, No. S263 ( 2019-12)
    Details
    In: Acta Ophthalmologica, Wiley, Vol. 97, No. S263 ( 2019-12)
    Abstract: Primary open‐angle glaucoma (POAG) is a chronic, progressive neuropathy of the optic nerve and one of the major causes of blindness worldwide [1]. ROCK inhibitors such as fasudil are a promising class of drugs on the market allowing a causative therapy of POAG. Unfortunately, a major drawback of topically applied fasudil is its high hydrophilicity and consequently low intraocular bioavailability [1] . In addition, short half‐life severely limits its time of action. Therefore, we propose intravitreal injectable fasudil loaded poly(lactide‐co‐glycolide) microspheres (fasudil‐MS) as promising depot formulation increasing the effect, stability and bioavailability of fasudil to a maximum. In different cell‐based assays the biological activity of fasudil‐MS was tested. Methods Fasudil‐MS were prepared by the water‐in‐oil‐in‐water solvent evaporation technique. Manufactured fasudil‐MS were characterized regarding size by laser diffraction, encapsulation efficiency by HPLC and in vitro release. Measurement of biologic activity of released drug was performed in different cell‐based assays. Therefore, preliminary cell studies were established with free fasudil and the glaucomatous factors connective tissue growth factor (CTGF) and transforming growth factor‐β2 (TGF‐β2) to analyze cell contractility and expression of a‐smooth muscle actin (a‐SMA) by qPCR. Results Fasudil‐MS had a size of 20‐25µm and spherical shape. Fasudil was released in a controlled biphasic releasing profile. In preliminary experiments, fasudil demonstrated its ability to diffuse through the vitreous body and was able to reduce the cell contractility as well as the gene expression of a‐SMA induced by CTGF and TGF‐β2. Conclusion The proposed formulation could be a promising strategy increasing therapy effectiveness. Reference Mietzner R, Breunig M. Causative glaucoma treatment: promising targets and delivery systems. Drug Discov Today. 2019.
    Type of Medium: Online Resource
    ISSN: 1755-375X , 1755-3768
    URL: Issue
    URL: Article
    DOI: 10.1111/aos.v97.s263
    DOI: 10.1111/j.1755-3768.2019.5146
    Language: English
    Publisher: Wiley
    Publication Date: 2019
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  • 2
    Online Resource
    Online Resource
    Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy
    MDPI AG ; 2020
    In:  Pharmaceutics Vol. 12, No. 8 ( 2020-07-27), p. 706-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 12, No. 8 ( 2020-07-27), p. 706-
    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.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics12080706
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
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  • 3
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    Online Resource
    Intracameral Delivery of Layer‐by‐Layer Coated siRNA Nanoparticles for Glaucoma Therapy
    Wiley ; 2018
    In:  Small Vol. 14, No. 50 ( 2018-12)
    Details
    In: Small, Wiley, Vol. 14, No. 50 ( 2018-12)
    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.
    Type of Medium: Online Resource
    ISSN: 1613-6810 , 1613-6829
    URL: Issue
    URL: Article
    DOI: 10.1002/smll.v14.50
    DOI: 10.1002/smll.201803239
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2168935-0
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  • 4
    Online Resource
    Online Resource
    Distribution of nanoparticles in the anterior chamber of porcine eyes
    Wiley ; 2019
    In:  Acta Ophthalmologica Vol. 97, No. S263 ( 2019-12)
    Details
    In: Acta Ophthalmologica, Wiley, Vol. 97, No. S263 ( 2019-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1755-375X , 1755-3768
    URL: Issue
    URL: Article
    DOI: 10.1111/aos.v97.s263
    DOI: 10.1111/j.1755-3768.2019.5145
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2466981-7
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  • 5
    Online Resource
    Online Resource
    Distribution of Gold Nanoparticles in the Anterior Chamber of the Eye after Intracameral Injection for Glaucoma Therapy
    MDPI AG ; 2021
    In:  Pharmaceutics Vol. 13, No. 6 ( 2021-06-17), p. 901-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 13, No. 6 ( 2021-06-17), p. 901-
    Abstract: In glaucoma therapy, nanoparticles (NPs) are a favorable tool for delivering drugs to the outflow tissues of the anterior chamber of the eye where disease development and progression take place. In this context, a prerequisite is an efficient enrichment of NPs in the trabecular meshwork with minimal accumulation in off-target tissues such as the cornea, lens, iris and ciliary body. We evaluated the optimal size for targeting the trabecular meshwork by using gold NPs of 5, 60, 80 and 120 nm with a bare surface (AuNPs) or coated with hyaluronic acid (HA-AuNPs). NPs were compared regarding their colloidal stability, distribution in the anterior chamber of the eye ex vivo and cellular uptake in vitro. HA-AuNPs demonstrated an exceptional colloidal stability. Even after application into porcine eyes ex vivo, the HA coating prevented an aggregation of NPs inside the trabecular meshwork. NPs with a diameter of 120 nm exhibited the highest volume-based accumulation in the trabecular meshwork. Off-target tissues in the anterior chamber demonstrated an exceptionally low gold content. Our findings are particularly important for NPs with encapsulated anti-glaucoma drugs because a higher particle volume would be accompanied by a higher drug payload.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics13060901
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
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