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  • 1
    In: Vaccines, MDPI AG, Vol. 9, No. 6 ( 2021-06-11), p. 642-
    Abstract: The delivery of HIV-1 envelope (Env) trimer-based immunogens on the surface of nanoparticles holds promise to promote immunogenicity with the aim of inducing a potent, durable and broad neutralizing antibody (bnAb) response. Towards that goal, we examined the covalent conjugation of Env to 100 nm and 200 nm silica nanoparticles (SiNPs) to optimize conjugation density and attachment stability. Env was redesigned to enable site-specific cysteine-mediated covalent conjugation while maintaining its structural integrity and antigenicity. Env was anchored to different sized SiNPs with a calculated spacing of 15 nm between adjacent trimers. Both particle sizes exhibited high in vitro stability over a seven-day period. After attachment, 100 nm particles showed better colloidal stability compared to 200 nm particles. Importantly, the antigenic profile of Env was not impaired by surface attachment, indicating that the quaternary structure was maintained. In vitro Env uptake by dendritic cells was significantly enhanced when Env was delivered on the surface of nanoparticles compared to soluble Env. Furthermore, multivalent Env displayed efficiently activated B cells even at Env concentrations in the low nanomolar range. In mice, antibody responses to nanoparticle-coupled Env were stronger compared to the free protein and had equivalent effects at lower doses and without adjuvant.
    Type of Medium: Online Resource
    ISSN: 2076-393X
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2703319-3
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  • 2
    In: Pharmaceuticals, MDPI AG, Vol. 15, No. 1 ( 2021-12-24), p. 18-
    Abstract: A root cause for the development and progression of primary open-angle glaucoma might be the loss of the Schlemm’s canal (SC) cell function due to an impaired Angiopoietin-1 (Angpt-1)/Tie2 signaling. Current therapeutic options fail to restore the SC cell function. We propose Angpt-1 mimetic nanoparticles (NPs) that are intended to bind in a multivalent manner to the Tie2 receptor for successful receptor activation. To this end, an Angpt-1 mimetic peptide was coupled to a poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) block co-polymer. The modified polymer allowed for the fabrication of Angpt-1 mimetic NPs with a narrow size distribution (polydispersity index 〈 0.2) and the size of the NPs ranging from about 120 nm (100% ligand density) to about 100 nm (5% ligand density). NP interaction with endothelial cells (HUVECs, EA.hy926) as surrogate for SC cells and fibroblasts as control was investigated by flow cytometry and confocal microscopy. The NP–cell interaction strongly depended on the ligand density and size of NPs. The cellular response to the NPs was investigated by a Ca2+ mobilization assay as well as by a real-time RT-PCR and Western blot analysis of endothelial nitric oxide synthase (eNOS). NPs with a ligand density of 25% opposed VEGF-induced Ca2+ influx in HUVECs significantly which could possibly increase cell relaxation and thus aqueous humor drainage, whereas the expression and synthesis of eNOS was not significantly altered. Therefore, we suggest Angpt-1 mimetic NPs as a first step towards a causative therapy to recover the loss of SC cell function during glaucoma.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2193542-7
    SSG: 15,3
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  • 3
    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
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
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  • 4
    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
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
    Location Call Number Limitation Availability
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