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Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery

The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administr...

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Detalles Bibliográficos
Autores principales: Kicková, Eva, Sadeghi, Amir, Puranen, Jooseppi, Tavakoli, Shirin, Sen, Merve, Ranta, Veli-Pekka, Arango-Gonzalez, Blanca, Bolz, Sylvia, Ueffing, Marius, Salmaso, Stefano, Caliceti, Paolo, Toropainen, Elisa, Ruponen, Marika, Urtti, Arto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779473/
https://www.ncbi.nlm.nih.gov/pubmed/35056906
http://dx.doi.org/10.3390/pharmaceutics14010012
Descripción
Sumario:The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan–dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan–dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan–dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan–dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.