RT Journal Article
T1 Novel water-soluble mucoadhesive carbosilane dendrimersfor ocular administration
A1 Bravo-Osuna, Irene
A1 Vicario-de-la-Torre, Marta
A1 Andrés-Guerrero, Vanessa
A1 Sánchez-Nieves, Javier
A1 Guzmán-Navarro, Manuel
A1 de la Matad, F. Javier
A1 Gómez, Rafael
A1 de las Heras, Beatriz
A1 Argüesoh, Pablo
A1 Poncheli, Gilles
A1 Herrero-Vanrell, Rocío
A1 Molina-Martínez, Irene Teresa
AB Purpose: To determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (Generations 1-3) as mucoadhesive polymers in eyedrop formulations. Methods: Cationic carbosilane dendrimers decorated with ammonium –NH3 + groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits. Results: The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral –NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 μM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 μM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0 8h and maximal intraocular pressure reduction. Conclusion: This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these polymers. Our results indicate that low amounts of cationic carbosilane dendrimers are well tolerated and able to improve the hypotensive effect of an acetazolamide solution. Our results suggest that carbosilane dendrimers can be used in a safe range of concentrations to enhance the bioavailability of drugs topically administered in the eye.
PB American Chemical Society (ACS)
SN 1543-8384
YR 2016
FD 2016-09-06
LK https://hdl.handle.net/20.500.14352/18753
UL https://hdl.handle.net/20.500.14352/18753
LA eng
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NO Ministerio de Economía, Industria y Competitividad (MINECO)
NO Comunidad de Madrid
NO Instituto de Salud Carlos III
NO Universidad Complutense de Madrid
NO Institute de Chimie du Centre National de Recherche Scientifique du France (CNRS)
NO US National Institutes of Health
DS Docta Complutense
RD 16 may 2024