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oai:docta.ucm.es:20.500.14352/187532024-09-27T15:16:26Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Bravo Osuna, Irene author Vicario De La Torre, Marta author Andrés Guerrero, Vanesa author Sánchez Nieves, Javier author Guzmán Navarro, Manuel author Matad, F. Javier De La author Gómez Aspe, Rafael author Heras Polo, Beatriz De Las author Argüesoh, Pablo author Poncheli, Gilles author Herrero Vanrell, María Del Rocío author Molina Martínez, Irene Teresa author 2016-09-06 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. 1543-8384 10.1021/acs.molpharmaceut.6b00182 https://hdl.handle.net/20.500.14352/18753 https//doi.org/10.1021/acs.molpharmaceut.6b00182 https://pubs.acs.org/ Novel water-soluble mucoadhesive carbosilane dendrimers for ocular administration