Novel water-soluble mucoadhesive carbosilane dendrimers for ocular administration
Autor: | Irene T. Molina-Martínez, Gilles Ponchel, Vanessa Andrés-Guerrero, Marta Vicario-de-la-Torre, Rocío Herrero-Vanrell, F. J. de la Mata, Irene Bravo-Osuna, Pablo Argüeso, Rafael Gómez, B. de las Heras, Javier Sánchez-Nieves, M. Guzmán-Navarro |
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Rok vydání: | 2016 |
Předmět: |
Male
Dendrimers Cell Survival Pharmaceutical Science Administration Ophthalmic 02 engineering and technology 010402 general chemistry 01 natural sciences Cell Line Allylamine chemistry.chemical_compound Tecnología farmaceútica In vivo Dendrimer Drug Discovery Polymer chemistry Mucoadhesion Animals Humans Carboxylate chemistry.chemical_classification Cationic polymerization Polymer Silanes Surface Plasmon Resonance 021001 nanoscience & nanotechnology Farmacia 0104 chemical sciences Bioavailability Acetazolamide chemistry Molecular Medicine Oftalmología Rabbits 0210 nano-technology |
Zdroj: | E-Prints Complutense. Archivo Institucional de la UCM instname E-Prints Complutense: Archivo Institucional de la UCM Universidad Complutense de Madrid |
Popis: | 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. |
Databáze: | OpenAIRE |
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