title: Novel Water-Soluble Mucoadhesive Carbosilane Dendrimers for Ocular Administration.
abstract: The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. 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. 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. 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.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.|Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III , Calle Profesor Martín Lagos, s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Bravo-Osuna
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.|Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III , Calle Profesor Martín Lagos, s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Vicario-de-la-Torre
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.|Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III , Calle Profesor Martín Lagos, s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Andrés-Guerrero
authors.affiliation: Department of Organic and Inorganic Chemistry, University of Alcalá , Plaza San Diego, 28801 Alcalá de Henares, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , Plaza San Diego, 28801 Alcalá de Henares, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Sánchez-Nieves
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Alcalá de Henares , Plaza San Diego, 28801 Alcalá de Henares, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Guzmán-Navarro
authors.affiliation: Department of Organic and Inorganic Chemistry, University of Alcalá , Plaza San Diego, 28801 Alcalá de Henares, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , Plaza San Diego, 28801 Alcalá de Henares, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: de la Mata
authors.affiliation: Department of Organic and Inorganic Chemistry, University of Alcalá , Plaza San Diego, 28801 Alcalá de Henares, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , Plaza San Diego, 28801 Alcalá de Henares, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Gómez
authors.affiliation: Department of Pharmacology, School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: de Las Heras
authors.affiliation: Schepens Eye Research Institute and Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School , Boston, Massachusetts 02114, United States.
authors.forename: P
authors.initials: P
authors.lastname: Argüeso
authors.affiliation: CNRS UMR 8612, Université de Paris Sud, Laboratoire de Physicochimie, Pharmacotechnie et Biopharmacie, Faculté de Pharmacie, Université Paris-Sud 5 , rue Jean-Baptiste Clément, 92 296 Châtenay-Malabry, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Ponchel
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.|Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III , Calle Profesor Martín Lagos, s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Herrero-Vanrell
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.|Pharmaceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC) and the Ocular Pathology National Net (OFTARED) of the Institute of Health Carlos III , Calle Profesor Martín Lagos, s/n, 28040 Madrid, Spain.|Instituto Universitario de Farmacia Industrial (IUFI), School of Pharmacy, University Complutense , Avenida Complutense, 28040 Madrid, Spain.
authors.forename: I T
authors.initials: IT
authors.lastname: Molina-Martínez
mesh_terms: D000086:Acetazolamide / Q000737:chemistry; D060433:Administration, Ophthalmic; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D011817:Rabbits; D012821:Silanes / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D020349:Surface Plasmon Resonance
chemical_list: D050091:Dendrimers; D012821:Silanes; C504072:carbosilane; D000086:Acetazolamide
keywords: carbosilane dendrimers; hypotensive activity; mucoadhesion; ocular transmembrane mucins; surface plasmon resonance (SPR)