Tiphany Grisin1, Christian Bories2, Martina Bombardi1,2, Philippe M Loiseau2, Valérie Rouffiac3, Audrey Solgadi4, Jean-Maurice Mallet5, Gilles Ponchel1, Kawthar Bouchemal6. 1. Faculté de Pharmacie, Institut Galien Paris Sud, UMR CNRS 8612, Univ. Paris-Sud, Université Paris-Saclay, 5, rue J-B. Clément, 92296, Châtenay-Malabry, France. 2. Faculté de Pharmacie, BioCIS « Biomolécules: Conception, Isolement, Synthèse » - « Chimiothérapie Antiparasitaire » UMR CNRS 8076, Univ. Paris-Sud, Université Paris-Saclay, 5, rue J.B. Clément, 92296, Châtenay-Malabry cedex, France. 3. Gustave Roussy, Imaging and Cytometry Platform, UMS AMMICa, Paris-Saclay University, Villejuif, F-94805, France. 4. Faculté de Pharmacie, Institut Paris Saclay d'Innovation Thérapeutique, UMS Inserm CNRS UPSud, Université Paris-Saclay, Châtenay-Malabry cedex, France. 5. Département de Chimie, École Normale Supérieure-PSL Research University, 75005, Paris, France. 6. Faculté de Pharmacie, Institut Galien Paris Sud, Junior member of the Institut Universitaire de France, UMR CNRS 8612, Univ. Paris-Sud, Université Paris-Saclay, 5, rue J-B. Clément, 92296, Châtenay-Malabry, France. kawthar.bouchemal@u-psud.fr.
Abstract
PURPOSE: The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity. METHODS: Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic® F127 20 wt% hydrogel. RESULTS: The formulation completely cured C. albicans vaginal infection in mice and had a superior activity in comparison with AmB-DOC without addition of chitosan micro-platelets. In vitro studies showed that the platelets significantly enhance AmB-DOC antifungal activity since the IC50 and the MIC90 decrease 4.5 and 4.8-times. Calculation of fractional inhibitory concentration index (FICI = 0.198) showed that chitosan micro-platelets act in a synergistic way with AmB-DOC against C. albicans. No synergy is found between spherical nanoparticles composed poly(isobutylcyanoacrylate)/chitosan and AmB-DOC. CONCLUSION: These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment.
PURPOSE: The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin Bdeoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity. METHODS: Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic® F127 20 wt% hydrogel. RESULTS: The formulation completely cured C. albicansvaginal infection in mice and had a superior activity in comparison with AmB-DOC without addition of chitosan micro-platelets. In vitro studies showed that the platelets significantly enhance AmB-DOC antifungal activity since the IC50 and the MIC90 decrease 4.5 and 4.8-times. Calculation of fractional inhibitory concentration index (FICI = 0.198) showed that chitosan micro-platelets act in a synergistic way with AmB-DOC against C. albicans. No synergy is found between spherical nanoparticles composed poly(isobutylcyanoacrylate)/chitosan and AmB-DOC. CONCLUSION: These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicanscandidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment.
Authors: Noelia Pérez-González; Nuria Bozal-de Febrer; Ana C Calpena-Campmany; Anna Nardi-Ricart; María J Rodríguez-Lagunas; José A Morales-Molina; José L Soriano-Ruiz; Francisco Fernández-Campos; Beatriz Clares-Naveros Journal: Gels Date: 2021-12-12