Supramolecular Chitosan Micro-Platelets Synergistically Enhance Anti-Candida albicans Activity of Amphotericin B Using an Immunocompetent Murine Model.
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.



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.



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 IC50and the MIC90decrease 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.



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.
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.
Tiphany
T
Grisin
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.
Christian
C
Bories
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.|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.
Martina
M
Bombardi
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.
Philippe M
PM
Loiseau
Gustave Roussy, Imaging and Cytometry Platform, UMS AMMICa, Paris-Saclay University, Villejuif, F-94805, France.
Valérie
V
Rouffiac
Faculté de Pharmacie, Institut Paris Saclay d'Innovation Thérapeutique, UMS Inserm CNRS UPSud, Université Paris-Saclay, Châtenay-Malabry cedex, France.
Audrey
A
Solgadi
Département de Chimie, École Normale Supérieure-PSL Research University, 75005, Paris, France.
Jean-Maurice
JM
Mallet
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.
Gilles
G
Ponchel
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.
Kawthar
K
Bouchemal
D000666:Amphotericin B / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001792:Blood Platelets / Q000737:chemistry*; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology*; D003840:Deoxycholic Acid / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D013552:Swine; D047391:alpha-Cyclodextrins / Q000737:chemistry
D000935:Antifungal Agents; D004338:Drug Combinations; D020100:Hydrogels; D047391:alpha-Cyclodextrins; D003840:Deoxycholic Acid; D020442:Poloxamer; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D048271:Chitosan; C032613:alpha-cyclodextrin
Candida albicans; amphotericin B; chitosan; micro-platelets