Polyhedral Oligomeric Silsesquioxane Hybrid Nanomicelles Loaded With Amphotericin B For Therapy Of Fungal Keratitis

Fungal keratitis is a corneal disease caused by pathogenic fungi that can lead to permanent loss of vision.Eye drops are commonly used for treatment of fungal keratitis,but there are still many limitations in clinical application.Due to the low solubility of drugs and eye blinking,tears,nasolacrimal drainage and other clearance mechanisms,common drugs are easy to remove quickly from the eyes,resulting in a very short time of action and low bioavailability of drugs.In order to achieve effective concentration,high-dose and high-frequency administration are often used in clinic,resulting in patient intolerance and low compliance.Efforts to resolve this hindrance include developing formulations that prolong drug retention on the ocular surface which can in turn improve therapeutic efficacy as well as reduce administration frequency.To extend drug residence time on the ocular surface,we designed a novel organic-inorganic hybrid consisting of a PEG-PPG copolymer modified with polyhedral oligomeric silsesquioxane(POSS)groups.POSS is a new generation of nano-cage structure with good biocompatibility,which provides a potential possibility to prolong the retention of micelles on the ocular surface.The amphiphilic polymer can be self-assembled into micelles to load insoluble drugs and improve the solubility of drugs.We verified the successful synthesis of the polymer POSS/PEG/PPG through nuclear magnetic resonance and infrared spectroscopy,and tested the thermal properties of the polymer through thermogravimetric analysis and differential scanning calorimetry.Next,we tested the polymer’s ability to form micelles and encapsulate amphotericin B(AMB).The results of in vitro cell experiments showed that the POSS micelles had good cell compatibility.The results of surface plasmon resonance showed that compared with the polymer without POSS,the affinity between the polymer and mucin was significantly enhanced by adding POSS group.Retention experiment of fluorescence in cornea showed that the micelles containing POSS significantly improved the adhesion and retension of drugs in ocular mucosa.We established a mouse model of fungal keratitis and used the antifungal drug amphotericin B(AMB)to determine the effect of POSS micelles on improving the treatment of fungal keratitis.The results showed that the mucoadhesive POSS micelles significantly improved the therapeutic effect of AMB on fungal keratitis.Moreover,POSS micelles containing AMB showed good safety and low irritation during ocular administration in vivo.Therefore,this POSS formulation bearing AMB has the potential to prolong drug retention time and improve its therapeutic efficacy in managing fungal keratitis.