Thermosensitive Tri-Block Polymer Nanoparticle-Hydrogel Composites as Payloads of Natamycin for Antifungal Therapy Against Fusarium Solani
Xiaoyuan Sha, Leung Chan, Xiaoyi Fan, Penghao Guo, Tianfeng Chen, Lian Liu, Jingxiang Zhong
Abstract
Purpose: Fusarium Solani is the principal pathogen associated with fungal keratitis. As a sensitive drug to F. Solani , natamycin (NAT) was limited by the poor penetration and low bioavailability in clinical application. The aim of this study was to develop a new type of tri-block polymer nanoparticle-gel complex ( [email protected] @NAT) for delivering NAT and evaluate its physicochemical properties, antifungal activity, safety, penetrability, adhesion, and efficacy in treating fungal keratitis. Methods: [email protected] was prepared and characterized with a nano-particle size analyzer, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR). The minimum inhibitory concentration (MIC), cytotoxicity, penetrability of NAT (Natacyn ® 5% ophthalmic suspension; Alcon) and [email protected] with different concentrations were assessed. The eye surface retention time, ocular irritation, and curative effect of the NAT ophthalmic suspension and [email protected] @NAT on a rabbit fungal keratitis model were evaluated. Results: [email protected] had a particle size of 150 nm, a positive surface charge, and a sustained-release effect. The MIC for F. Solani was 2 μg/mL. A cytotoxicity test and ocular irritation test showed that [email protected] and [email protected] @NAT had good biocompatibility and no obvious irritation for rabbit corneas. Penetration experiments confirmed that [email protected] can successfully enter corneal epithelial cells and through the cornea to enter the anterior chamber. Compared with NAT ophthalmic suspension, [email protected] @NAT had stronger cornea permeation at the same concentration. The therapeutic effect and precorneal retention ability of the NAT ophthalmic suspension and [email protected] @NAT on the fungal keratitis rabbit model were compared. [email protected] @NAT achieved a better therapeutic effect at a lower drug concentration, and its eye surface retention time was significantly longer than that of the NAT ophthalmic suspension. Conclusion: [email protected] @NAT was shown to be a safe and effective nanodrug delivery system for NAT. It has great potential to improve the cure rate of fungal keratitis, reduce the administration frequency during the treatment process, and improve patient compliance. Graphical Abstract: Keywords: fungal keratitis, natamycin, nanoparticles, ocular drug delivery, tri-block polymer