Collagen-Modified Nanocarriers for Enhanced Ocular Delivery of Isavuconazole in Fungal Keratitis

Abstract

In this study, isavuconazole (ISC)-loaded collagen-modified niosomes and nanostructured lipid carriers (NLCs) were developed for the treatment of fungal keratitis, which results in severe visual impairment. Niosomes were prepared by thin-film hydration using sorbitan monolaurate and cholesterol. NLCs were prepared using Compritol HD5 ATO and Miglyol (R) as lipids by hot homogenization. Collagen was crosslinked using EDC ((1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), NHS (N-hydroxysuccinimide), and DSPE-PEG2000-COOH. Niosomes and NLCs had particle sizes of 167.27 +/- 0.4 nm and 197.87 +/- 5.46 nm, respectively, with low PDI (Polydispersity index) values (0.35-0.4) and negative zeta potentials (ZP) (-14.17 +/- 0.15 to -51.67 +/- 0.91 mV). The encapsulation efficiency (%EE) of the formulations prepared without collagen modification was 76.65% for niosomes and 98.75% for NLCs. Following collagen modification, the %EE decreased to 70.03% for niosomes and 91.75% for NLCs, corresponding to reductions of 6.62% and 7%, respectively. Cryo-TEM/TEM confirmed spherical, uniform nanostructures with collagen corona. Franz-cell studies using bovine cornea demonstrated markedly improved permeation: niosomes delivered highest ISC (85.31%, p < 0.05). However, the corneal drug deposition increased from 0.01 mg/mL (ISC solution) to 0.11 mg/mL via NLCs. >90% cell viability for all systems was confirmed on human corneal epithelial cells. In-vivo studies demonstrated ISC-loaded collagen-modified NLC and niosomes reduced clinical keratitis scores and fungal loads. IL-1 beta (Interleukin-1 beta), IL-6 (Interleukin-6), TNF-alpha (Tumor Necrosis Factor-alpha), and Caspase-3 levels were significantly lowered in both groups. These findings demonstrate that collagen-functionalized nanosystems significantly enhance ISC delivery and represent a promising platform for topical antifungal therapy.