Abstract
PURPOSE: Apatinib (Apa) is a novel anti-vascular endothelial growth factor with the potential to treat diabetic retinopathy (DR); a serious condition leading to visual impairment and blindness. DR treatment relies on invasive techniques associated with various complications. Investigating topical routes for Apa delivery to the posterior eye segment is thus promising but also challenging due to ocular barriers. Hence, the study objective was to develop Apa-loaded bovine serum albumin nanoparticles (Apa-BSA-NPs) coated with hyaluronic acid (HA); a natural polymer possessing unique mucoadhesive and viscoelastic features with the capacity to actively target CD44 positive retinal cells, for topical administration in DR. METHODS: Apa-BSA-NPs were prepared by desolvation using glutaraldehyde for cross-linking. HA-coated BSA-NPs were also prepared and HA: NPs ratio optimized. Nanoparticles were characterized for colloidal properties, entrapment efficiency (EE%), in vitro drug release and mucoadhesive potential. In vitro cytotoxicity on rabbit corneal epithelial cells (RCE) was assessed using MTT assay, while efficacy was evaluated in vivo in a diabetic rat model by histopathological examination of the retina by light and transmission electron microscopy. Retinal accumulation of fluorescently labeled BSA-NP and HA-BSA-NP was assessed using confocal microscope scanning. RESULTS: Apa-HA-BSA-NPs prepared under optimal conditions showed size, PdI and zeta potential: 222.2±3.56 nm, 0.221±0.02 and -37.3±1.8 mV, respectively. High EE% (69±1%), biphasic sustained release profile with an initial burst effect and mucoadhesion was attained. No evidence of cytotoxicity was observed on RCE cells. In vivo histopathological studies on DR rat model revealed alleviated retinal micro- and ultrastructural changes in the topical HA-Apa-BSA-NP treated eyes with normal basement membrane and retinal thickness comparable to normal control and intravitreally injected nanoparticles. Improved retinal accumulation for HA-BSA-NP was also observed by confocal microscopy. CONCLUSION: Findings present HA-Apa-BSA-NPs as a platform for enhanced topical therapy of DR overcoming the devastating ocular complications of the intravitreal route.