Hyaluronic Acid Coated Albumin Nanoparticles for Enhanced Drug Delivery to the Retina

Abstract

Aim Recent studies have shown that Connexin43 mimetic peptide (Cx43 MP) can prevent secondary damage following several retinal ischaemic and inflammatory disorders by blocking uncontrolled Cx43 hemichannel opening. However, efficient retinal delivery remains challenging due to limitations in peptide stability and the presence of various ocular physiological barriers. The overall aim of this study is therefore to develop a novel nanocarrier system to effectively deliver Cx43 MP to the retina for the long-term treatment of chronic retinal disorders. Methods Hyaluronic acid (HA) coated albumin nanoparticles (NPs) encapsulating Cx43 MP were prepared and initially characterized in vitro. The diffusive mobility of NPs through the vitreous and their permeation across the retina after intravitreal injection ex vivo without and with the application of ultrasound were also investigated. Moreover, the influence of ageing related vitreous liquefaction on NP diffusion was evaluated in an ex vivo enzymatically digested vitreous model. Finally, in vivo biodistribution, retention, retinal targeting, and therapeutic efficacy of Cx43 MP encapsulated NPs were investigated in a rat model of retinal ischaemia-reperfusion injury. Results HA coated NPs achieved sustained Cx43 MP release for over four months in vitro, enhanced cellular uptake with good biocompatibility, and excellent ex vivo retinal tissue permeability. The diffusive mobility of NPs through the vitreous and their permeation across the retina were further improved by applying short pulses of ultrasound without causing any detectable damage to the ocular tissues. After enzymatic degradation, the ex vivo liquefied vitreous provided reduced steric hindrance and enhanced convective flow within the vitreous, resulting in increased intravitreal NP mobility. In vivo results showed that HA coated NPs rapidly diffused through the vitreous and specifically targeted the retina following intravitreal injection. NP elimination was relatively low resulting in sustained therapeutic efficacy in the treatment of retinal ischaemia-reperfusion injury compared to the free peptide in solution. Conclusions Superior properties of HA coated albumin NPs, including their good biocompatibility, small size and negative surface charge enabling rapid vitreous diffusion, high drug loading, sustained release and active retinal targeting capabilities, render them promising nanocarriers for enhanced peptide delivery in the treatment of chronic retinal disorders.