Rescue the retina after the ischemic injury by polymer-mediated intracellular superoxide dismutase delivery

Abstract

Oxidative stress is a hallmark of the pathophysiogenesis of retinal ischemia. The direct delivery of antioxidant enzymes such as superoxide dismutase (SOD) into retinal cells provides a promising option for the down-regulation of oxidative stress in retinal ischemia, however, efficient intracellular protein delivery remains a major challenge for this application. Here, a boronic acid-rich polymer was used for the intracellular delivery of SOD both in vitro and in vivo. The polymer assembled with SOD into uniform nanoparticles with high binding affinity, and transported the cargo protein into several cell lines with maintained bioactivity and low cytotoxicity. We investigated the intraocular biodistribution, therapeutic efficacy and safety of the SOD nanoformulation in a retinal ischemia/reperfusion (I/R) injury model. After intravitreal injection, the nanoparticles rapidly diffused through the vitreous and penetrated into retinal ganglion cells (RGCs). Compared to free SOD, the nanoformulation exhibited much enhanced therapeutic efficacy with reduced RGC apoptosis and protected retinal function. Enzymatic results confirmed that the SOD nanoformulation reduced malondialdehyde expression and increased glutathione level in the ocular tissues, and thereby down-regulated oxidative stress and prevented RGC loss. Overall, this work offers a new therapeutic option for the treatment of retinal ischemic disorders by direct delivery of antioxidant proteins.

Keywords: Cytosolic protein delivery; Dendrimer; Polymer; Retinal ischemia; SOD.