Abstract
Purpose :
Bacterial endophthalmitis is a debilitating infectious disease caused by bacterial pathogens introduced into the eye during surgery or trauma, leading to blindness. Our study found that in endophthalmitis, the protective antioxidant activity of glutathione peroxidase 4 (GPX4) is significantly diminished, enhancing retinal cell death via ferroptosis, a process dependent on iron and toxic lipid accumulation. We hypothesized that selenium (Se) is an essential component of GPX4, and Se nanoparticle formulation with antibiotic targeting could potentially attenuate ferroptosis and improve cell survival during this endophthalmitis.
Methods :
Selenium nanoparticles (SeNPs) were synthesized and tested alone or in combination with the antibiotic vancomycin. In vitro studies were conducted using mouse bone marrow-derived macrophages (BMDMs) or retinal Müller glia cells challenged with Staphylococcus aureus. The direct antimicrobial activity of SeNPs was evaluated using broth dilution and disc diffusion methods against methicillin-resistant S. aureus (MRSA) and the laboratory strain RN6390. In vivo studies were performed by intravitreal injection of SeNPs in a mouse model of S. aureus endophthalmitis. The progression of the disease was evaluated using non-invasive methods such as electroretinography (ERG), as well as invasive methods including assessment of bacterial burden and cytokine levels.
Results :
Our nanoformulations revealed that the SeNPs had a size range of 40-60 nm with a negative zeta potential. The loading of vancomycin onto these nanoparticles was found to be 92%. Our data demonstrated that Selenium nanoformulations exhibited potent antibacterial activity against S. aureus, including MRSA and RN6390 strains, with a minimum inhibitory concentration (MIC) of 0.5ug/ml. Furthermore, SeNPs treatment restored GPX4 levels, reduced lipid peroxidation, and inhibited bacterial-induced ferroptosis in retinal cells.
Conclusions :
Our findings demonstrate that SeNPs loaded with vancomycin effectively kill bacterial strains and enhance antioxidant signaling by increasing GPX4 expression. Thus, this dual-acting nanoformulations holds promise as a therapeutic agent for bacterial endophthalmitis
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.