Sequential drug release of co-assembled supramolecular hydrogel as synergistic therapy against Staphylococcus aureus endophthalmitis

Abstract Although endophthalmitis is a serious sight-threatening disorder, combining anti-inflammatory agents and antibiotics has provided new methods for effectively controlling it. This paper reports that the co-assembly of a sparingly soluble antibiotic (levofloxacin; Lev) and dexamethasone-peptide amphiphile (Dex-SA-RGD) instantly generates a macroscopically supramolecular hydrogel (Lev/Dex-SA-RGD) without any external stimulus under physiological conditions, which could be used in synergistic therapy to cure endophthalmitis induced by Staphylococcus aureus (i.e., S. aureus). The resulting co-assembled supramolecular hydrogel was thoroughly characterized using rheology, circular dichroism, and transmission electron microscopy. An in vitro drug release study showed that Lev was rapidly released from the supramolecular hydrogel within 6 h, while Dex-SA-RGD escaped from the supramolecular hydrogel as a result of matrix erosion, and then acted as a prodrug to provide the sequentially slow release of active dexamethasone via the hydrolytic route. The Lev/Dex-SA-RGD supramolecular hydrogel showed high antibacterial activities against both gram-negative and gram-positive strains. Moreover, a rabbit endophthalmitis model induced by S. aureus showed that the intravitreal injection of the Lev/Dex-SA-RGD supramolecular hydrogel resulted in excellent therapeutic efficacy with no apparent damage or destruction of the retina, and dramatically suppressed inflammatory responses (e.g., leukocyte and lymphocyte infiltration, microglial activation, cytokine production, and retinal cell death). As a rational approach to investigate and apply the co-assembled hydrogel, this work presents the potential of synergistic intervention to prevent retinal tissue damage and vision impairment, and ultimately shows the clinical benefits of using supramolecular hydrogels for ocular drug delivery.