Cation instructed steroidal prodrug supramolecular hydrogel

In the present study, we propose an ionic coordination strategy for the design of a steroidal prodrug supramolecular hydrogel. The hydrogel composed of nanofibril networks formed spontaneously by the introduction of divalent cations (e.g., Mg2+, Ca2+, Zn2+ and Fe2+) and NH4+ to a succinated dexamethasone (Dex-SA) aqueous solution at room temperature. The formation of the nanofibril structure was dominantly driven by the ionic coordination with the assistance of a delicate balance of multiple noncovalent interactions. A rheological analysis indicated that the formed Ca2+/Dex-SA supramolecular hydrogel exhibits dominant elastic and thixotropic properties. The formed Ca2+/Dex-SA supramolecular hydrogel allowed the gradual release of Dex and Dex-SA in vitro, and the drug release behaviour can be finely tuned by changing the Ca2+ concentration. Storage stability studies showed that Dex-SA in hydrogel underwent an apparent chemical decomposition at 4 °C and 37 °C. In contrast, the Dex-SA xerogel was quite stable without any obvious chemical decomposition of Dex-SA in storage at -20 °C for 35 days, and it was able to turn into a hydrogel again within one minute after rehydration. The formed Ca2+/Dex-SA supramolecular hydrogel caused negligible cytotoxicity against HCEC and L-929 cells at drug concentrations up to 2 mM, as indicated by the in vitro cytotoxicity tests. Additionally, the proposed Ca2+/Dex-SA supramolecular hydrogel displayed a comparable anti-inflammatory efficacy with Dexp via the downregulation of NO, TNF-α and IL-6 expression in lipopolysaccharide (LPS)-activated RAW264.7 macrophage. Overall, the cation instructed steroidal prodrug supramolecular hydrogel might be a promising ophthalmic drug delivery system for anti-inflammatory therapy.