Core-Cross-Linking of Polymeric Micelles by Di-para-Substituted S‑Aroylthiooximes as Linkers for Controlled H₂S Release

As one of the gasotransmitters, the therapeutic effects of hydrogen sulfide (H₂S) were reported widespread in recent years. Considering the short physiological half-life and significant dose-dependent effects of H₂S, it is vital to achieve controlled H₂S delivery for biomedical applications. Polymeric micelles have been explored to regulate H₂S delivery. However, the dilution-induced dissociation of micelles in physiological conditions limits their therapeutic effects. The circulation stability of polymeric micelles could be improved through core-cross-linking, but reduced H₂S releasing efficiency is usually unavoidable. To solve these problems, we developed di-para-substituted S-aroylthiooximes (p-diSATOs) as linkers, which integrated cross-linking of micelle core and conjugation of H₂S donors through one simple reaction. Compared with SATO-bearing non-cross-linked micelle, the core-cross-linked micelle (CCM) prepared through this method exhibited initial rapid H₂S release owing to the electron-withdrawing effect of p-diSATOs, and subsequently, a sustained release could last for a long period of time. Considering the characteristic H₂S releasing behavior of CCM, it may accelerate wound healing through initial efficient and subsequent prolonged pro-healing effects. As a proof of concept, we explored the therapeutic potential of CCM using a murine burn wound model, which exhibited pro-healing effect on burn wounds.