Disease‐Triggered Drug Release Effectively Prevents Acute Inflammatory Flare‐Ups, Achieving Reduced Dosing

For conditions with inflammatory flare-ups, fast drug-release from a depot is crucial to reduce cell infiltration and prevent long-term tissue destruction. While this concept has been explored for chronic diseases, preventing acute inflammatory flares has not been explored. To address this issue, we developed a preventative inflammation-sensitive system and applied it to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release was first demonstrated from a pH-responsive acetalated dextran particle loaded with dexamethasone (AcDex-DXM), reducing proinflammatory cytokines in vitro as efficiently as free drug. Then, using the air pouch model of gout, mice were pre-treated 24 hours before inducing inflammation. AcDex-DXM reduced overall cell infiltration with decreased neutrophils, increased monocytes, and diminished cytokines and chemokines. In a more extended prophylaxis model, murine joints were pre-treated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduced the overall joint inflammation, where neither free drug nor a conventional drug-depot achieved adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation was demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares.