Center of Excellence in Nanomedicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, Departments of NanoEngineering and Materials Science and Engineering, University of California, San Diego, La Jolla, CA, 92093, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093, USA.
Small. 2018 Aug;14(32):e1800703. doi: 10.1002/smll.201800703. Epub 2018 Jul 15.
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, a preventative inflammation-sensitive system is developed and applied to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release is 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 are pretreated 24 h before inducing inflammation. AcDex-DXM reduces overall cell infiltration with decreased neutrophils, increases monocytes, and diminishes cytokines and chemokines. In a more extended prophylaxis model, murine joints are pretreated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduces the overall joint inflammation, where neither free drug nor a conventional drug-depot achieves adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation is demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares.
对于炎症爆发的情况，从储存库中快速释放药物对于减少细胞浸润和防止长期组织破坏至关重要。虽然这个概念已经在慢性疾病中得到了探索，但预防急性炎症爆发尚未得到探索。为了解决这个问题，开发并应用了一种预防性炎症敏感系统来治疗急性痛风，在这种情况下，数以百万计的炎症细胞迅速募集，导致剧烈和使人虚弱的疼痛。首先，从负载地塞米松的 pH 响应缩醛化葡聚糖颗粒（AcDex-DXM）中快速释放药物，体外释放的地塞米松与游离药物一样高效地减少促炎细胞因子。然后，使用痛风气囊模型，在诱导炎症前 24 小时对小鼠进行预处理。AcDex-DXM 减少了整体细胞浸润，减少了中性粒细胞，增加了单核细胞，并减少了细胞因子和趋化因子。在更扩展的预防模型中，在开始炎症前八天将鼠关节预处理。在量化细胞浸润后，只有 AcDex-DXM 减少了整体关节炎症，游离药物和常规药物储存库都没有达到足够的抗炎效果。在这里，证明了疾病触发药物输送比游离药物和缓慢释放储存库更能有效预防急性炎症。这种方法和结果为多种急性炎症疾病提供了令人兴奋的治疗机会。
