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

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Disease‐Triggered Drug Release Effectively Prevents Acute Inflammatory Flare‐Ups, Achieving Reduced Dosing
Small ( IF 13.0 ) Pub Date : 2018-07-15 , DOI: 10.1002/smll.201800703
Alexandra Stubelius ₁ , Wangzhong Sheng ₁ , Sangeun Lee ₁ , Jason Olejniczak ₂ , Monica Guma ₃ , Adah Almutairi ₁

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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.

中文翻译：

疾病引发的药物释放有效预防急性炎症发作，实现减少剂量

对于炎症发作的情况，从储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。虽然这一概念已被探索用于慢性疾病，但预防急性炎症发作尚未被探索。为了解决这个问题，开发了一种预防性炎症敏感系统，并将其应用于急性痛风，这种疾病会迅速招募数以百万计的炎症细胞，导致难以忍受和衰弱的疼痛。首先证明了负载地塞米松 (AcDex-DXM) 的 pH 响应性乙醛化葡聚糖颗粒可快速释放药物，与游离药物一样有效地在体外减少促炎细胞因子。然后，使用痛风气囊模型，在诱导炎症前对小鼠进行 24 小时预处理。 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。在更广泛的预防模型中，在引发炎症前八天对小鼠关节进行预处理。在量化细胞浸润后，只有 AcDex-DXM 可以减轻整体关节炎症，其中游离药物和传统药物长效制剂都无法达到足够的抗炎作用。在此，证明了疾病触发的药物递送在预防急性炎症方面比游离药物和缓释储库具有优越的功效。这种方法和结果为患有急性发作的多种炎症性疾病提供了令人兴奋的治疗机会。

更新日期：2018-07-15

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