促炎细胞因子
免疫系统
药理学
败血症
伏立诺他
炎症
PLGA公司
趋化因子
脂多糖
化学
免疫学
组蛋白脱乙酰基酶
癌症研究
医学
生物化学
组蛋白
体外
基因
作者
Nhu Truong,Andrea L. Cottingham,Shruti Dharmaraj,Jacob R. Shaw,Jackline Joy Lasola,Christopher C. Goodis,Steven Fletcher,Ryan M. Pearson
摘要
Excessive immune activation and immunosuppression are opposing factors that contribute to the dysregulated innate and adaptive immune responses seen in severe inflammation and sepsis. Here, a novel analog of the histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA-OH), was incorporated into immunomodulatory poly(lactic acid)-based nanoparticles (iNP-SAHA) by employing a prodrug approach through the covalent modification of poly(lactic-co-glycolic acid) (PLGA) with SAHA-OH. iNP-SAHA formulation allowed for controlled incorporation and delivery of SAHA-OH from iNP-SAHA and treatment led to multimodal biological responses including significant reductions in proinflammatory cytokine secretions and gene expression, while increasing the survival of primary macrophages under lipopolysaccharide (LPS) challenge. Using a lethal LPS-induced endotoxemia mouse model of sepsis, iNP-SAHA administration improved the survival of mice in a dose-dependent manner and tended to improve survival at the lowest doses compared to iNP control. Further, iNP-SAHA reduced the levels of plasma proinflammatory cytokines and chemokines associated with sepsis more significantly than iNP and similarly improved inflammation-induced spleen and liver toxicity as iNP, supporting its potential polypharmacological activity. Collectively, iNP-SAHA offers a potential drug delivery approach to modulate the multifaceted inflammatory responses observed in diseases such as sepsis.
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