BACKGROUND Dual inhibitors of the 5-lipoxygenase-activating protein (FLAP) and the microsomal prostaglandin E2 synthase-1 (mPGES-1) may exert better anti-inflammatory efficacy and lower risks of adverse effects versus non-steroidal anti-inflammatory drugs. Despite these advantages, many dual FLAP/mPGES-1 inhibitors are acidic lipophilic molecules with low solubility and strong tendency for plasma protein binding that limit their bioavailability and bioactivity. Here, we present the encapsulation of the dual FLAP/mPGES-1 inhibitor BRP-187 into the biocompatible polymers acetalated dextran (Acdex) and poly(lactic-co-glycolic acid) (PLGA) via nanoprecipitation. RESULTS The nanoparticles containing BRP-187 were prepared by the nanoprecipitation method and analyzed by dynamic light scattering regarding their hydrodynamic diameter, by scanning electron microscopy for morphology properties, and by UV-VIS spectroscopy for determination of the encapsulation efficiency of the drug. Moreover, we designed fluorescent BRP-187 particles, which showed high cellular uptake by leukocytes, as analyzed by flow cytometry. Finally, BRP-187 nanoparticles were tested in human polymorphonuclear leukocytes and macrophages to determine drug uptake, cytotoxicity, and efficiency to inhibit FLAP and mPGES-1. CONCLUSION Our results demonstrate that encapsulation of BRP-187 into Acdex and PLGA is feasible, and both PLGA- and Acdex-based particles loaded with BRP-187 are more efficient in suppressing 5-lipoxygenase product formation and prostaglandin E2 biosynthesis in intact cells as compared to the free compound, particularly after prolonged preincubation periods.

中文翻译：

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将双FLAP / mPEGS-1抑制剂BRP-187封装到缩醛化的葡聚糖和PLGA纳米颗粒中可改善其细胞生物活性。

背景技术与非甾体抗炎药相比，5-脂氧合酶激活蛋白（FLAP）和微粒体前列腺素E2合酶-1（mPGES-1）的双重抑制剂可发挥更好的抗炎功效，并降低不良反应的风险。尽管具有这些优点，许多双重FLAP / mPGES-1抑制剂是酸性亲脂性分子，具有低溶解度和很强的血浆蛋白结合趋势，从而限制了它们的生物利用度和生物活性。在这里，我们介绍了通过纳米沉淀将双FLAP / mPGES-1抑制剂BRP-187封装到生物相容性聚合物中，包括乙缩醛化的葡聚糖（Acdex）和聚乳酸-乙醇酸（PLGA）。结果采用纳米沉淀法制备了含BRP-187的纳米颗粒，并通过动态光散射对其流体动力学直径进行了分析，通过扫描电子显微镜观察其形态特征，并通过紫外可见光谱法确定药物的包封效率。此外，我们设计了荧光BRP-187颗粒，通过流式细胞仪分析，该颗粒显示出白细胞对细胞的高摄取。最后，在人多形核白细胞和巨噬细胞中测试了BRP-187纳米颗粒，以确定药物的吸收，细胞毒性以及抑制FLAP和mPGES-1的效率。结论我们的结果表明，将BRP-187封装到Acdex和PLGA中是可行的，并且与BGA-187和基于Acdex的BRP-187颗粒相比，在完整细胞中抑制5-脂氧合酶产物的形成和前列腺素E2的生物合成更有效。游离化合物，尤其是在延长的预温育期后。