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 FLAP/mPEGS-1 双重抑制剂 BRP-187 封装到乙酰化葡聚糖和 PLGA 纳米颗粒中可提高其细胞生物活性。


背景 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）的双重抑制剂可能发挥更好的抗炎功效并降低不良反应的风险。尽管有这些优点，许多 FLAP/mPGES-1 双重抑制剂是酸性亲脂性分子，溶解度低，血浆蛋白结合倾向强，限制了其生物利用度和生物活性。在这里，我们展示了通过纳米沉淀将双重 FLAP/mPGES-1 抑制剂 BRP-187 封装到生物相容性聚合物乙酰化葡聚糖 (Acdex) 和聚乳酸-乙醇酸 (PLGA) 中。结果采用纳米沉淀法制备了含有BRP-187的纳米颗粒，并通过动态光散射分析了其流体动力学直径，通过扫描电子显微镜分析了形态特性，并通过紫外-可见光谱分析了药物的包封率。此外，我们设计了荧光 BRP-187 颗粒，通过流式细胞术分析，该颗粒显示出白细胞的高细胞摄取率。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，以确定药物摄取、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，并且与相比，负载 BRP-187 的基于 PLGA 和 Acdex 的颗粒在抑制完整细胞中 5-脂氧合酶产物形成和前列腺素 E2 生物合成方面更有效到游离化合物，特别是在长时间的预孵育之后。