Improved Bioactivity of the Natural Product 5-Lipoxygenase Inhibitor Hyperforin by Encapsulation into Polymeric Nanoparticles.,Molecular Pharmaceutics

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Improved Bioactivity of the Natural Product 5-Lipoxygenase Inhibitor Hyperforin by Encapsulation into Polymeric Nanoparticles.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-02-07 , DOI: 10.1021/acs.molpharmaceut.9b01051
Anja Traeger _{1,

2} , Susanna Voelker ₃ , Blerina Shkodra-Pula ₁ , Christian Kretzer ₃ , Stephanie Schubert _{2,

4} , Michael Gottschaldt _{1,

2} , Ulrich S Schubert _{1,

2} , Oliver Werz _{2,

3}

Affiliation

Hyperforin, a highly hydrophobic prenylated acylphloroglucinol from the medical plant St. John's Wort, possesses anti-inflammatory properties and suppresses the formation of proinflammatory leukotrienes by inhibiting the key enzyme 5-lipoxygenase (5-LO). Despite its strong effectiveness and the unique molecular mode of interference with 5-LO, the high lipophilicity of hyperforin hampers its efficacy in vivo and, thus, impairs its therapeutic value, especially because of poor water solubility and strong plasma (albumin) protein binding. To overcome these hurdles that actually apply to many other hydrophobic 5-LO inhibitors, we have encapsulated hyperforin into nanoparticles (NPs) consisting of acetalated dextran (AcDex) to avoid plasma protein binding and thus improve its cellular supply under physiologically relevant conditions. Encapsulated hyperforin potently suppressed 5-LO activity in human neutrophils, but it failed to interfere with 5-LO activity in a cell-free assay, as expected. In the presence of human serum albumin (HSA), hyperforin was unable to inhibit cellular 5-LO activity, seemingly because of strong albumin binding. However, when encapsulated into NPs, hyperforin caused strong inhibition of 5-LO activity in the presence of HSA. Together, encapsulation of the highly hydrophobic hyperforin as a representative of lipophilic 5-LO inhibitors into AcDex-based NPs allows for efficient inhibition of 5-LO activity in neutrophils in the presence of albumin because of effective uptake and circumvention of plasma protein binding.

中文翻译：

通过封装到聚合物纳米粒子中，天然产物5-脂氧合酶抑制剂Hyperforin的生物活性得到改善。

Hyperforin是来自药用植物St. John's Wort的高度疏水的烯丙基化酰基间苯三酚，具有抗炎特性，并通过抑制关键酶5-脂氧合酶（5-LO）抑制促炎性白三烯的形成。尽管Hyperforin具有强大的功效和独特的干扰5-LO的分子模式，但其高亲脂性却阻碍了其在体内的功效，因此损害了其治疗价值，尤其是由于水溶性差和血浆（白蛋白）蛋白结合力强。为了克服实际上适用于许多其他疏水性5-LO抑制剂的这些障碍，我们将Hyperforin封装在由缩醛化葡聚糖（AcDex）组成的纳米颗粒（NPs）中，以避免血浆蛋白结合，从而在生理相关条件下改善其细胞供应。胶囊化的hyperforin在人嗜中性粒细胞中有效抑制了5-LO的活性，但正如预期的那样，它在无细胞试验中未能干扰5-LO的活性。在人血清白蛋白（HSA）存在的情况下，hyperforin不能抑制细胞的5-LO活性，这似乎是由于强白蛋白结合所致。但是，当被封装到NP中时，在HSA存在下，hyperforin会强烈抑制5-LO活性。总之，将高疏水性高蛋白作为亲脂性5-LO抑制剂的代表封装到基于AcDex的NP中，可以有效抑制白蛋白存在下嗜中性粒细胞中的5-LO活性，这是由于有效摄取和规避了血浆蛋白结合。如预期的那样。在人血清白蛋白（HSA）存在的情况下，hyperforin不能抑制细胞的5-LO活性，这似乎是由于强白蛋白结合所致。但是，当被封装到NP中时，在HSA存在下，hyperforin会强烈抑制5-LO活性。总之，将高疏水性高蛋白作为亲脂性5-LO抑制剂的代表封装到基于AcDex的NP中，可以有效抑制白蛋白存在下嗜中性粒细胞中的5-LO活性，这是由于有效摄取和规避了血浆蛋白结合。如预期的那样。在人血清白蛋白（HSA）存在的情况下，hyperforin不能抑制细胞的5-LO活性，这似乎是由于强白蛋白结合所致。但是，当被封装到NP中时，在HSA存在下，hyperforin会强烈抑制5-LO活性。总之，将高疏水性高蛋白作为亲脂性5-LO抑制剂的代表封装到基于AcDex的NP中，可以有效抑制白蛋白存在下嗜中性粒细胞中的5-LO活性，这是由于有效摄取和规避了血浆蛋白结合。

更新日期：2020-02-10

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