Improved Bioactivity of the Natural Product 5-Lipoxygenase Inhibitor Hyperforin by Encapsulation into Polymeric Nanoparticles
| Autor: | Susanna Voelker, Michael Gottschaldt, Blerina Shkodra-Pula, Christian Kretzer, Anja Traeger, Stephanie Schubert, Ulrich S. Schubert, Oliver Werz |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Neutrophils Anti-Inflammatory Agents Pharmaceutical Science Blood Donors Capsules Serum Albumin Human 02 engineering and technology Plasma protein binding Phloroglucinol 030226 pharmacology & pharmacy 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems 0302 clinical medicine Prenylation Drug Discovery medicine Humans Lipoxygenase Inhibitors Cells Cultured Biological Products Arachidonate 5-Lipoxygenase biology Plant Extracts Terpenes Chemistry Albumin Water 021001 nanoscience & nanotechnology Human serum albumin Healthy Volunteers Hyperforin Dextran Solubility Lipophilicity Arachidonate 5-lipoxygenase Biophysics biology.protein Nanoparticles Molecular Medicine 0210 nano-technology Hypericum Protein Binding medicine.drug |
| Zdroj: | Molecular Pharmaceutics. 17:810-816 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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