Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
R&D Reagents, Chemical Biology Department, Miltenyi Biotec B.V. & Co. KG, 51429 Bergisch Gladbach, Germany.
Int J Mol Sci. 2023 Jan 11;24(2):1392. doi: 10.3390/ijms24021392.
Prostaglandin E2 (PGE2) is an important maturation mediator for dendritic cells (DCs). However, increased PGE2 levels in the tumor exert immunosuppressive effects on DCs by signaling through two E-Prostanoid (EP) receptors: EP2 and EP4. Blocking EP-receptor signaling of PGE2 with antagonists is currently being investigated for clinical applications to enhance anti-tumor immunity. In this study, we investigated a new delivery approach by encapsulating EP2/EP4 antagonists in polymeric nanoparticles. The nanoparticles were characterized for size, antagonist loading, and release. The efficacy of the encapsulated antagonists to block PGE2 signaling was analyzed using monocyte-derived DCs (moDCs). The obtained nanoparticles were sized between 210 and 260 nm. The encapsulation efficacy of the EP2/EP4 antagonists was 20% and 17%, respectively, and was further increased with the co-encapsulation of both antagonists. The treatment of moDCs with co-encapsulation EP2/EP4 antagonists prevented PGE2-induced co-stimulatory marker expression. Even though both antagonists showed a burst release within 15 min at 37 °C, the nanoparticles executed the immunomodulatory effects on moDCs. In summary, we demonstrate the functionality of EP2/EP4 antagonist-loaded nanoparticles to overcome PGE2 modulation of moDCs.
前列腺素 E2（PGE2）是树突状细胞（DCs）成熟的重要介质。然而，肿瘤中 PGE2 水平的升高通过两种 E-前列腺素（EP）受体：EP2 和 EP4 信号传导对 DCs 发挥免疫抑制作用。目前正在研究用拮抗剂阻断 PGE2 的 EP 受体信号传导，以用于增强抗肿瘤免疫的临床应用。在这项研究中，我们通过将 EP2/EP4 拮抗剂包封在聚合物纳米粒子中，研究了一种新的递药方法。对纳米粒子的大小、拮抗剂的负载和释放进行了表征。使用单核细胞衍生的树突状细胞（moDCs）分析了封装的拮抗剂阻断 PGE2 信号的功效。获得的纳米粒子的粒径在 210nm 至 260nm 之间。EP2/EP4 拮抗剂的包封效率分别为 20%和 17%，并且通过共包封两种拮抗剂进一步增加。用共包封的 EP2/EP4 拮抗剂处理 moDCs 可防止 PGE2 诱导的共刺激标志物表达。尽管两种拮抗剂在 37°C 下 15 分钟内均迅速释放，但纳米粒子对 moDCs 仍具有免疫调节作用。总之，我们证明了载有 EP2/EP4 拮抗剂的纳米粒子可克服 PGE2 对 moDCs 的调节作用。
