Tailored PGE2 Immunomodulation of moDCs by Nano-Encapsulated EP2/EP4 Antagonists

• Published in: International journal of molecular sciences Vol. 24; no. 2; p. 1392
• Main Authors: Bödder, Johanna, Kok, Leanne M, Fauerbach, Jonathan A, Flórez-Grau, Georgina, de Vries, I Jolanda M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11-01-2023; MDPI
• Subjects: Antagonists; Blocking; Cancer; Clinical trials; delivery; Dendritic cells; Dinoprostone - metabolism; Encapsulation; EP2/EP4 antagonist; Genotype & phenotype; Immunomodulation; Immunotherapy; Monocytes; Monocytes - metabolism; Nanoparticles; Prostaglandin E2; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Tumor necrosis factor-TNF; Tumors; EP2/EP4 antagonist; delivery; dendritic cells; nanoparticles; prostaglandin E2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.