Encapsulation of the novel mPGES-1 inhibitor TG554 in acetalated dextran nanoparticles

Abstract

Chronic inflammatory conditions remain a major therapeutic challenge, driving the demand for more selective and well-tolerated treatment options. The 2-amino-1,3,4-oxadiazole-based TG554, a novel and highly potent inhibitor of microsomal prostaglandin E₂ synthase-1 (mPGES-1), offers a promising route to more precisely modulate inflammation. However, its lipophilicity necessitates an advanced drug delivery approach. To overcome its solubility-related limitations, a biodegradable acetalated dextran (AcDex) nanoparticle system was developed using a robust batch nanoprecipitation protocol performed under cleanroom conditions following a predefined batch record. The resulting TG554-loaded AcDex nanoparticles exhibited favorable physicochemical properties, including a narrow size distribution profile, sufficient drug loading, and excellent colloidal stability. Their hydrodynamic properties, morphology, degradation behavior, and encapsulation efficiency were assessed using dynamic light scattering (DLS), scanning electron microscopy (SEM), and high-performance liquid chromatography (HPLC). In human pro-inflammatory M1 monocyte-derived macrophages (M1-MDM), the nanoparticles demonstrated high biocompatibility, cellular uptake, and efficient intracellular drug delivery, resulting in marked biological activity as confirmed by flow cytometry, confocal microscopy, and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analysis. Together, this work reports a robust biopolymer-based nanoformulation of TG554 that provides a strong foundation for further preclinical investigations and future in vivo evaluation.