Pluronic F127/lecithin PLGA nanoparticles as carriers of monocyte-targeted jakinibs: a potential therapeutic platform

Aim: In this study, PLGA nanoparticles (PNPs) emulsified in Pluronic F127 (F127)/Lecithin (LEC) were designed to load Itacitinib (ITA), a selective JAK1 inhibitor, for targeting human monocytes. Materials & methods: The physicochemical characteristics of empty and ITA-loaded F127/LEC PNPs were analyzed. The binding and internalization of NPs in leukocytes were evaluated. The effect of NPs on monocyte activation and JAK1 inhibition was assessed. Results: F127/LEC PNPs were selectively bound and internalized by monocytes, sparing other leukocytes. ITA-F127/LEC PNPs significantly dampened monocyte activation. They also inhibited the monocyte's ability to promote T-cell proliferation and inhibited proinflammatory cytokine production. Conclusion: ITA-loaded F127/LEC PNPs showed potential for monocyte-targeted therapy, offering new avenues for disease treatment. The F127/LEC PNPs exhibited a uniform particle size distribution with an average size exceeding 150 nm. The encapsulation efficiency of Itacitinib (ITA) in F127/LEC PNPs was 50.59%. The nanoparticles maintained stability for 10 days at four Celsius degrees, with consistent size and ζ-potential. F127/LEC PNPs were selectively bound and were internalized by monocytes, sparing other leukocyte subpopulations. This selective uptake suggests the potential for targeted drug delivery to monocytes. ITA-F127/LEC PNPs significantly reduced the release of proinflammatory cytokines (TNF-α, IL-12, IL-1β, and IL-10) in IFN-γ-stimulated monocytes. Both free and encapsulated ITA inhibited STAT1 phosphorylation in IFN-γ-stimulated monocytes, aligning with previous studies on JAK inhibitors. ITA-F127/LEC PNPs inhibited the ability of monocytes to stimulate T-cell proliferation. This effect consistently reduced surface expression markers and proinflammatory cytokine production. PLGA nanoparticles displayed a biphasic release of ITA, with an initial burst release of 34% within 4 h, followed by a slower release over the next 10 h (∼40%). The Korsmeyer-Peppas model best described the release profile, indicating a Fickian diffusion pattern. ITA-loaded F127/LEC PNPs showed promising therapeutic potential for targeting monocytes in diseases where they play a crucial role. The nanoparticles effectively suppressed monocyte activation and function in vitro, suggesting potential applications in various inflammatory diseases. Monocytes selectively bind and internalize F127/LEC PNPs, highlighting their potential as vehicles for targeted drug delivery. Encapsulation of ITA in these nanoparticles could increase local drug concentration while reducing systemic side effects. Further, in vivo research is essential to validate these findings and thoroughly assess the clinical applications of these nanoparticles. The project's next phase will focus on evaluating the biosafety, biodistribution, and in vivo therapeutic effectiveness of ITA-F127/LEC PNPs in murine models.