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

<b>Aim:</b> 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. <b>Materials &amp; methods:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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 <i>in vitro</i>, 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, <i>in vivo</i> 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 <i>in vivo</i> therapeutic effectiveness of ITA-F127/LEC PNPs in murine models.