Dexamethasone phosphate-loaded folate-conjugated polymeric nanoparticles for selective delivery to activated macrophages and suppression of inflammatory responses

Activated macrophages play a central role in the pathology of inflammatory diseases by secreting pro-inflammatory cytokines. In this study, we have developed folate-conjugated dexamethasone phosphate (DP)-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) that can selectively target to activated macrophages for alleviation of inflammatory responses. DP was loaded into PLGA nanoparticles in an amorphous form using an ionic interaction between DP, zinc, and PLGA. Folic acid (FA) was used as a targeting ligand for activated macrophages and conjugated onto DPNPs (FA-DPNPs). The mean particle size of DPNPs and FA-DPNPs was 126 +/- 36 and 133 +/- 28 nm, respectively. The zeta potential of DPNPs and FA-DPNPs were -13.5 +/- 0.4 mV and -14.9 +/- 0.9 mV, respectively. Sustained and controlled DP release over 48 hours from DPNPs and FA-DPNPs was observed. The low cellular uptake of both DPNPs and FA-DPNPs was observed in normal RAW264.7 macrophages, whereas significantly higher cellular uptake of FA-DPNPs was observed as compared to DPNPs in activated RAW264.7 macrophages. The production of pro-inflammatory cytokines (IL-6 and TNF-alpha) and nitric oxide (NO) from activated macrophages was inhibited more significantly by FA-DPNPs than by free DP and DPNPs. Taken together, DP-loaded nanoparticles, especially when conjugated with FA, were selectively internalized by activated macrophages and effectively suppressed inflammatory responses. DP loaded folate-conjugated PLGA nanoparticles presented in this study may offer a promising approach of targeted delivery to activated macrophages for the treatment of inflammatory diseases.