Development and evaluation of glycine conjugated polypropyleneimine dendrimers for targeted chloroquine delivery

Abstract This study investigates the synthesis and evaluation of glycine-conjugated 5.0G polypropyleneimine dendrimers as an advanced nanocarrier system for the selective delivery of chloroquine. 5.0G PPI dendrimers were synthesized via a divergent method and subsequently conjugated with glycine. Comprehensive characterization confirmed the successful modification and an increase in nanocarrier size. Drug loading studies demonstrated a significantly enhanced entrapment of chloroquine (57.5% vs. 44.5%) in glycine-conjugated formulations, attributed to the potential complexation and sealing of dendritic branches. In vitro release profiles revealed a substantial reduction in chloroquine release from the glycine-coated dendrimers, indicating a sustained-release capability crucial for prolonged therapeutic action (only 32.07% release over 24 h compared to 88.80% from uncoated). Crucially, macrophage uptake studies indicated a four-fold reduction in phagocytic uptake of glycine-conjugated formulations, suggesting an effective bypass of macrophage recognition, thereby potentially minimizing non-specific clearance. In vivo pharmacokinetic analyses in rats showed a prolonged plasma concentration of chloroquine with the glycine-conjugated system, extending detectability up to 11 h. Furthermore, organ distribution studies highlighted a remarkable increase in liver accumulation (45.6% of the initial dose) compared to uncoated dendrimers or free drug, indicating highly effective liver targeting. These findings highlight the significant potential of glycine-conjugated PPI dendrimers to achieve highly efficient and sustained targeted drug delivery, particularly to the liver, while simultaneously reducing macrophage-mediated clearance.