Development of CD33-Targeted Dual Drug-Loaded Nanoparticles for the Treatment of Pediatric\nAcute Myeloid Leukemia

Paediatric acute\nmyeloid leukemia (AML) is a heterogeneous hematological\nmalignancy still heavily reliant on traditional chemotherapeutic approaches.\nCombination treatments have shown to be a superior approach, but their\nsuccess is often hindered by side effects and different drugs’\npharmacokinetics. Here, we investigated ABT-737 and Purvalanol A as\na potential drug pairing for pediatric AML and described the development\nof CD33-targeted polymeric nanoparticles (NPs) to enable their simultaneous\ntargeted codelivery. Separate drug encapsulation within poly(lactic-<i>co</i>-glycolic acid) (PLGA) NPs was optimized prior to coencapsulation\nof both drugs at a synergistic ratio in PEGylated PLGA NPs. The therapeutic\neffects of formulations were evaluated in a panel of pediatric AML\ncells, and dual drug-loaded NPs (dual NPs) demonstrated significantly\nenhanced apoptotic cell death. Moreover, conjugation to gemtuzumab\nresulted in improved NP binding and internalization in CD33-positive\ncells. Finally, CD33-targeted dual-loaded NPs showed enhanced cytotoxicity\nto CD33-positive AML cells via CD33-mediated targeted drug delivery.