The Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, U.K.
Biomacromolecules. 2024 Oct 14;25(10):6503-6514. doi: 10.1021/acs.biomac.4c00672. Epub 2024 Sep 5.
Paediatric acute myeloid leukemia (AML) is a heterogeneous hematological malignancy still heavily reliant on traditional chemotherapeutic approaches. Combination treatments have shown to be a superior approach, but their success is often hindered by side effects and different drugs' pharmacokinetics. Here, we investigated ABT-737 and Purvalanol A as a potential drug pairing for pediatric AML and described the development of CD33-targeted polymeric nanoparticles (NPs) to enable their simultaneous targeted codelivery. Separate drug encapsulation within poly(lactic--glycolic acid) (PLGA) NPs was optimized prior to coencapsulation of both drugs at a synergistic ratio in PEGylated PLGA NPs. The therapeutic effects of formulations were evaluated in a panel of pediatric AML cells, and dual drug-loaded NPs (dual NPs) demonstrated significantly enhanced apoptotic cell death. Moreover, conjugation to gemtuzumab resulted in improved NP binding and internalization in CD33-positive cells. Finally, CD33-targeted dual-loaded NPs showed enhanced cytotoxicity to CD33-positive AML cells via CD33-mediated targeted drug delivery.
儿科急性髓细胞白血病（AML）是一种异质性血液恶性肿瘤，仍然严重依赖于传统的化疗方法。联合治疗已被证明是一种更优越的方法，但它们的成功往往受到副作用和不同药物药代动力学的影响。在这里，我们研究了 ABT-737 和 Purvalanol A 作为儿科 AML 的潜在药物组合，并描述了靶向 CD33 的聚合物纳米颗粒（NPs）的开发，以实现它们的同时靶向共递。在聚（乳酸-乙醇酸）（PLGA）NPs 中分别包封药物，然后在聚乙二醇化 PLGA NPs 中以协同比例共包封两种药物，对制剂进行了优化。在一系列儿科 AML 细胞中评估了制剂的治疗效果，双载药 NPs（dual NPs）显示出明显增强的细胞凋亡。此外，与吉妥珠单抗缀合可提高 CD33 阳性细胞中 NP 的结合和内化。最后，通过 CD33 介导的靶向药物递送，CD33 靶向的双载药 NPs 对 CD33 阳性 AML 细胞表现出增强的细胞毒性。
