Development of CD33-Targeted Dual Drug-Loaded Nanoparticles for the Treatment of Pediatric Acute Myeloid Leukemia.

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2024-10-14 Epub Date: 2024-09-05 DOI:10.1021/acs.biomac.4c00672

Ana M Carvalho, Michelle K Greene, Peter Smyth, Alexander Mutch, Kirsty M McLaughlin, Lauren V Cairns, Ken I Mills, Karen D McCloskey, Christopher J Scott

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Abstract

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-co-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.

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开发用于治疗小儿急性髓性白血病的 CD33 靶向双药物载体纳米粒子

小儿急性髓性白血病（AML）是一种异质性血液恶性肿瘤，目前仍严重依赖传统的化疗方法。联合治疗已被证明是一种优越的方法，但其成功往往受到副作用和不同药物药代动力学的阻碍。在此，我们研究了 ABT-737 和 Purvalanol A 作为治疗小儿急性髓细胞性白血病的潜在配对药物，并介绍了 CD33 靶向聚合物纳米颗粒（NPs）的开发过程，以实现它们的同步靶向联合给药。先优化了聚乳酸-聚乙二醇酸（PLGA）NPs中的单独药物封装，然后在PEG化的PLGA NPs中以协同比例共同封装两种药物。在一组儿科急性髓细胞性白血病细胞中对制剂的治疗效果进行了评估，结果表明，双重药物负载的 NPs（双重 NPs）显著增强了细胞凋亡。此外，与吉妥珠单抗共轭可改善 NP 在 CD33 阳性细胞中的结合和内化。最后，CD33 靶向双载药 NPs 通过 CD33 介导的靶向药物递送增强了对 CD33 阳性 AML 细胞的细胞毒性。

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来源期刊

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.