多功能纳米颗粒已引起肿瘤学和癌症治疗领域的重视。事实上，它们能够通过创建一个刺激响应的靶向药物传递系统来解决肿瘤治疗关键点，该系统可以在体内循环中稳定存在，有效穿透肿瘤组织，然后大量积聚在肿瘤细胞中。本研究通过静电相互作用，在阳离子药物载体（聚（β-氨基酯-胆固醇，PAE-Chol））上涂覆了一个肿瘤酸度敏感的“可脱落”FA修饰的β-羧酸酰胺官能化PEG层（叶酸-聚乙二醇-2,3-二甲基马来酸酐，FA-PEG-DA），制备出一款新型的逐级pH响应多功能纳米颗粒（FPDPCNPs/DTX）以用于靶向传递抗肿瘤药物多西紫杉醇（DTX）。通过zeta电位测定，确认了FPDPCNPs/DTX的电荷屏蔽行为。纳米颗粒的表面电荷在涂覆PEG后能够从正电变为负电。细胞毒性实验中，FDPCNPs/DTX的IC50值比PEG“不可脱落”纳米颗粒高出3.04倍。体内实验结果进一步显示，FPDPCNPs/DTX具有增强的肿瘤靶向效应，FPDPCNPs/DTX的肿瘤抑制率高达81.99%，是游离DTX的1.51倍。在酸性微环境和叶酸受体（FR）介导的靶向作用下，FPDPCNPs/DTX促进了MCF-7细胞对DTX的摄取。总之，作为一种多功能纳米药物传递系统，FPDPCNPs/DTX为高效传递抗肿瘤药物提供了有希望的策略。版权所有 © 2023 Elsevier B.V. 发表。

Multifunctional nanoparticles have attracted significant attentions for oncology and cancer treatment. In fact, they could address critical point for tumour treatment by creating a stimuli-responsive targeted drug delivery system that can exist stably in the systemic circulation, efficiently penetrate the tumour tissue, and then accumulate in tumour cells in large quantities. A novel stepwise pH-responsive multifunctional nanoparticles (FPDPCNPs/DTX) for targeted delivery of the antitumour drug docetaxel (DTX) is prepared by coating a tumour acidity-sensitive "sheddable" FA modified β-carboxylic amide functionalized PEG layer (folic acid-polyethylene glycol-2,3-dimethylmaleic anhydride, FA-PEG-DA) on the cationic drug-loaded core (poly(β-amino ester-cholesterol, PAE-Chol) through electrostatic interaction in this study. The charge shielding behavior of the FPDPCNPs/DTX was confirmed by zeta potential assay. The surface charges of the nanoparticles can change from positive to negative after PEG coating. The IC50 values of FDPCNPs/DTX was 3.04 times higher than that of PEG "unsheddable" nanoparticles in cytotoxicity experiments. The results of in vivo experiment further showed that FPDPCNPs/DTX had enhanced tumour targeting effect, the tumour inhibition rate of FPDPCNPs/DTX was as high as 81.99%, which was 1.51 times that of free DTX. Under a micro acidic environment and folate receptor (FR)-mediated targeting, FPDPCNPs/DTX contributed to more uptake of DTX by MCF-7 cells. In summary, FPDPCNPs/DTX as a multifunctional nano-drug delivery system provides a promising strategy for efficiently delivering antitumour drugs.Copyright © 2023. Published by Elsevier B.V.