Abstract

Tumour-associated macrophages (TAMs) represent an attractive cell target for anticancer therapy. However, selective and efficient targeting of TAMs remains difficult. Here, we constructed a novel dually functionalised nanoparticle platform (s-T_pep-NPs) by surface co-modification of nanoparticles (NPs) with tuftsin (T_pep) and legumain protease-sheddable polyethylene glycol 5k (PEG_5k) to achieve selective targeted delivery to TAMs. The fluorescence resonance energy transfer experiment and in vitro cellular uptake assay confirmed that s-T_pep-NPs can responsively shed PEG_5k and transform into active T_pep-NPs upon the cleavage of legumain that is overexpressed on TAM surfaces, which then promotes TAM phagocytosis through Fc receptor-mediated pathways. Owing to the shielding effect by legumain-sheddable PEG_5k, s-T_pep-NPs can effectively decrease the T_pep-induced non-specific accumulation in mononuclear phagocyte system (MPS) organs during systemic circulation. Moreover, s-T_pep-NPs can significantly enhance the tumoural accumulation and improve the specificity and efficiency of targeting to TAMs, as compared with both controls of T_pep-NPs and non-sheddable ns-T_pep-NPs. Overall, this study provides a robust nanoplatform with a novel avenue for improved selectivity of targeted delivery to TAMs.

摘要

肿瘤相关巨噬细胞 (TAM) 代表了一种有吸引力的抗癌治疗细胞靶点。然而，选择性和有效地靶向 TAM 仍然很困难。_{在这里，我们通过纳米颗粒 (NPs) 与 tuftsin (T pep} ) 和legumain 蛋白酶可脱落聚乙二醇 5k (PEG _5k )的表面共修饰构建了一种新型的双功能化纳米颗粒平台 ( s -T _pep -NPs)以实现选择性靶向交付给 TAM。荧光共振能量转移实验和体外细胞摄取试验证实s -T _pep -NPs 可以响应性脱落 PEG _5k并转化为活性 T _pep- 切割在 TAM 表面过表达的豆类蛋白后的 NP，然后通过 Fc 受体介导的途径促进 TAM 吞噬作用。由于legumain可脱落的PEG _5k的屏蔽作用，s -T _pep -NPs可以有效减少T _pep诱导的体循环期间单核吞噬细胞系统（MPS）器官中的非特异性积累。此外，与 T _pep -NPs 和不可脱落的ns -T _{pep的对照相比，} s -T _pep -NPs 可以显着增强肿瘤积累并提高靶向 TAMs 的特异性和效率-NP。总体而言，这项研究提供了一个强大的纳米平台，为提高靶向递送至 TAM 的选择性提供了一种新途径。