Legumain protease-sheddable PEGylated, tuftsin-modified nanoparticles for selective targeting to tumour-associated macrophages

• Published in: Journal of drug targeting 2022-01, Vol.30 (1), p.82-93
• Main Authors: Liang, De-Sheng, Wen, Zu-Jun, Wang, Jia-Hui, Zhu, Fang-Fang, Guo, Feng, Zhou, Jian-Liang, Xu, Jian-Jun, Zhong, Hai-Jun
• Format: Article
• Language: English
• Subjects: Legumain-sheddable PEGylation; nanoparticles; selective targeting; tuftsin-modified; tumour-associated macrophage
• ISSN: 1061-186X; 1029-2330
• DOI: 10.1080/1061186X.2021.1906886

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.