期刊
COLLOIDS AND SURFACES B-BIOINTERFACES
卷 197, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.colsurfb.2020.111442
关键词
Legumain protease-activable; Tuftsin; Tumor-associated macrophage; Dual-targeting; Cancer chemotherapy
资金
- National Natural Science Foundation of China [81760640, 81560576]
- Youth Science Foundation of Jiangxi Province of China [20192BAB215062]
- cultivation project of scientific research of Medical Department of Nanchang University [PY201809]
In this study, a novel dual-targeting nanoparticle system for TAMs and tumor cells was developed for cancer chemotherapy. The system can be activated to promote tumor cells internalization and TAMs phagocytosis, leading to enhanced efficacy against tumor growth and TAMs depletion.
M2 tumor-associated macrophages (TAMs) play a pivotal role in cancer progression and therapy resistance. Inhibition of TAMs is of great significance to reshape the protumor environment to benefit therapeutic outcomes. In this work, we developed a novel TAMs and tumor cells dual-targeting nanoparticle (AT(pep)-NPs) system for cancer chemotherapy by integrating a docetaxel (DTX)-loaded nanocarrier and a multi-function peptide AT(pep), which is composed of a phagocytosis-stimulating peptide-tuftsin (T-pep) fused with a substrate peptide-alaninealanine-asparagine (AAN) of endoprotease legumain. In vitro protelytic and cellular uptake assays confirmed AT(pep)-NPs can be responsively activated into T-pep-NPs by cleavage of legumain that is overexpressed in both tumor cells and TAMs, which then promoted tumor cells internalization and TAMs phagocytosis through neuropilin-1/Fc receptor pathways. Due to AAN deactivation effect, AT(pep)-NPs can effectively decrease the T-pep-induced non-specific uptake by M1-polarized and normal macrophage during systemic circulation. Our results of in vivo experiments demonstrated AT(pep)-NPs outperformed T-pep-NPs in tumor and TAMs dual-targeting delivery efficiency with markedly enhanced efficacy against both tumor growth inhibition and TAMs depletion. Overall, this study offers a novel approach for development of multitargeted delivery vehicle for improved cancer chemotherapy.
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