期刊
ACS APPLIED MATERIALS & INTERFACES
卷 10, 期 15, 页码 12351-12363出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.7b18437
关键词
multidrug resistance; glucose transporter targeting; mitochondria targeting; tumor microenvironment
资金
- National Natural Science Foundation of China [81673680]
- Graduate Independent Subjects of Beijing University of Chinese Medicine [2016-JYB-XS081]
Multidrug resistance (MDR) is thought to be the major obstacle leading to the failure of paditaxel (PTX) chemotherapy. To solve this problem, a glucose transporter-mediated and matrix metalloproteinase 2 (MMP2)-triggered mitochondrion targeting conjugate [glucose-polyethylene glycol (PEG)-peptide triphenylphosponium-polyamidoamine (PAMAM)-PTX] composed of a PAMAM dendrimer and enzymatic detachable glucose PEG was constructed for mitochondrial delivery of PTX. The conjugate was characterized by a 30 nm sphere particle, MMP2sensitive PEG outer layer detachment from PAMAM, and glutathione (GSH)-sensitive PTX release. It showed higher cellular uptake both in glucose transporter 1 (GLUT1) overexpressing MCF-7/MDR monolayer cell (2D) and multicellular tumor spheroids (3D). The subcellular location study showed that it could specifically accumulate in the mitochondria. Moreover, it exhibited higher cytotoxicity against MCF-7/MDR cells, which significantly reverse the MDR of MCF-7/MDR cells. The MDR reverse might be caused by reducing the ATP content through destroying the mitochondrial membrane as well as by down-regulating P-gp expression. In vivo imaging and tissue distribution indicated more conjugate accumulated in the tumor of the tumor-bearing mice model. Consequently, the conjugate showed better tumor inhibition rate and lower body weight loss, which demonstrated that it possessed high efficiency and low toxicity. This study provides glucose-mediated GLUT targeting, MMP2-responsive PEG detachment, triphenylphosponium-mediated mitochondria targeting, and a GSH-sensitive intracellular drug release conjugate that has the potential to be exploited for overcoming MDR of PTX.
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