期刊
ADVANCED FUNCTIONAL MATERIALS
卷 30, 期 9, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201904697
关键词
charge reversal; mitochondrial metabolism; multistage mitochondrial targeting; beta-glucuronidase
类别
资金
- National Natural Science Foundation of China [81972894, 81673364, 21808028]
- Ministry of Science and Technology of the People's Republic of China [2017ZX09101001006]
- Fundamental Research Funds for the Central Universities [2632018ZD13, 2018011013]
- Six Talents Summit Program of Jiangsu Province
- Priority Academic Program Development of Jiangsu Higher Education Institutions
Blocking cancer metabolism represents an attractive therapeutic strategy for cancer treatment. However, the lack of selective mitochondria targeting compromises the efficacy and safety of antimetabolic agents. Given that beta-glucuronidase (beta-G) is overexpressed in the tumor extracellular microenvironment and intracellular endosomes and lysosomes, a new concept of pro-staramine is proposed to achieve multistage tumor mitochondrial targeting. The pro-staramine, namely GluAcNA, is engineered by conjugating a beta-glucuronic acid to staramine via a seamless linker. When exposed to beta-G, the beta-glucuronic acid in GluAcNA can be hydrolyzed, followed by a rapid 1,6-self-elimination of the seamless, thus transforming anionic GluAcNA to cationic staramine. Liposomes containing GluAcNA (GluAcNA-Lip) show long-circulating characteristics and undergo a sequentially beta-G-triggered activation, resulting in a cation-driven mitochondrial accumulation. The multistage mitochondrial targeting and the promising antitumoral efficacy of GluAcNA-Lip are validated by employing lonidamine as a model drug.
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