Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 86, Issue 4, Pages 589-598Publisher
WILEY-BLACKWELL
DOI: 10.1111/cbdd.12525
Keywords
asparagine endopeptidase; doxorubicin; hypoxia; legumain; N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin; prodrug; SiHa cells
Funding
- China Postdoctoral Science Foundation [2013M542234]
- Science and Technology Planning Project of Guangdong Province [2013B021800085]
- Science and Technology Project Guangzhou City Grant [2014J4100058]
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Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side-effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin (CBZ-AAN-Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain-specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ-AAN-Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain.
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