Cancer Targeted Enzymatic Theranostic Prodrug: Precise Diagnosis and Chemotherapy

被引:77
作者
Shin, Weon Sup [1 ]
Han, Jiyou [2 ]
Verwilst, Peter [1 ]
Kumar, Rajesh [1 ]
Kim, Jong-Hoon [2 ]
Kim, Jong Seung [1 ]
机构
[1] Korea Univ, Dept Chem, Seoul 136701, South Korea
[2] Korea Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Lab Stem Cells & Tissue Regenerat, Seoul 136713, South Korea
基金
新加坡国家研究基金会;
关键词
NAD(P)H-QUINONE OXIDOREDUCTASE NQO1; DT-DIAPHORASE; DELIVERY; EXPRESSION; ACTIVATION; RELEASE; CELLS; GENE;
D O I
10.1021/acs.bioconjchem.6b00184
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
The development of targeted and effective theranostic (therapeutic and diagnostic) chemotherapeutic agents is highly desirable for precise diagnosis and treatment of cancer. To realize this goal, we developed a cancer-targeting and enzyme triggered theranostic prodrug 1, containing 7-ethyl-10-hydroxycamptothecin (SN-38), a well-known anticancer drug, which inhibits topoisomerase I in the cell nucleus; hydroquinone as an enzyme-triggered moiety; and biotin as a cancer targeting unit. Enzyme-triggered theranostic prodrug 1 selectively targets cancer cells and is subsequently activated in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), a cytosolic flavoprotein that catalyzes the two-electron reduction of quinone moieties with the concomitant consumption of NADH or NADPH as electron donors. High levels of NQO1 were found in a variety of cancer cell lines compared to healthy cells, and therefore, it is an excellent target for the development of cancer targeted drug delivery systems. Upon preferential cancer cell delivery and uptake, aided by biotin, the enzyme-triggered theranostic prodrug 1 is cleaved by NQO1, with the subsequent release of SN-38, inhibiting topoisomerase I, leading to apoptosis. The drug release and induced apoptosis of cancer cells expressing both biotin receptors and high levels of NQO1 was simultaneously monitored via the innate fluorescence of the released SN-38 by confocal microscopy. In vitro and in vivo studies showed an effective inhibition of cancer growth by the enzyme-triggered theranostic prodrug 1. Thus, this type of enzyme-triggered targeted prodrug therapy is an interesting and promising approach for future cancer treatment.
引用
收藏
页码:1419 / 1426
页数:8
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