title: Cancer Targeted Enzymatic Theranostic Prodrug: Precise Diagnosis and Chemotherapy.
abstract: 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
  
  
  
  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.
authors.affiliation: Department of Chemistry, Korea University , Seoul 136-701, Korea.
authors.forename: Weon Sup
authors.initials: WS
authors.lastname: Shin
authors.affiliation: Department of Biotechnology, Laboratory of Stem Cells and Tissue Regeneration, College of Life Sciences & Biotechnology, Korea University , Seoul 136-713, Republic of Korea.
authors.forename: Jiyou
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Chemistry, Korea University , Seoul 136-701, Korea.
authors.forename: Peter
authors.initials: P
authors.lastname: Verwilst
authors.affiliation: Department of Chemistry, Korea University , Seoul 136-701, Korea.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Biotechnology, Laboratory of Stem Cells and Tissue Regeneration, College of Life Sciences & Biotechnology, Korea University , Seoul 136-713, Republic of Korea.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Korea University , Seoul 136-701, Korea.
authors.forename: Jong Seung
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D000077146:Irinotecan; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D002166:Camptothecin