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 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1419-1426 |
| Number of pages | 8 |
| Journal | Bioconjugate Chemistry |
| Volume | 27 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2016 May 18 |
Fingerprint
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Organic Chemistry
- Pharmaceutical Science
- Biomedical Engineering
- Pharmacology
Cite this
Cancer Targeted Enzymatic Theranostic Prodrug : Precise Diagnosis and Chemotherapy. / Shin, Weon Sup; Han, Jiyou; Verwilst, Peter; Kumar, Rajesh; Kim, Jong-Hoon; Kim, Jong Seung.
In: Bioconjugate Chemistry, Vol. 27, No. 5, 18.05.2016, p. 1419-1426.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cancer Targeted Enzymatic Theranostic Prodrug
T2 - Precise Diagnosis and Chemotherapy
AU - Shin, Weon Sup
AU - Han, Jiyou
AU - Verwilst, Peter
AU - Kumar, Rajesh
AU - Kim, Jong-Hoon
AU - Kim, Jong Seung
PY - 2016/5/18
Y1 - 2016/5/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84971265317&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84971265317&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.6b00184
DO - 10.1021/acs.bioconjchem.6b00184
M3 - Article
C2 - 27135737
AN - SCOPUS:84971265317
VL - 27
SP - 1419
EP - 1426
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
SN - 1043-1802
IS - 5
ER -