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A self-immolative and DT-diaphorase-activatable prodrug for drug-release tracking and therapy
Bowen Li1, Peilian Liu, Donghang Yan
1State Key Lab of Luminescent Materials & Devices, College of Materials Science & Engineering, South China University of Technology, Guangzhou 510640, P. R. China. mcfzeng@scut.edu.cn shzhwu@scut.edu.cn.
Abstract:
DT-diaphorase, which catalyzes the reduction of various biological substances like quinones, is overexpressed in some malignant tumors. However, exploiting this attractive property for the controlled release of an active drug from a prodrug is yet to be fully taken advantage of. Herein we report a DT-diaphorase-based prodrug for concomitant drug-release imaging and cancer chemotherapy. This prodrug system is composed of two camptothecin (CPT) moieties as the active anticancer drug, a DT-diaphorase-responsive quinone propionic acid moiety and a set of self-immolative linkers. The presence of DT-diaphorase leads to the release of two CPT molecules and restores the fluorescence of the latter, thereby realizing the fluorescence monitoring of the DT-diaphorase level as well as the tracking of CPT release. Upon internalization by DT-diaphorase overexpressing cells, the prodrug can release fluorescent CPT and exhibit high cytotoxicity (half-maximal inhibitory concentration 0.71 μM) towards the cancer cells. This prodrug features on-demand enzyme-biomarker-triggered drug release as well as self-monitoring of drug release, therapeutic effect and biomarker level. This new strategy may provide an effective approach for constructing prodrugs with enhanced drug loading as well as controllability for drug release and tracking.
Insights
Researchers developed a novel prodrug that releases the anticancer drug camptothecin (CPT) in response to DT-diaphorase (DTD) enzyme levels. This DTD-activated prodrug enables simultaneous cancer imaging and chemotherapy, offering controlled drug release and tracking.
Area of Science:
- Biomedical Engineering
- Drug Delivery Systems
- Cancer Therapeutics
Background:
- DT-diaphorase (DTD) is an enzyme overexpressed in certain malignant tumors.
- Controlled drug release from prodrugs targeting DTD remains an underexplored area.
- Developing strategies for targeted cancer therapy and real-time monitoring is crucial.
Purpose of the Study:
- To design and synthesize a novel prodrug system for DT-diaphorase-triggered simultaneous drug release and cancer imaging.
- To evaluate the prodrug's efficacy in delivering camptothecin (CPT) and its cytotoxicity against cancer cells.
- To establish a self-monitoring system for drug release, therapeutic effect, and enzyme levels.
Main Methods:
- Synthesis of a prodrug comprising two camptothecin (CPT) moieties linked via a DT-diaphorase-responsive quinone propionic acid unit and self-immolative linkers.
- In vitro evaluation of prodrug activation by DT-diaphorase, leading to CPT release and fluorescence restoration.
- Assessment of prodrug cytotoxicity in DT-diaphorase-overexpressing cancer cells.
Main Results:
- The prodrug successfully released two CPT molecules upon encountering DT-diaphorase.
- Restoration of fluorescence allowed for monitoring of DT-diaphorase levels and CPT release.
- The prodrug demonstrated high cytotoxicity against cancer cells with a half-maximal inhibitory concentration (IC50) of 0.71 μM.
- The system enabled on-demand, enzyme-biomarker-triggered drug release and self-monitoring capabilities.
Conclusions:
- A novel DT-diaphorase-activated prodrug system has been developed for combined cancer chemotherapy and imaging.
- This strategy allows for controlled drug release, real-time monitoring of therapeutic effects, and assessment of enzyme biomarker levels.
- The prodrug design offers potential for enhanced drug loading and improved controllability in cancer treatment.
