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A General Strategy for Macrotheranostic Prodrug Activation: Synergy between the Acidic Tumor Microenvironment and
Yansong Dong1, Yalan Tu1, Kewei Wang2
1Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510006, P. R. China.
Abstract:
Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH-responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor-specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.
Insights
This study introduces a novel prodrug activation strategy using tumor acidity and click chemistry. This approach overcomes tumor heterogeneity by enabling specific drug activation in the acidic tumor microenvironment, enhancing therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Drug Delivery
- Nanotechnology
Background:
- Tumor heterogeneity poses a challenge for prodrugs relying on endogenous stimuli for activation.
- Existing bioorthogonal prodrug strategies often depend on specific receptors or enzymes, limiting their general applicability.
- The acidic extracellular tumor microenvironment is a ubiquitous characteristic that can be exploited for targeted drug delivery.
Purpose of the Study:
- To develop a general strategy for bioorthogonal prodrug activation by integrating the acidic tumor microenvironment with click chemistry.
- To design a pH-responsive polymer system for controlled release and activation of a macrotheranostic prodrug.
- To demonstrate tumor-specific fluorescence activation and phototoxicity restoration using the developed system.
Main Methods:
- Synthesized a tumor pH-responsive polymer functionalized with tetrazine groups.
- Formulated a macrotheranostic prodrug (CyPVE) with a vinyl ether group.
- Investigated the disassembly of polymer micelles in response to acidic pH.
- Evaluated tumor-specific fluorescence and phototoxicity in vitro and in vivo.
Main Results:
- The tetrazine-functionalized polymer formed unreactive micelles in blood but disassembled at tumor-specific acidic pH.
- The acidic microenvironment triggered the click reaction between tetrazine and vinyl ether groups, activating the prodrug.
- Demonstrated significant tumor-specific fluorescence enhancement.
- Restored phototoxicity specifically within the tumor site, indicating effective prodrug activation.
Conclusions:
- The integration of the acidic tumor microenvironment and bioorthogonal click chemistry offers a generalizable strategy for prodrug activation.
- This pH-responsive polymer system effectively targets and activates prodrugs in tumors, overcoming limitations of heterogeneity.
- This approach holds promise for enhanced cancer therapy through precise, tumor-specific drug activation.
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