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A reactive oxygen species-triggerable theranostic prodrug system
Feiyang Liu1, Lingyan Liu2, Peng Wei2
1State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry and Chemical Engineering, Donghua University, Shanghai 201620, China; Guangxi Key Laboratory of Special Biomedicine; School of Medicine, Guangxi University, Nanning 530004, China.
Abstract:
Abnormally elevated levels of reactive oxygen species (ROS) are considered one of the characteristics of tumors and have been extensively employed in the construction of tumor-activated prodrugs. However, ideal ROS-activated molecular triggers that possess high sensitivity and easy functionalization for tailoring specific prodrugs, remain scarce. In this work, we developed a highly reactive oxygen species (hROS, such as •OH, ONOO- and HOCl)-responsive molecular trigger (namely FDROS-4) through the conjunction of methylene blue (MB) and 2, 6-bis (hydroxymethyl) aniline via urea bond, integrating imaging and therapeutic functions. FDROS-4 could be readily modified as multifunctional prodrugs and efficiently activated by hROS, leading to the release of near-infrared emissive MB and parent drugs. By using chlorambucil as a model drug and incorporating varying numbers of galactose as liver-targeting ligands, we designed and synthesized a series of prodrugs named FDROS-6, FDROS-7, and FDROS-8. The optimal prodrug, FDROS-7, could self-assemble into monocomponent nanoparticles, exhibiting enhanced biocompatibility and therapeutic efficacy compared to the parent drug. This hROS-activated molecular trigger holds promise for the development of stimulus-responsive prodrugs in chemotherapy.
Insights
Researchers developed a novel molecular trigger sensitive to highly reactive oxygen species (hROS) for tumor-activated prodrugs. This innovation enables targeted drug delivery and imaging, showing promise for enhanced chemotherapy.
Area of Science:
- Biomedical Engineering
- Organic Chemistry
- Oncology
Background:
- Elevated reactive oxygen species (ROS) are a hallmark of tumors, driving interest in ROS-activated prodrugs.
- Existing ROS-activated molecular triggers lack sensitivity and ease of functionalization for specific prodrug development.
Purpose of the Study:
- To develop a highly reactive oxygen species (hROS)-responsive molecular trigger with integrated imaging and therapeutic capabilities.
- To synthesize and evaluate novel prodrugs utilizing this trigger for targeted cancer therapy.
Main Methods:
- Conjunction of methylene blue (MB) and 2,6-bis(hydroxymethyl)aniline via a urea bond to create the FDROS-4 trigger.
- Modification of FDROS-4 with chlorambucil and galactose ligands to create liver-targeting prodrugs (FDROS-6, -7, -8).
- Assessment of prodrug self-assembly, biocompatibility, and therapeutic efficacy.
Main Results:
- The developed FDROS-4 trigger is efficiently activated by hROS (•OH, ONOO-, HOCl), releasing MB and parent drugs.
- Liver-targeting prodrugs were successfully synthesized, with FDROS-7 showing optimal performance.
- FDROS-7 self-assembled into nanoparticles, demonstrating improved biocompatibility and therapeutic efficacy over the parent drug.
Conclusions:
- The novel hROS-activated molecular trigger (FDROS-4) offers high sensitivity and functionalization potential.
- Targeted prodrugs, like FDROS-7, show promise for enhanced chemotherapy delivery and efficacy.
- This platform holds potential for developing advanced stimulus-responsive prodrugs.
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