Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor Therapy
Abstract Endogenous stimuli‐responsive prodrugs, due to their disease lesion specificity and reduced systemic toxicity, have been widely explored for antitumor therapy. However, reactive oxygen species (ROS) as classical endogenous stimuli in the tumor microenvironment (TME) are not enough to achiev...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202409960 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841543155489439744 |
|---|---|
| author | Shanshan Jiang Bhaskar Gurram Junfei Zhu Shan Lei Yifan Zhang Ting He Oya Tagit Hui Fang Peng Huang Jing Lin |
| author_facet | Shanshan Jiang Bhaskar Gurram Junfei Zhu Shan Lei Yifan Zhang Ting He Oya Tagit Hui Fang Peng Huang Jing Lin |
| author_sort | Shanshan Jiang |
| collection | DOAJ |
| description | Abstract Endogenous stimuli‐responsive prodrugs, due to their disease lesion specificity and reduced systemic toxicity, have been widely explored for antitumor therapy. However, reactive oxygen species (ROS) as classical endogenous stimuli in the tumor microenvironment (TME) are not enough to achieve the expected drug release. Herein, a ROS‐activatable heterodimeric prodrug‐loaded enzyme assembly is developed for self‐boosting programmable release of multiple therapeutic agents. The heterodimeric prodrug NBS‐TK‐PTX (namely NTP) is composed of 5‐(ethylamino)‐9‐diethylaminobenzo[a]phenothiazinium chloride analog (NBS), paclitaxel (PTX) and ROS‐responsive thioketal (TK) linker, which shows a strong binding affinity with glucose oxidase (GOx), thus obtaining NTP@GOx assembly. Notably, the enzymatic activity of GOx in NTP@GOx is inhibited by NTP. The programmable release is achieved by following steps: i) NTP@GOx is partially dissociated in acidic TME, thus releasing a small segment of NTP and GOx. Thereupon, the enzymatic activity of GOx is recovered; ii) GOx‐triggered pH reduction further facilitates the dissociation of NTP@GOx, thus accelerating a large amount of NTP and GOx release; iii) The TK linker of prodrug NTP is cleaved by hydrogen peroxide generated by GOx catalysis, thus expediting the release of NBS for Type‐I photodynamic therapy and PTX for chemotherapy, respectively. The NTP@GOx shows great potential for multimodal synergistic cancer therapy. |
| format | Article |
| id | doaj-art-895565bdce4d47c0be4723dbe9d2f3f4 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-895565bdce4d47c0be4723dbe9d2f3f42025-01-13T15:29:43ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202409960Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor TherapyShanshan Jiang0Bhaskar Gurram1Junfei Zhu2Shan Lei3Yifan Zhang4Ting He5Oya Tagit6Hui Fang7Peng Huang8Jing Lin9Marshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaMarshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaMarshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaMarshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaMarshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaMarshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaDepartment of BioInterfaces Institute for Chemistry and Bioanalytics School of Life Sciences FHNW University of Applied Sciences and Arts Northwestern Switzerland Muttenz 4132 SwitzerlandNanophotonics Research Center Shenzhen Key Laboratory of Micro‐Scale Optical Information Technology Institute of Microscale Optoelectronics Shenzhen University Shenzhen 518060 ChinaMarshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaMarshall Laboratory of Biomedical Engineering International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics School of Biomedical Engineering Shenzhen University Medical School Shenzhen University Shenzhen 518055 ChinaAbstract Endogenous stimuli‐responsive prodrugs, due to their disease lesion specificity and reduced systemic toxicity, have been widely explored for antitumor therapy. However, reactive oxygen species (ROS) as classical endogenous stimuli in the tumor microenvironment (TME) are not enough to achieve the expected drug release. Herein, a ROS‐activatable heterodimeric prodrug‐loaded enzyme assembly is developed for self‐boosting programmable release of multiple therapeutic agents. The heterodimeric prodrug NBS‐TK‐PTX (namely NTP) is composed of 5‐(ethylamino)‐9‐diethylaminobenzo[a]phenothiazinium chloride analog (NBS), paclitaxel (PTX) and ROS‐responsive thioketal (TK) linker, which shows a strong binding affinity with glucose oxidase (GOx), thus obtaining NTP@GOx assembly. Notably, the enzymatic activity of GOx in NTP@GOx is inhibited by NTP. The programmable release is achieved by following steps: i) NTP@GOx is partially dissociated in acidic TME, thus releasing a small segment of NTP and GOx. Thereupon, the enzymatic activity of GOx is recovered; ii) GOx‐triggered pH reduction further facilitates the dissociation of NTP@GOx, thus accelerating a large amount of NTP and GOx release; iii) The TK linker of prodrug NTP is cleaved by hydrogen peroxide generated by GOx catalysis, thus expediting the release of NBS for Type‐I photodynamic therapy and PTX for chemotherapy, respectively. The NTP@GOx shows great potential for multimodal synergistic cancer therapy.https://doi.org/10.1002/advs.202409960antitumor therapyglucose oxidaseheterodimeric prodrugreactive oxygen speciesself‐boosted programmable release |
| spellingShingle | Shanshan Jiang Bhaskar Gurram Junfei Zhu Shan Lei Yifan Zhang Ting He Oya Tagit Hui Fang Peng Huang Jing Lin Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor Therapy Advanced Science antitumor therapy glucose oxidase heterodimeric prodrug reactive oxygen species self‐boosted programmable release |
| title | Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor Therapy |
| title_full | Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor Therapy |
| title_fullStr | Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor Therapy |
| title_full_unstemmed | Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor Therapy |
| title_short | Self‐Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug‐Enzyme Assembly for Antitumor Therapy |
| title_sort | self boosting programmable release of multiple therapeutic agents by activatable heterodimeric prodrug enzyme assembly for antitumor therapy |
| topic | antitumor therapy glucose oxidase heterodimeric prodrug reactive oxygen species self‐boosted programmable release |
| url | https://doi.org/10.1002/advs.202409960 |
| work_keys_str_mv | AT shanshanjiang selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT bhaskargurram selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT junfeizhu selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT shanlei selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT yifanzhang selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT tinghe selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT oyatagit selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT huifang selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT penghuang selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy AT jinglin selfboostingprogrammablereleaseofmultipletherapeuticagentsbyactivatableheterodimericprodrugenzymeassemblyforantitumortherapy |