Self‐boosting programmable release of multiple therapeutic agents by activatable heterodimeric prodrug‐enzyme assembly for antitumor therapy

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.

Schlagwörter

antitumor therapy, glucose oxidase, heterodimeric prodrug, reactive oxygen species, self-boosted programmable release

Fachgebiet (DDC)

610 - Medizin und Gesundheit

Projekt

Veranstaltung

Startdatum der Ausstellung

Enddatum der Ausstellung

Startdatum der Konferenz

Enddatum der Konferenz

Datum der letzten Prüfung

ISBN

ISSN

2198-3844

Sprache

Englisch

Während FHNW Zugehörigkeit erstellt

Ja

Zukunftsfelder FHNW

Future Health

Publikationsstatus

Veröffentlicht

Begutachtung

Peer-Review der ganzen Publikation

Open Access-Status

Gold

Lizenz

Zitation

Jiang, S., Gurram, B., Zhu, J., Lei, S., Zhang, Y., He, T., Tagit, O., Fang, H., Huang, P., & Lin, J. (2025). Self‐boosting programmable release of multiple therapeutic agents by activatable heterodimeric prodrug‐enzyme assembly for antitumor therapy. Advanced Science, 12(2), 2409960. https://doi.org/10.1002/advs.202409960

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