An enzyme-responsive double-locked amonafide prodrug for the treatment of glioblastoma with minimal side effects.

ABSTRACT: Amonafide (ANF), a topoisomerase II inhibitor and DNA intercalator, has exhibited promise in phase II trials but faces significant limitations due to adverse side effects. Here, we have developed a novel enzyme-triggered fluorogenic prodrug, AcKLP, that incorporates dual-locked enzyme activation, ensuring that the prodrug remains inactive until it confronts the unique enzymatic environment of glioblastoma cells. This approach minimizes premature activation and reduces toxicity to normal cells, with an IC₅₀ > 100 μM for human umbilical vein endothelial cells (HUVEC) and ∼2.3 μM for human glioblastoma cells (U87). Upon activation of AcKLP by two distinct enzymes prevalent in glioblastoma cells, amonafide is released and emits a fluorescence signal response, facilitating treatment

SUBMITTER: Cheng W 

PROVIDER: S-EPMC11528907 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature