Tongyu Li, Wanchuan Zhuang, Shufang Fan, Ping Yi, Lixia Sheng, Wenbin Qian, Guifang Ouyang
The clinical utility of histone deacetylase inhibitors (HDACi) like vorinostat (SAHA) in lymphoma is constrained by poor pharmacokinetics and off-target toxicity. To address this, we developed a reactive oxygen species (ROS)-responsive homodimeric SAHA prodrug (SAHA-tk-SAHA) linked via a thioketal bridge, which self-assembled into PEGylated nanoparticles (tk-diSAHA NP). These monodisperse nanoparticles (119.3 ± 4.0 nm) demonstrated excellent stability and ROS-triggered drug release (68.18 ± 2.25% with 10 mM H 2 O 2 vs 6.24% in PBS over 48 h). In vitro, tk-diSAHA NP induced G 0 /G 1 cell cycle arrest and apoptosis in lymphoma cells. In A20 lymphoma-bearing mice, intravenous tk-diSAHA NP achieved superior tumor growth inhibition (615.18 ± 147.88 mm 3 ) compared to oral SAHA (1134.78 ± 311.31 mm 3, p < 0.05), with enhanced histone H3 acetylation in tumors and no appreciable systemic toxicity. This ROS-activatable nanoprodrug platform presents a promising strategy to enhance the efficacy and safety of HDACi-based epigenetic therapy for lymphoma.