A ROS-Responsive Dimeric Prodrug Nanoassembly for Amplified Epigenetic Therapy of Lymphoma

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 H2O2 vs 6.24% in PBS over 48 h). In vitro, tk-diSAHA
NP induced G0/G1 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
mm3) compared to oral SAHA (1134.78 ± 311.31 mm3, 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.