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A ROS-Responsive Dimeric Prodrug Nanoassembly for Amplified Epigenetic Therapy of Lymphoma
Tongyu Li1,2, Wanchuan Zhuang3, Shufang Fan1
1Department of Hematology, The First Affiliated Hospital of Ningbo University, 59 Liuting Road, Ningbo, Zhejiang 315010, China.
Journal of Medicinal Chemistry
|March 1, 2026
Summary
We developed novel nanoparticles that deliver HDAC inhibitors (HDACi) specifically to lymphoma tumors. This targeted approach enhances treatment efficacy and reduces toxicity, offering a promising new strategy for epigenetic therapy.
Area of Science:
- Oncology
- Nanotechnology
- Pharmacology
Background:
- Histone deacetylase inhibitors (HDACi) show promise in lymphoma treatment but are limited by poor pharmacokinetics and toxicity.
- Vorinostat (SAHA) is an HDACi with constrained clinical utility in lymphoma.
Purpose of the Study:
- To develop a reactive oxygen species (ROS)-responsive nanoprodrug system for enhanced HDACi delivery in lymphoma.
- To improve the efficacy and safety of HDACi-based epigenetic therapy.
Main Methods:
- A homodimeric SAHA prodrug (SAHA-tk-SAHA) was synthesized using a thioketal linker, self-assembling into PEGylated nanoparticles (tk-diSAHA NP).
- Nanoparticle characterization, ROS-triggered drug release studies, and in vitro evaluation on lymphoma cells were performed.
- In vivo efficacy and toxicity were assessed in A20 lymphoma-bearing mice.
Main Results:
- tk-diSAHA NP demonstrated stable, monodisperse characteristics (119.3 ± 4.0 nm) with significant ROS-triggered SAHA release.
- In vitro studies showed tk-diSAHA NP induced G0/G1 cell cycle arrest and apoptosis in lymphoma cells.
- Intravenous tk-diSAHA NP significantly inhibited tumor growth in mice compared to oral SAHA, with enhanced tumor acetylation and no systemic toxicity.
Conclusions:
- The ROS-activatable tk-diSAHA NP platform effectively targets lymphoma, enhancing HDACi efficacy.
- This nanoprodrug strategy offers a promising approach to improve the therapeutic index of HDAC inhibitors for lymphoma treatment.
