Dual-trigger hyaluronic acid nanoprodrug incorporating a 2-nitrobenzenesulfonyl linker for CD44-targeted and glutathione-responsive drug delivery.

Authors

Tomona Yukimura, Tomohiro Seki, Toshinobu Seki

Published in

International journal of pharmaceutics. Pages 127157. Jul 04, 2026. Epub Jul 04, 2026.

Abstract

Selective intracellular activation of anticancer agents while minimizing toxicity toward non-target tissues remains a major challenge in drug delivery systems (DDSs) and prodrug design. In this study, we designed a hyaluronic acid-based prodrug system, HA-Ns-Dox, that integrates receptor-mediated cellular uptake with intracellular glutathione (GSH)-responsive activation. A doxorubicin (Dox) prodrug modified with a 2-nitrobenzenesulfonyl (Ns) group was synthesized and subsequently conjugated to hyaluronic acid (HA) via click chemistry to generate HA-Ns-Dox with both CD44-targeting capability and GSH-responsive activation properties. HA-Ns-Dox formed stable nanosized assemblies in aqueous solution and exhibited high stability under low-GSH conditions mimicking extracellular environments, whereas concentration-dependent activation of Dox was observed under high-GSH conditions mimicking intracellular reductive environments. In vitro studies demonstrated that HA-Ns-Dox was selectively internalized into the CD44-high human breast cancer cell line MDA-MB-231, accompanied by intracellular prodrug activation and nuclear accumulation of Dox. In contrast, cellular uptake and activation were minimal in the CD44-low cell line MCF-7, and cytotoxicity was significantly suppressed even at high concentrations. Cytotoxicity studies further revealed that HA-Ns-Dox exhibited significant antiproliferative activity in CD44-high cells while substantially reducing toxicity toward non-target cells. Collectively, these findings demonstrate the potential of combining CD44-targeted delivery with GSH-responsive prodrug activation to improve cancer cell selectivity.

PMID:
42401301
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

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