In this work, we investigate whether S-nitrosoglutathione (GSNO)-conjugated hyaluronic acid-based self-assembled nanoparticles (GSNO-HANPs) can be useful as a chemosensitizing agent to improve the anticancer activity of doxorubicin (DOX). The GSNO-HANPs were prepared by aqueous assembly of GSNO-conjugated HA with grafted poly(lactide- co-glycolide). Aqueous GSNO stability shielded within the assembled environments of the GSNO-HANPs was greatly enhanced, compared to that of free GSNO. The NO release from the GSNO-HANPs was facilitated in the presence of hyaluronidase-1 (Hyal-1) and ascorbic acid at intracellular concentrations. Microscopic analysis showed GSNO-HANPs effectively generated NO within the cells. We observed that NO made the human MCF-7 breast cancer cells vulnerable to DOX. This chemosensitizing activity was supported by the observation of an increased level of ONOO- (peroxynitrite), a highly reactive oxygen species, upon co-treatment with the GSNO-HANPs and DOX. Apoptosis assays showed that GSNO-HANP alone exhibited negligible cytotoxic effects and reinforced apoptotic activity of DOX. Animal experiments demonstrated the effective accumulation of GSNO-HANPs in solid MCF-7 tumors and effectively suppressed tumor growth in combination with DOX. This hyaluronic acid-based intracellularly NO-releasing nanoparticles may serve as a significant chemosensitizing agent in treatments of various cancers.
Keywords: chemosensitizing effect; doxorubicin; hyaluronic acid; intracellular delivery; nitric oxide.