Intracellular NO-Releasing Hyaluronic Acid-Based Nanocarriers: A Potential Chemosensitizing Agent for Cancer Chemotherapy

Abstract

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.

Evaluation of Hyaluronic Acid to Modulate Oral Squamous Cell Carcinoma Growth In Vitro

“…In fact, some evidence now suggests that CD44 acts as a receptor for proteolytically-modified HA and may be responsible for the modulation of intracellular signaling associated with increased proliferation and invasive capacity [17,26,27]. However, because the production of proteolytic enzymes with their cognate targets may be tightly regulated within these tumors, administration of intact, exogenous HA and the delivery of chemotherapeutic agents conjugated with HA has been sufficient in clinical studies to improve patient outcomes and reduce metastatic phenotypes in many cancer types [17,18,[28][29][30].…”

Therapeutic Delivery of Nitric Oxide Utilizing Saccharide-Based Materials

“…Lee’s group synthesized GSNO–hyaluronic acid-based nanoparticles (GSNO–HANPs) from PLGA-grafted hyaluronic acid and GSNO. The GSNO–HANPs were able to release 95.8% of NO with the presence of hyaluronidase and ascorbic acid in 24 h. The GSNO–HANPs also self-assembled into nanoparticles and were effective in suppressing solid MCF-7 tumor growth in combination with doxorubicin (DOX) …”

“…The GSNO−HANPs were able to release 95.8% of NO with the presence of hyaluronidase and ascorbic acid in 24 h. The GSNO−HANPs also self-assembled into nanoparticles and were effective in suppressing solid MCF-7 tumor growth in combination with doxorubicin (DOX). 94 S-Nitrosated dextran was reported by the Reynolds group, where dextran C2-OH was modified to a thiol functionality and then nitrosated the thiol to make the RSNO donor for NO release. The RSNOdextran was degraded by dextranase and could release NO for more than 6 h, with the cumulative NO of 0.13−0.16 mmol g −1 .…”

Hyaluronic Acid Nanoparticles as Nanomedicine for Treatment of Inflammatory Diseases

“…In another study, Kim et al reported HA-based NO-releasing PNPs to improve the anticancer activity of DOX. This PNPs may serve as a significant chemosensitizing agent in treatments of various cancers [ 120 ]. Recent advances on HA-drug conjugates and HA-based NPs for cancer therapy have been well described elsewhere [ 60 ].…”