Abstract
Drug resistance and off-target toxicity are two of the greatest challenges to chemotherapeutic melanoma treatments. Nitric oxide (NO) represents an attractive alternative to conventional therapeutics due to its numerous anticancer properties and low probability of engendering resistance. As NO is highly reactive, macromolecular NO donors are needed for the controlled and targeted delivery of NO for therapeutic applications. Herein, mesoporous silica nanoparticles (MSNs) coated with hyaluronic acid (HA) were developed as a NO delivery system to facilitate controlled delivery to cancer cells through both passive and active targeting via the enhanced permeation and retention effect and directed binding of HA with CD44 receptors, respectively. The aminosilane modification, HA concentration, and HA molecular weight were systematically evaluated to facilitate the MSN coating and NO loading. The hydrodynamic diameter and dispersity of the nanoparticles increased after HA coating due to the hydrophilic nature of HA, with greater increases observed at higher HA molecular weight. Lower starting concentrations of HA and aminosilanes with longer alkyl chains favored more efficient HA coating. Faster NO-release kinetics and lower NO payloads were observed for the HA-coated MSNs relative to uncoated MSNs. However, the localized delivery of NO to cancer cells through the active targeting conferred by HA increased levels of oxidative stress and induced mitochondria-mediated apoptosis in melanoma cells. Cytotoxicity was also evaluated against human dermal fibroblasts, with the use of 6 kDa HA-coated MSNs resulting in the greatest therapeutic indices. Enhanced internalization of HA-coated nanoparticles into melanoma cells versus uncoated nanoparticles was visualized with confocal microscopy and quantified by fluorescence spectroscopy. In total, HA-coated MSNs represent a promising NO delivery system for potential use as a chemotherapeutic for skin melanomas.