Singlet oxygen‐responsive hyaluronate dot clusters for tumor therapy

Abstract

AbstractIn this study, we developed nanoclusters that respond to singlet oxygen and can be adjusted in size to enhance the efficacy of tumor therapy. Specifically, we engineered nanoclusters, denoted as dHAc‐PSDA‐Ce6, through the covalent conjugation of hyaluronate dots (dHA) with 3,3‐(propane‐2,2‐diylbis(sulfanediyl))dipropionic acid (PSDA) as a cleavable crosslinker mediated by singlet oxygen, and chlorin e6 (Ce6) as a representative model drug for photodynamic therapy. The hyaluronic acid (HA) component within dHAc‐PSDA‐Ce6 was harnessed for the specific targeting of CD44 receptors that are overexpressed on tumor cells. Upon subjecting the vicinity of tumor cells to light irradiation, the PSDA crosslinker within dHAc‐PSDA‐Ce6 undergoes cleavage, likely facilitated by the singlet oxygen generated by Ce6. This cleavage process leads to the formation of dHA‐Ce6 molecules. We hypothesized that a nanocluster, circulating safely within the bloodstream, would undergo a transformation into individual dHA‐Ce6 molecules upon light irradiation at the localized tumor site. This transformation, in turn, enhances the photodynamic antitumor effect. Our in vitro investigations have demonstrated the remarkable efficacy of dHAc‐PSDA‐Ce6 in inducing tumor cell death upon light irradiation. Furthermore, our in vivo biodistribution studies have revealed the substantial accumulation of these nanoclusters within the tumor site. We anticipate that this singlet oxygen‐responsive nanocluster harbors substantial promise for enhancing tumor accumulation and fortifying the effectiveness of tumor eradication.