Hyaluronic acid-conjugated gliadin nanoparticles for targeted delivery of usnic acid in breast cancer: An <i>in vitro</i>/<i>in vivo</i> translational study

Abstract

Usnic acid (UA) has been used as an antitumor drug; however, its hepatotoxicity hinders its therapeutic use. This study aimed to design a targeted nanocarrier loaded with UA for drug delivery to breast cancer tissue. UA was loaded in gliadin nanoparticles (GNPs) using a desolvation method and conjugated with hyaluronic acid (HA) to target CD44 receptors. After determining the physicochemical properties of the NPs, their cytotoxicity and drug uptake were studied in the 4T1 cell line. The antitumor activity and histopathological effects were assessed in vivo in BALB/c mice. HA-conjugated UA-loaded GNPs (HA-UA-GNP) showed a significantly higher cytotoxic effect and cellular uptake in the 4T1 cell line compared to non-targeted UA-GNPs and free UA. When CD44 receptors were saturated, the cytotoxicity of HA-UA-GNPs on 4T1 cells decreased significantly. Tumor growth in mice treated with HA-UA-GNPs was significantly less than in UA-GNPs or free UA treatment groups. The higher cytotoxic effect and cellular uptake of HA-UA-GNPs compared to the equal dosage of non-targeted UA-GNPs and the free drug showed a successful CD44 targeting. Histochemical findings showed a higher necrosis level in the group treated with HA-UA-GNPs compared to those treated with UA-GNPs, which could be due to the targeting procedure. In conclusion, the designed nanoparticulate formulation of gliadin, functionalized with HA, served as an effective approach for the delivery of UA to breast cancer tissue in vitro and in vivo.