Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy

Abstract

The integration of active targeted drug delivery and stimuli-dependent drug release in one nanocarrier holds great potential for enhancing anticancer efficacy and limiting adverse effects. Herein, we prepared hyaluronic acid (HA)-modified dendrimer encapsulating gold nanoparticles (AuDEN) as active targeted drug delivery nanocarriers for effective treatment of ovarian cancer. Resulting nanocarriers could load doxorubicin (DOX) efficiently with high drug loading content and chemical stability through self-assembly of thiolated DOX on the Au surface of nanocarriers. Surface-exposed HA in these nanocarriers made it possible to deliver the nanodrug (denoted as HA-AuDEN-DOX) to cluster determinant 44-overexpressing cancer cells. DOX was then released in an acidic tumor microenvironment with a high glutathione (GSH) concentration. HA-AuDEN-DOX greatly delayed DOX release under a physiological condition (pH 7.4), whereas a burst release of DOX was observed under an acidic condition (pH 5.6) in the presence of GSH. In comparison with free-DOX, HA-AuDEN-DOX showed enhanced cytotoxicity to cancer cells, demonstrating an enhanced cellular uptake and a superior IC50 value of 2.72 μM. Importantly, cellular internalization pathways of HA-AuDEN-DOX to SK-OV-3 cells were estimated, showing the following quantitative values: receptor-mediated endocytosis, 31.5%; caveolae-mediated endocytosis, 28.7%; macropinocytosis, 26.1%. In vivo anticancer activity and biodistributions of HA-AuDEN-DOX were evaluated with an SK-OV-3 xenograft tumor-bearing mouse model, revealing an outstanding treatment-control (T/C) ratio of 66% (about four times higher than free-DOX treated value of 16.4%) for tumor growth inhibition. Compared to the administration of free-DOX, HA-AuDEN-DOX showed a decreased cardiotoxic effect. Furthermore, immunohistochemical study of Ki67 antigen expression revealed the effective suppression of cell proliferation in xenograft ovarian tumor tissues after HA-AuDEN-DOX treatment. These features highlight a promising application of HA-AuDEN-DOX for the treatment of ovarian cancer with cluster determinant 44 overexpression.