Hepatocellular carcinoma (HCC) is the third most common cause of
cancer death worldwide.
Epirubicin (EPI), an
anthracycline derivative, is one of the main line treatments for HCC. However, serious side effects including
cardiomyopathy and
congestive heart failure limit its long term administration. Our main goal is to develop a delivery strategy that ensures improved efficacy of the chemotherapeutic agent together with reduced
cardiotoxicity. In this context, EPI was loaded in
chitosan-PLGA nanoparticles linked with
asialofetuin (EPI-NPs) selectively targeting hepatocytes. In an attempt to reduce
cardiotoxicity, targeted EPI-NPs were coadministered with
tocotrienols. EPI-NPs significantly enhanced the antiproliferative effect compared to free EPI as studied on Hep G2 cell line. Nanoencapsulated EPI injected in HCC mouse model revealed higher p53-mediated apoptosis and reduced angiogenesis in the
tumor. Combined
therapy of EPI-NPs with
tocotrienols further enhanced apoptosis and reduced
VEGF level in a dose dependent manner. Assessment of
cardiotoxicity indicated that EPI-NPs diminished the high level of proinflammatory
cytokine tumor necrosis factor-α (TNF-α) as well as oxidative stress-induced
cardiotoxicity as manifested by reduced level of lipid peroxidation products (
TBARS) and
nitric oxide (NO). EPI-NPs additionally restored the diminished level of
superoxide dismutase (SOD) and
reduced glutathione (GSH) in the heart. Interestingly,
tocotrienols provided both antitumor activity and higher protection against oxidative stress and
inflammation induced by EPI in the heart. This hepatocyte-targeted biodegradable nanoparticle/
tocotrienol combined
therapy represents intriguing therapeutic strategy for EPI providing not only superior efficacy but also higher safety levels.