Herein, both strategies of synergistic drug combination
together with dual active tumor targeting were combined for effective
therapy of hepatocellular carcinoma (HCC). Therefore, based on the
tumor sensitizing action, the herbal quercetin (QRC) was co-delivered
with the targeted therapeutic drug sorafenib (SFB), preformulated
as phospholipid complex, via protein shell-oily core nanocapsules
(NCs). Inspired by the targeting action of lactoferrin (LF) via binding
to LF receptors overexpressed by HCC cells, LF shell was electrostatically
deposited onto the drug-loaded oily core to elaborate LF shell-oily
core NCs. For dual tumor targeting, lactobionic acid (LA) or glycyrrhetinic
acid (GA) was individually coupled to LF shell for binding to asialoglycoprotein
and GA receptors on liver cancer cells, respectively. Compared to
LF and GA/LF NCs, the dual-targeted LA/LF-NCs showed higher internalization
into HepG2 cells with 2-fold reduction in half-maximal inhibitory
concentration compared to free combination therapy after 48 h. Moreover,
dual-targeted LF-NCs showed powerful in vivo antitumor efficacy. It
was revealed as significant downregulation of the mRNA expression
levels of nuclear factor-kappa B and tumor necrosis factor α
as well as suppression of Ki-67 protein expression level in diethylnitrosamine
(DEN)-induced HCC mice (P < 0.05). Furthermore,
dual-targeted LF-NCs attenuated the liver toxicity induced by DEN
in animal models. Overall, this study proposes dual-targeted LF-NCs
for combined delivery of SFB and QRC as a potential therapeutic HCC
strategy.