HepG2 exosomes coated luteolin nanoparticles remodeling hepatic stellate cells and combination with sorafenib for the treatment of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and recurrence rate. The efficacy of the first-line drug sorafenib is impeded by drug resistance, which is closely related to activated hepatic stellate cells (HSCs). The natural product luteolin is good at alleviating the activation of HSC. However, its clinical application is limited to poor solubility, bioavailability and lacking of HSCs targeting effects. This study aims to construct luteolin-loaded biomimetic nanoparticles based on HepG2 exosomes for targeting HSCs and enhancing the therapeutic effects of sorafenib on HCC. The HepG2 exosomes extracted were identified by size distribution, Zeta potential and characteristic proteins. Luteolin-loaded polylactic acid-glycolic acid (PLGA) nanoparticles (Lut-NPs) were prepared and wrapped by HepG2 exosomes to form biomimetic nanoparticles (Exo-Lut-NPs). A HepG2 cell sorafenib-resistant model induced by LX2 cell conditioned medium (CM) was established to evaluate the effects of Exo-Lut-NPs on reversing sorafenib-resistant in vitro. And the combined therapeutic effects of Exo-Lut-NPs with sorafenib were evaluated on a HepG2/LX2 subcutaneous xenograft tumor model in vivo. The particle size, drug loading capacity and encapsulation efficiency of Exo-Lut-NPs were 165 ± 10 nm, 2.6 ± 0.2% and 56.9 ± 4.3%, respectively. The in vitro HepG2 sorafenib-resistant model was induced by the CM of LX2 cells, and the results showed that Exo-Lut-NPs partially reversed the sorafenib resistance of HepG2 cells by affecting the CM of LX2 cells. The combined therapy of Exo-Lut-NPs with sorafenib markedly suppressed tumor growth in a HepG2/LX2 subcutaneous xenograft tumor model. This study suggests that the Exo-Lut-NP is a novel and promising biomimetic delivery system which can combine with sorafenib for HCC therapy.