Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex.

Co-delivery multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a pH sensitive mesoporous silica nanoparticles (MSN) based controlled release nanoparticles for co-delivery of sorafenib (SO), a multi-tyrosine kinase inhibitor, and ursolic acid (UA), a sensitive agent for SO, was developed, which was decorated with pH sensitive chitosan (CS) and lactobionic acid (LA) targeting to asialoglycoprotein receptor (ASGPR) over-expressing hepatocellar carcinoma cells (denoted as USMNs-CL). The nanocomplex enhanced bioavailability of hydrophobic drugs, efficient tumor cell targeting and exhibited pH-responsive function and sustained release profile. USMNs-CL showed synergistic cytotoxicity and could attenuate the adhesion, migration of ASGPR over-expressing liver cancer SMMC-7721 cells at non-toxic concentrations. Moreover, the complex nanoparticles significantly increased the cellular apoptosis and down-regulated the expression of EGFR and VEGFR2 proteins related with cell proliferation and tumor angiogenesis. In vivo, compared with UA or SO alone, the nanocomplex significantly reduced the tumor burden in hepatocellular carcinoma (HCC) H22 tumor-bearing mice model and inhibited the lung metastasis in the H22 lung metastasis models. Overall, co-delivery of UA and SO by MSN-CS-LA nanocarriers could provide a promising strategy for HCC combinational therapy, especially for the HCC metastasis chemoprevention.