A pH‑responsive hyaluronic acid nano‑vehicle co‑encapsulating doxorubicin and all‑trans retinoic acid for the inhibition of hepatic stellate cell‑induced tumor growth and metastasis

All-trans retinoic acid (ATRA) has been implicated in the differentiation of hepatic stellate cells (HSCs). In the present study, the liver-targeting hyaluronic acid micelles (ADHG) were prepared for co-delivery of ATRA and doxorubicin (DOX) to block the HSC-hepatoma interrelation. To simulate the tumor microenvironment, an in vitro dual-cell model and an in vivo co-implantation mouse model were established for anticancer studies. The experimental methods involved the MTT assay, wound-healing assay, cellular uptake, flow cytometry and and in vivo antitumor study. The results revealed that the HSCs in the research models notably promoted tumor proliferation and migration. Furthermore, ADHG were readily internalized by cancer cells and HSCs simultaneously, and widely distributed in cancer regions. The in vivo antitumor studies demonstrated that ADHG could notably decrease HSC activation and extracellular matrix deposition, as well as constrain tumor growth and metastasis. Therefore, ATRA could facilitate DOX-induced anti-proliferation and anti-metastasis effects, and ADHG are a promising nano-sized formulation for the combination therapy of hepatocellular carcinoma.