Curcumin and berberine co-loaded liposomes for anti-hepatocellular carcinoma therapy by blocking the cross-talk between hepatic stellate cells and tumor cells

Abstract

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME). In hepatocellular carcinoma (HCC), quiescent hepatic stellate cells (HSCs) could be activated to become CAFs, which play a critical role in tumor progression and drug resistance. Therefore, recent efforts have been focused on combining anti-HSC and pro-apoptotic activities to improve anti-tumor efficacy of drugs. In this study, glycyrrhetinic acid and hyaluronic acid–modified liposomes (GA-HA-Lip) were prepared for co-delivery of curcumin (CUR) and berberine (BBR) for the treatment of HCC. Furthermore, we established the LX-2+BEL-7402 co-cultured cell model and implanted the m-HSCs+H22 cells into a mouse to evaluate the anti-tumor effect of CUR&BBR/GA-HA-Lip both in vitro and in vivo. The results showed that CUR&BBR/GA-HA-Lip could accumulate in tumor tissues and be taken up by HSCs and BEL-7402 cells simultaneously. Compared with free CUR, the combination therapy based on GA-HA-Lip exhibits stronger pro-apoptotic and anti-proliferation effect both in vitro and in vivo. The anti-tumor mechanistic study revealed that CUR&BBR/GA-HA-Lip could inhibit the activation of HSCs and restrain drug resistance of tumor cells. In summary, CUR&BBR/GA-HA-Lip could be a promising nano-sized formulation for anti-tumor therapy.

Gambogic acid inhibits HBx-mediated hepatitis B virus replication by targeting the DTX1-Notch signaling pathway

“…In particular, Guo and his partner found that GA could inhibit human telomerase reverse transcriptase gene expression in human hepatoma SMMC-7721 cells, resulting in the inhibition of HCC development ( Nie et al., 2009 ). Another study found that GA could induce antiproliferation in HCC cell lines ( Wu et al., 2022 ). Because HBV is closely related to HCC, we wanted to explore whether GA plays an essential role in HBV.…”

Multifunctional and stimuli-responsive liposomes in hepatocellular carcinoma diagnosis and therapy

“…Both curcumin and berberine have been loaded on liposomes and they show high accumulation at tumor tissue. This co-delivery stimulates apoptosis and suppresses proliferation, and one of its benefits is disrupting the interaction of cancer cells and hepatic stellate cells in HCC therapy [110] .…”

“…Such drug-loaded liposomes showed uptake by HCC cells and cancer-associatd fibroblasts that suppressed tumorigenesis in vitro and in vivo, and disrupted the invasion [217] . In another effort, GA/HA-functionalized liposomes were utilized to co-deliver berberine and curcumin that were able to stimulate apoptosis in tumor cells and impair their proliferation [110] . The HCC cells demonstrate overexpression of folate receptor to bring up folate for their proliferation.…”

Hyaluronic Acid-Mediated Phenolic Compound Nanodelivery for Cancer Therapy

“…Finally, there exists only one study for each of the three remaining flavonoids recently enclosed in HA-containing nanosystems (i.e., the flavonol kaempherol, the flavanone The nanoformulations designed for the targeted delivery of phenolic compounds (PheCs) to cancer cells are, in most cases, polymeric nanoparticles (NPs) having hyaluronic acid (HA) among the constituent polymers or NPs decorated at the surface with HA alone or accompanied by additional targeting ligands. Among the additional targeting ligands used, there are: fucoidan, that functions as a ligand for P-selectin and helps the nanosystems to be internalized in cancer cells [42,44,46]; EGF Receptor-Targeted Peptide (GE11) for binding to EGFR overexpressed in prostate cancer [49]; folic acid and biotin functioning as ligands for the respective receptors, both overexpressed in cancer cells [67]; mannose for the binding to the CD206 receptor for specifically targeting the tumor-associated macrophages (TAMs) [68]; glycyrrhetinic acid (GA) that binds to the specific receptor overexpressed in hepatocarcinoma cells and in activated hepatic stellate cells (HSCs) [73]; riboflavin [74]. Besides HA, other bioactive constituents of the nanoformulation shells are: the bisphosphonate alendronate, able to specifically target osteosarcoma cells [69]; D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), able to inhibit P-gp efflux pumps, thus overcoming multidrug resistance (MDR) in cancer [40].…”