Co-Delivery of Curcumin and Capsaicin by Dual-Targeting Liposomes for Inhibition of aHSC-Induced Drug Resistance and Metastasis

Abstract

Recent research studies have shown that the low survival rate of liver cancer is due to drug resistance and metastasis. In the tumor microenvironment (TME), activated hepatic stellate cells (aHSCs) have been proven to favor the development of liver cancer. Hence, the combination therapy dual-targeting aHSCs and tumor cells might be an effective strategy for treatment of liver cancer. In this study, the novel multifunctional liposomes (CAPS-CUR/GA&Gal-Lip) were prepared for co-delivery of curcumin (CUR) and capsaicin (CAPS), in which glycyrrhetinic acid (GA) and galactose (Gal) were chosen as targeting ligands to modify the liposomes (Lip) for dual-targeting liver cancer. To mimic TME, a novel HSCs+HepG2 (human hepatoma cell line) cocultured model was established for the antitumor effect in vitro. The results showed that, compared to HepG2 cells alone, the cocultured model promoted drug resistance and migration by upregulating the expression of P-glycoprotein (P-gp) and Vimentin, which were effectively inhibited by CAPS-CUR/GA&Gal-Lip. The efficacy of the in vivo antitumor was evaluated by three mice models: subcutaneous H22 (mouse hepatoma cell line) tumor-bearing mice, H22+m-HSC (mouse hepatic stellate cell) tumor-bearing mice, and orthotopic H22 cells-bearing mice. The results showed that CAPS-CUR/GA&Gal-Lip exhibited lesser extracellular matrix (ECM) deposition, lesser tumor angiogenesis, and superior antitumor effect compared with the no-and/or Gal-modified Lip, which was attributed to the simultaneous blocking of the activation of HSCs and inhibition of the metastasis of tumor cells. The dualtargeting method using Lip is thus a potential strategy for liver cancer treatment.

Dual-Ligand-Modified Liposomes Co-Loaded with Anti-Angiogenic and Chemotherapeutic Drugs for Inhibiting Tumor Angiogenesis and Metastasis

“…DSPE-PEG-Gal was synthesized by the reaction of DSPE-PEG-COOH and D-GalN in the presence of EDC and NHS in our previous study. 31 CUCA/GA&Gal-Lip were prepared by reverse-phase evaporation method ( Figure 1C ). Firstly, EPC and cholesterol were mixed in chloroform (ratio of EPC and cholesterol was 3:1), then DSPE-PEG-Gal, DSPE-PEG-GA and Cur were added to this system (the ratios of DSPE-PEG-GAL/EPC, DSPE-PEG-GA/EPC and Cur/EPC were 1:20).…”

Recent Advances in Glycyrrhetinic Acid-Functionalized Biomaterials for Liver Cancer-Targeting Therapy

“…An innovative dual ligand-modified TDDS was recently proposed by Qi et al, who developed GA and Gal-functionalized DSPE-PEG liposomes for the co-delivery of CUR and capsaicin (CAPS), known for its anticarcinogenic, antiproliferative, and antioxidative effects [ 94 ], for liver cancer treatment [ 55 ]. The drugs loaded in this system are targeted to different components of the tumor environment.…”

“…An intelligent pH-sensitive DDS of CAPS/GA-sulfated HA (sHA) DOX-loaded NPs was developed for liver-targeting co-delivery of DOX and CAPS [ 64 ]. The potential role of CAPS against tumor growth has been described above [ 55 ]. Furthermore, CD44 receptors are specifically overexpressed on aHSCs, so that HA-based NPs can specifically target these cells.…”

In vitro and in vivo Evaluation of a Novel Estrogen-Targeted PEGylated Oxaliplatin Liposome for Gastric Cancer

“…Recently, researchers have focused on tumor-targeted liposomal delivery system. Lactoferrin, 20 galactose 21 and glycyrrhetinic acid, 22 , 23 and so on were used to modify liposomes to target drugs into the tumor tissue more effectively. Estrogen receptors belong to the nuclear receptor protein family 24 involved in various physiological processes such as cell growth, reproduction, development, and differentiation.…”