Galactosylated Liposomes for Targeted Co-Delivery of Doxorubicin/Vimentin siRNA to Hepatocellular Carcinoma

Abstract

The combination of therapeutic nucleic acids and chemotherapeutic drugs has shown great promise for cancer therapy. In this study, asialoglycoprotein receptors (ASGPR) targeting-ligand-based liposomes were tested to determine whether they can co-deliver vimentin siRNA and doxorubicin to hepatocellular carcinoma (HCC) selectively. To achieve this goal, we developed an ASGPR receptor targeted co-delivery system called gal-doxorubicin/vimentin siRNA liposome (Gal-DOX/siRNA-L). The Gal-DOX/siRNA-L was created via electrostatic interaction of galactose linked-cationic liposomal doxorubicin (Gal-DOX-L) on vimentin siRNA. Previous studies have shown that Gal-DOX/siRNA-L inhibited tumor growth by combined effect of DOX and vimentin siRNA than single delivery of either DOX or vimentin siRNA. These Gal-DOX/siRNA-Ls showed stronger affinity to human hepatocellular carcinoma cells (Huh7) than other cells (lung epithelial carcinoma, A549). These liposomes also have demonstrated that novel hepatic drug/gene delivery systems composed of cationic lipid (DMKE: O,O’-dimyristyl-N-lysyl glutamate), cholesterol, galactosylated ceramide, POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), and PEG2000-DSPE (distearoyl phosphatidyl ethanolamine) at 2:1:1:1:0.2 (moral ratios) can be used as an effective drug/gene carrier specifically targeting the liver in vivo. These results suggest that Gal-DOX-siRNA-L could effectively target tumor cells, enhance transfection efficacy and subsequently achieve the co-delivery of DOX and siRNA, demonstrating great potential for synergistic anti-tumor therapy.

Targeted delivery of microRNA‐199a‐3p using self‐assembled dipeptide nanoparticles efficiently reduces hepatocellular carcinoma in mice

“…We found significantly higher accumulation of Cy3‐RΔF‐LA/miR NPs in the cytoplasm, indicating their efficient delivery and endosomal escape ability. The enhanced cellular uptake for the targeted NPs than the non‐targeted NPs in HCC cells was in agreement with earlier studies which have described the use of LA as the targeting ligand …”

“…The enhanced cellular uptake for the targeted NPs than the nontargeted NPs in HCC cells was in agreement with earlier studies which have described the use of LA as the targeting ligand. (19,39,40) miRNAs have been shown to have profound effect on a wide variety of cellular processes including cell proliferation, migration and apoptosis. (6) Functional efficacy of RDF-LA/miR NPs in Huh7 cells with regard to these biological activities was investigated.…”

Combinatorial therapeutic approaches with RNAi and anticancer drugs using nanodrug delivery systems

“…Simple PEGylated liposomes [51], advanced stimuli-responsive liposomes [52,53], and targeting liposomes [54,55] have all been constructed for siRNA/chemotherapeutic co-delivery in cancer. Using a PEGylated liposome to co-deliver, BCL2 siRNA with docetaxel successfully inhibited lung cancer in vitr o and in vivo [51].…”

“…Another study demonstrated the targeted co-delivery of siRNA and chemotherapeutic agent to liver tumors [54]. A liposomal carrier for the co-delivery of vimentin siRNA and doxorubicin was prepared from a mixture of lipids: DMKE (O,O’-dimyristyl-N-lysyl glutamate), cholesterol, galactosylated ceramide, POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), and PEG2000-DSPE (distearoyl phosphatidyl ethanolamine).…”

Liver‑targeted delivery of liposome‑encapsulated curcumol using galactosylated‑stearate

“…Due to these characteristics, liposomes have previously been used as carriers of anticarcinogens (18)(19)(20). Galactosylated-liposomes, which specifically bind with the asialoglyco protein receptor (ASGPR) on the surface of liver cells are a type of liver targeting preparation (21). These liposomes may be transferred to liver cells via receptor-mediated endocytosis (RME) (22).…”