Co-delivery of curcumin and PTTG1 siRNA by galactose receptor-targeted liposomes for enhanced anti-tumor effects in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies posing a serious threat to human health worldwide. To date, the efficacy of chemotherapy in HCC has been limited because of drug resistance. To overcome this, combination therapy with chemotherapeutic drugs and siRNA represents a new strategy to improve anticancer effects through synergistic effects. Therefore, this study examined the efficacy of combination therapy for HCC, wherein two types of hepatoma-targeting ligand-based liposomes were used to co-deliver curcumin and pituitary tumor modifying gene-1 (PTTG1) siRNA. First, curcumin (Cur) was encapsulated in POPC-based neutral liposomes with surface-exposed galactose residues (Gal-POPC/Cur). Second, PTTG1 siRNA (siPTTG1) was complexed with liposomes containing a galactose ligand based on cationic lipids (Gal-DOTAP/siPTTG1). Under optimized experimental conditions, curcumin and siPTTG1 were effectively loaded into the respective liposomes (Gal-POPC/Cur or Gal-DOTAP/siPTTG1). These liposomes with selected sizes and zeta potentials effectively accumulated at the tumor sites and entered HCC cells. Moreover, they showed higher cytotoxic effects on cancer cells in the Gal-POPC/Cur and Gal-DOTAP/siPTTG1 groups than in the group treated with non-target liposomes. The two combination treatments exhibited excellent anticancer effects by inhibiting the expression of Bcl-2 gene and increasing the expression of Caspase-3 gene in hepatocellular carcinoma. Tumor growth was effectively inhibited by intravenous injection of Gal-POPC/Cur and Gal-DOTAP/siPTTG1 into nude mice carrying subcutaneous human Huh-7 xenografts. Overall, these results demonstrate the high potential of liver-targeted liposome nano-pharmaceuticals carrying curcumin and PTTG1 siRNA to improve HCC treatment.