Development of an efficient liposomal DOX delivery formulation for HCC therapy by targeting CK2

Hepatocellular carcinoma (HCC) is a digestive tract cancer with high mortality and poor prognosis, especially in China. Current chemotherapeutic drugs lead to poor prognosis, low efficacy, and high side effects due to weak targeting specificity and rapidly formed multidrug resistance (MDR). Based on the previous studies on the doxorubicin (DOX) formulation for cancer targeting therapy, we developed a novel DOX delivery formulation for the targeting chemotherapy of HCC and DOX resistant HCC. HCSP4 was previously screened and casein kinase 2 alpha (CK2 alpha) was predicted as its specific target on HCC cells in our lab. In the study, miR125a-5p was firstly predicted as an MDR inhibiting miRNA, and then CK2 alpha was validated as the target of HCSP4 and miR125a-5p using CK2 alpha-/-HepG2 cells. Based on the above, an HCC targeting and MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p was synthesized and tested for its HCC therapeutic efficacy in vitro. The results showed that the liposomal DOX delivery formulation targeted to HCC cells specifically and sensitively, and presented the satisfied therapeutic efficacy for HCC, particularly for DOX resistant HCC. The potential therapeutic mechanism of the DOX delivery formulation was explored, and the formulation inhibited the expression of MDR-relevant genes including ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein), ATP-binding cassette subfamily C member 5 (ABCC5), enhancer of zeste homolog 2 (EZH2), and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). Our study presents a novel targeting chemotherapeutic drug formulation for the therapy of HCC, especially for drug resistant HCC, although it is primarily and needs further study in vivo, but provided a new strategy for the development of novel anticancer drugs. Ruixia Zhao et al developed an MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p for HCC targeting chemotherapy. Their results showed that the liposomal DOX delivery formulation could target to HCC cells specifically and enhance the therapeutic efficacy efficiently, particularly for DOX resistant HCC. The formulation inhibited the expression of MDR-relevant genes including ABCB1, ABCC5, EZH2 and ATP1B1. This study used a new designation for cancer targeting and MDR inhibiting chemotherapeutic drug formulation, and provided a new reference for the development of novel anticancer drugs. image