Novel chondroitin sulfate-binding cationic liposomes loaded with cisplatin efficiently suppress the local growth and liver metastasis of tumor cells in vivo

Abstract

An increased level of chondroitin sulfate (CS) expression on the cell surface is often associated with malignant transformation and the progression of tumor cells. In this study, CSs expressed on highly metastatic tumor cells were used as a target for the selective delivery of anticancer drugs by polyethylene glycol (PEG)-coated liposomes that contained a new cationic lipid 3,5-dipentadecycloxybenzamidine hydrochloride (TRX-20). We found that PEG-coated TRX-20 liposomes (TRX-20 liposomes) bound preferentially to certain CSs, such as CS B, CS D, and CS E, whereas PEG-coated liposomes lacking TRX-20 showed no significant binding to any of the glycosaminoglycans tested. In vitro, TRX-20 liposomes, but not plain PEG liposomes, avidly bound to and were readily internalized by highly metastatic tumor cells such as LM8G5 and ACHN cells, which express large amounts of CS on the cell surface. When TRX-20 liposomes were loaded with cisplatin, they effectively killed the CS-expressing tumor cells in vitro, whereas cisplatin-PEG liposomes lacking TRX-20 were totally ineffective. When injected systemically, TRX-20 liposomes preferentially accumulated in the liver and in solid s.c. LM8G5 tumors. Therapeutic experiments in mice bearing a s.c. LM8G5 tumor revealed that cisplatin-loaded TRX-20 liposomes were significantly more effective in reducing the local tumor growth than cisplatin-loaded plain PEG liposomes or free cisplatin. Furthermore, the cisplatin-loaded TRX-20 liposomes markedly suppressed metastatic spreading of LM8G5 tumor cells to the liver, significantly increasing the survival time of the tumor-bearing mice. These results demonstrate that the CS-targeted delivery of anticancer drugs by novel cationic liposomes represents a potentially useful strategy to prevent the local growth and metastasis, particularly to the liver, of tumor cells that have enhanced expression of CS.