Repositioning of zoledronic acid for breast cancer using transferrin-conjugated liposome

Abstract

Zoledronic acid (ZOL) is one of the most potent nitrogen containing bisphosphonates (N-BP) which are used for cancer-induced skeletal disease by inhibiting osteoclast-mediated bone resorption. It acts by inhibiting the farnesyldiphosphate synthase which is one of several key enzymes in the mevalonate pathway consequently leading to osteoclast apoptosis. From recent studies, direct anti-cancer effects of bisphosphonates, particularly ZOL, was demonstrated in breast cancers. The synergic anti-cancer effects of ZOL treated with other anti-cancer agents in breast cancer cells were also reported. However, pharmacokinetic properties of ZOL have limited its cytotoxic activities because almost 60 % of injected ZOL are disposed into bone and 40 % of the dose cleared rapidly from blood, so that not enough dose of ZOL delivered to the cancer cells. For this reason, we introduced transferrin-conjugated long-circulating liposomes as targeted delivery system for enhancing the anti-cancer effect of ZOL. Transferrin receptors have been explored as a target to deliver therapeutics into cancer cells due to their increased expression on malignant cells. Liposomes were prepared by a reverse-phase evaporation vesicle method with aqueous ZOL solution. Transferrins were attached to the neutral liposomes via free thiols (-SH) to the PDP-end of the pyridylthiopropionoylamino-PEG-distearoyl-phosphatidyethanolamine (PDP-PEG-DSPE). Liposomes were characterized by measuring size distribution and zeta potential. The mean diameter of liposomes was 190 nm, and the encapsulation efficiency of ZOL was about 10 %, which was determined by HPLC analysis. Based on the 50 % inhibitory concentration (IC50) of ZOL against breast cancer cell MDA-MB-231, increased anti-cancer effect of transferrin-conjugated liposomal ZOL was evaluated compared to free ZOL and non-conjugated liposomal ZOL. In conclusion, transferrin-conjugated liposome can enhance the anti-cancer effect of ZOL and it is suggested that ZOL can be used as an anti-cancer agent with this formulation in breast cancer patients. © 2013 The Korean Society of Pharmaceutical Sciences and Technology.