[摘要]：Introduction: Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, is a potent inhibitor of farnesylpyrophosphate synthase with poor in vitro cytotoxic activity as a result of its limited diffusion into tumor cells. The purpose of this study was to investigate whether liposomes targeted to the folate receptor (FR) can effectively deliver ZOL to tumor cells and enhance its in vitro cytotoxicity. Methods: ZOL was entrapped in the water phase of liposomes of various compositions with or without a lipophilic folate ligand. Stability and blood levels after i.v. injection were checked. The in vitro cytotoxic activity and cell uptake of liposomal ZOL (L-ZOL) were examined on various human and mouse cell lines. Results: All formulations were highly stable and resulted in high blood levels in contrast to free ZOL which was rapidly cleared from plasma. Non-targeted L-ZOL was devoid of any in vitro activity at concentrations up to 200 mu M. In contrast, potent cytotoxic activity of folate-targeted L-ZOL (FTL-ZOL) was observed, with optimal activity, reaching the sub-micromolar range, for dipalmitoyl-phosphatidylglycerol (DPPG)-containing liposomes and relatively lower activity for pegylated (PEG) formulations. IC50 values of FTL-ZOL on FR-expressing tumor cells were > 100-fold lower than those of free ZOL Compared to doxorubicin, the cytotoxicity of DPPG-FTL-ZOL was equivalent in drug-sensitive cell lines, and greatly superior in drug-resistant cell lines. When tested on the non-FR upregulated cell lines, the cytotoxicity of FTL-ZOL was lower but still superior to that of L-ZOL The uptake of ZOL by FR-expressing tumor cells was enhanced similar to 25-fold with DPPG-FTL-ZOL, and only similar to 4-fold with PEG-FTL-ZOL. Conclusions: FR targeting of ZOL using liposomes is an effective means to exploit the tumor cell growth inhibitory properties of ZOL DPPG-FTL-ZOL is significantly more efficient at intracellular delivery of ZOL than PEG-FTL-ZOL in FR-expressing tumor cells. (C) 2010 Elsevier B.V. All rights reserved.
