Two branched fructose modification improves tumor targeting delivery of liposomes to breast cancer in intro and in vivo

Abstract Breast cancer is the leading cause of cancer death for females and needs more specific treatments. d -fructose is a promising ligand targeting to glucose transporter 5 (GLUT5) on breast cancer cells, and single-branched fructose has been used for targeting nanoparticles. However, the impact of two-branched fructose on targeting delivery remains to be elucidated. In this study, we synthesized a two-branched fructose ligand, prepared fructose-decorating liposomes and evaluated them in vitro and in vivo. The results showed liposomes were approximately 102 nm–107 nm in size, with −3.19 mV to −3.61 mV zeta potential, and their encapsulation efficiency of paclitaxel (PTX) were 87% ~ 91%. The liposomes decorated with two-branched fructose (Fru2-Lip) had the highest cellular uptake and cytotoxicity in 4T1 cells and MCF7 cells in vitro, and the strongest in vivo targeting delivery and accumulation in breast tumor sites, even compared with the liposomes decorated with two equivalent fructose. Further investigation of the mechanism underlying the increased targeting released the two-branched fructose had a 7.93 kcal/mol higher binding free energy to GLUT5, compared with the single-branched fructose. These results illustrated the two-branched fructose can significantly enhance the tumor-targeting of liposomes and supported the application of multi-branched ligands for the design of tumor-specific targeting delivery system.