Co-delivery of TRAIL and bortezomib via liposomes demonstrates enhanced antitumor efficacy in vivo

Resistance against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death of cancer cells is a major obstacle in clinical application of TRAIL. Bortezomib (BTZ) is the first-generation proteasome inhibitor to enhance TRAIL-mediated apoptosis and overcome tumor cell resistance to TRAIL, therefore we developed a novel nanodrug called LSBTZ-TRAIL to co-deliver TRAIL and BTZ via liposomes. TRAIL was coupled to the surface of the liposome by DSPE-PEG 2000 -NHS, while BTZ was encapsulated in the internal aqueous phase. LSBTZ-TRAIL was characterized with a particle size of 147.00 ± 1.300 nm, polydispersity index (PDI) of 0.056 ± 0.005 and zeta potential of -8.17 ± 0.600 mV. LSBTZ-TRAIL did not change the secondary structure of TRAIL, and LSBTZ-TRAIL was stable in 50% fetal bovine serum and tumor microenvironment. In vitro, the cell killing capacity of LSBTZ-TRAIL was 1.16-6.22 times that of TRAIL + BTZ. Mechanistically, LSBTZ-TRAIL induced apoptosis of tumor cells by up-regulating the death receptor (DR4/5) and activating the caspase signaling pathway. In vivo and in vitro uptake experiments, LS-TRAIL accumulated more in tumor cells or tissues than LS. In vivo , the antitumor effect of LSBTZ-TRAIL was 2.62 times that of TRAIL + BTZ, and prolonged the survival and blood circulation time of mice. In addition, safety evaluation showed that LSBTZ-TRAIL had no acute toxic effects in vivo . These results suggested that the liposomal co-delivery system of TRAIL and BTZ significantly enhance their antitumor effects and provide a new approach to overcome TRAIL-resistance.