Brain glioma has become a great threat to human health in decades. To maximize the therapeutic
efficacy of brain glioma as well as minimize the side effects, drugs should be penetrated
through the blood brain barrier (BBB) and then targeted to the brain carcinoma cells with effective
concentration. A dual-ligand delivery strategy was employed to achieve both of these goals. Herein,
both specific targeting ligand transferrin and cell-penetrating peptide TAT were conjugated onto
liposomes (TF/TAT-LP) to develop a brain glioma dual-ligand delivery system. Synergistic combination
of doxorubicin (DOX) and paclitaxel (PTX), compared with using them separately, could more efficiently
suppress tumor aggravation. In vitro studies including cellular uptake and three-dimensional (3D) tumor spheroid
penetration assays proved that TF/TAT-LP could target brain endothelial and carcinoma cells with deeply penetration
through the endothelial monolayers and target to the core of the tumor spheroids. In vivo imaging proved that the
TF/TAT-LP possesses the highest tumor distribution, which was also confirmed by fluorescent images of the brain section.
Ultimately, the DOX and PTX-loaded TF/TAT-LP (TF/TAT-PTX/DOX-LP) shows the best anti-glioma effect with
improvement of glioma bearing survival time. In conclusion, synergistic combination of doxorubicin and paclitaxel delivered
by the TF/TAT-LP could efficiently target to the brain glioma with satisfying treatment efficiency, which may be a
promising formulation for glioma therapy.