Synergistic Dual-Ligand Doxorubicin Liposomes Improve
Targeting and Therapeutic Efficacy of Brain Glioma in Animals
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Abstract
Therapeutic outcome for the treatment
of glioma was often limited
due to low permeability of delivery systems across the blood–brain
barrier (BBB) and poor penetration into the tumor tissue. In order
to overcome these hurdles, we developed the dual-targeting doxorubicin
liposomes conjugated with cell-penetrating peptide (TAT) and transferrin
(T7) (DOX-T7-TAT-LIP) for transporting drugs across the BBB, then
targeting brain glioma, and penetrating into the tumor. The dual-targeting
effects were evaluated by both <i>in vitro</i> and <i>in vivo</i> experiments. <i>In vitro</i> cellular
uptake and three-dimensional tumor spheroid penetration studies demonstrated
that the system could not only target endothelial and tumor monolayer
cells but also penetrate tumor to reach the core of the tumor spheroids
and inhibit the growth of the tumor spheroids. <i>In vivo</i> imaging further demonstrated that T7-TAT-LIP provided the highest
tumor distribution. The median survival time of tumor-bearing mice
after administering DOX-T7-TAT-LIP was significantly longer than those
of the single-ligand doxorubicin liposomes and free doxorubicin. In
conclusion, the dual-ligand liposomes comodified with T7 and TAT possessed
strong capability of synergistic targeted delivery of payload into
tumor cells both <i>in vitro</i> and <i>in vivo</i>, and they were able to improve the therapeutic efficacy of brain
glioma in animals