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The integrin αvβ3 receptor and Lactoferrin receptor (LfR) are over-expressed in both cerebral microvascular endothelial cells and glioma cells. RGD tripeptide and Lf can specifically bind with integrin αvβ3 receptor and LfR, respectively. In our study, RGD and Lf dual-modified liposomes loaded with docetaxel (DTX) were designed to enhance the brain targeting effect and treatment of glioma. Our in vitro studies have shown that RGD-Lf-LP can significantly enhance the cellular uptake of U87 MG cells and human cerebral microvascular endothelial cells (hCMEC/D3) when compared to RGD modified liposomes (RGD-LP) and Lf modified liposomes (Lf-LP). Free RGD and Lf competitively reduced the cellular uptake of RGD-Lf-LP, in particular, free RGD played a main inhibitory effect on cellular uptake of RGD-Lf-LP in U87 MG cells, yet free Lf played a main inhibitory effect on cellular uptake of RGD-Lf-LP in hCMEC/D3 cells. RGD-Lf-LP can also significantly increase penetration of U87 MG tumor spheroids, and RGD modification plays a dominating role on promoting the penetration of U87 MG tumor spheroids. The results of in vitro BBB model were shown that RGD-Lf-LP-C6 obviously increased the transport of hCMEC/D3 cell monolayers, and Lf modification plays a dominating role on increasing the transport of hCMEC/D3 cell monolayers. In vivo imaging proved that RGD-Lf-LP shows stronger targeting effects for brain orthotopic gliomas than that of RGD-LP and Lf-LP. The result of tissue distribution confirmed that RGD-LF-LP-DTX could significantly increase brain targeting after intravenous injection. Furthermore, RGD-LF-LP-DTX (a dose of 5 mg kg−1 DTX) could significantly prolong the survival time of orthotopic glioma-bearing mice. In summary, RGD and LF dual modification are good combination for brain targeting delivery, RGD-Lf-LP-DTX could enhance brain targeting effects, and is thus a promising chemotherapeutic drug delivery system for treatment of glioma. [ABSTRACT FROM AUTHOR]