Multifunctional targeted liposomal drug delivery for efficient glioblastoma treatment
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Zakia Belhadj1, Changyou Zhan2, Man Ying1, Xiaoli Wei1,3, Cao Xie1, Zhiqiang Yan4 and Weiyue Lu1,3,5
1Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, P.R. China
2Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
3State Key Laboratory of Medical Neurobiology & The Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, P.R. China
4Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China
5State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200433, P.R. China
Weiyue Lu, email: [email protected]
Keywords: multifunctional liposomes, blood–brain barrier, blood–brain tumor barrier, glioma, pharmacodynamics
Received: February 24, 2017 Accepted: April 21, 2017 Published: May 18, 2017
Glioblastoma multiforme (GBM) has been considered to be the most malignant brain tumors. Due to the existence of various barriers including the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) greatly hinder the accumulation and deep penetration of chemotherapeutics, the treatment of glioma remains to be the most challenging task in clinic. In order to circumvent these hurdles, we developed a multifunctional liposomal glioma-targeted drug delivery system (c(RGDyK)/pHA-LS) modified with cyclic RGD (c(RGDyK)) and p-hydroxybenzoic acid (pHA) in which c(RGDyK) could target integrin αvβ3 overexpressed on the BBTB and glioma cells and pHA could target dopamine receptors on the BBB. In vitro, c(RGDyK)/pHA-LS could target glioblastoma cells (U87), brain capillary endothelial cells (bEnd.3) and umbilical vein endothelial cells (HUVECs) through a comprehensive pathway. Besides, c(RGDyK)/pHA-LS could also increase the cytotoxicity of doxorubicin encapsulated in liposomes on glioblastoma cells, and was able to penetrate inside the glioma spheroids after traversing the in vitro BBB and BBTB. In vivo, we demonstrated the targeting ability of c(RGDyK)/pHA-LS to intracranial glioma. As expected, c(RGDyK)/pHA-LS/DOX showed a median survival time of 35 days, which was 2.31-, 1.76- and 1.5-fold higher than that of LS/DOX, c(RGDyK)-LS/DOX, and pHA-LS/DOX, respectively. The findings here suggested that the multifunctional glioma-targeted drug delivery system modified with both c(RGDyK) and pHA displayed strong antiglioma efficiency in vitro and in vivo, representing a promising platform for glioma therapy.
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