Multifunctional targeted liposomal drug delivery for efficient glioblastoma treatment

Zakia Belhadj; Changyou Zhan; Man Ying; Xiaoli Wei; Cao Xie; Zhiqiang Yan; Weiyue Lu

doi:10.18632/oncotarget.17976

Multifunctional targeted liposomal drug delivery for efficient glioblastoma treatment

Oncotarget. 2017 May 18;8(40):66889-66900. doi: 10.18632/oncotarget.17976. eCollection 2017 Sep 15.

Authors

Zakia Belhadj¹, Changyou Zhan², Man Ying¹, Xiaoli Wei^{1

3}, Cao Xie¹, Zhiqiang Yan⁴, Weiyue Lu^{1

3

5}

Affiliations

¹ Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, P.R. China.
² Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China.
³ State Key Laboratory of Medical Neurobiology & The Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, P.R. China.
⁴ Institute 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.
⁵ State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200433, P.R. China.

Abstract

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 α_vβ₃ 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.

Keywords: blood–brain barrier; blood–brain tumor barrier; glioma; multifunctional liposomes; pharmacodynamics.