title: Design of Y-shaped targeting material for liposome-based multifunctional glioblastoma-targeted drug delivery.
abstract: Since the treatment of glioma in clinic has been hindered by the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), multifunctional glioma-targeted drug delivery systems that can circumvent both barriers have received increasing scrutiny. Despite recent research efforts have been made to develop multifunctional glioma-targeted liposomes by decorating two or more ligands, few successful trials have been achieved due to the limitation of ligand density on the surface of liposomes. In this study, we designed a Y-shaped multifunctional targeting material c(RGDyK)-pHA-PEG-DSPE, in which cyclic RGD (c(RGDyK)) and p-hydroxybenzoic acid (pHA) were linked with a short spacer. Since c(RGDyK) and pHA could respectively circumvent the BBTB and BBB, c(RGDyK)-pHA-PEG-DSPE-incorporated liposomes could achieve multifunctional glioma-targeted drug delivery with maximal density of both functional moieties. c(RGDyK)-pHA-PEG-DSPE-incorporation enhanced cellular uptake of liposomes in bEnd.3, HUVECs and U87 cells, and increased cytotoxicity of doxorubicin (DOX) loaded liposomes on glioblastoma cells. c(RGDyK)-pHA-PEG-DSPE-incorporated liposomes (c(RGDyK)-pHA-LS) could deeply penetrate the 3D glioma spheroids after crossing the BBB and BBTB models in vitro. Moreover, in vivo fluorescence imaging showed the highest tumor distribution of c(RGDyK)-pHA-LS than did plain liposomes (no ligand modification) and liposomes modified with a single ligand (either c(RGDyK) or pHA). When loaded with DOX, c(RGDyK)-pHA-LS displayed the best anti-glioma effect with a median survival time (36.5days) significantly longer than that of DOX loaded plain liposomes (26.5days) and liposomes modified with a single ligand (28.5days for RGD and 30days for pHA). These results indicated that design of Y-shaped targeting material was promising to maximize the multifunctional targeting effects of liposomes on the therapy of glioma.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Zakia
authors.initials: Z
authors.lastname: Belhadj
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Man
authors.initials: M
authors.lastname: Ying
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Xie
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, PR China.
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhan
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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, PR China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China; State Key Laboratory of Medical Neurobiology, The Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, PR China; State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200433, PR China. Electronic address: wylu@shmu.edu.cn.
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008081:Liposomes; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010226:Parabens / Q000008:administration & dosage* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D010226:Parabens; D010456:Peptides, Cyclic; D010714:Phosphatidylethanolamines; C507169:cyclic arginine-glycine-aspartic acid peptide; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D004317:Doxorubicin; C038193:4-hydroxybenzoic acid
keywords: Blood-brain barrier (BBB); Blood-brain tumor barrier (BBTB); Glioma; Liposome; Targeted drug delivery; Y-shaped multifunctional targeting material