title: Multifunctional liposomes loaded with paclitaxel and artemether for treatment of invasive brain glioma.
abstract: Invasive brain glioma is the most lethal type of cancer and is highly infiltrating. This leads to an extremely poor prognosis and makes complete surgical removal of the tumor virtually impossible. Non-penetration of therapeutic drugs across the blood-brain barrier (BBB), brain cancer stem cells (CSCs), and brain cancer vasculogenic mimicry (VM) results in relapse after surgical and radio therapy. We developed a functional targeting chemotherapy for transporting drugs across the BBB, destroying VM channels, and eliminating CSCs and cancer cells in the brain. The studies were undertaken on brain glioma cells in vitro and in brain glioma-bearing rats. Using paclitaxel as the anticancer drug and artemether as the regulator of apoptosis and inhibitor of VM channels, a kind of functional targeting paclitaxel plus artemether liposomes was developed by modifying two new functional materials: a mannose-vitamin E derivative conjugate (MAN-TPGS1000) and a dequalinium-lipid derivative conjugate (DQA-PEG2000-DSPE). The transport mechanism across the BBB was associated with receptor-mediated endocytosis by MAN-TPGS1000 conjugate via glucose transporters and adsorptive-mediated endocytosis by DQA-PEG2000-DSPE conjugate via electric charge-based interactions. The efficacy was related to the destruction of VM channels by regulating VM indicators, as well as the induction of apoptosis in brain cancer cells and CSCs by activating apoptotic enzymes and pro-apoptotic proteins and inhibiting anti-apoptotic proteins. These data suggest that the chemotherapy using functional targeting paclitaxel plus artemether liposomes could provide a new strategy for treating invasive brain glioma.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xiu-Ying
authors.initials: XY
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Meng-Ge
authors.initials: MG
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Ji-Feng
authors.initials: JF
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Rui-Jun
authors.initials: RJ
authors.lastname: Ju
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Cheng-Xiang
authors.initials: CX
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xue-Tao
authors.initials: XT
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Mu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zeng
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Jin-Ning
authors.initials: JN
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: luwl@bjmu.edu.cn.
authors.forename: Wan-Liang
authors.initials: WL
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003868:Dequalinium / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D005910:Glioma / Q000188:drug therapy*; D008081:Liposomes / Q000494:pharmacology*; D008297:Male; D008358:Mannose / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D017239:Paclitaxel / Q000494:pharmacology*; D010714:Phosphatidylethanolamines / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000494:pharmacology
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000970:Antineoplastic Agents; D037621:Artemisinins; D008081:Liposomes; D010714:Phosphatidylethanolamines; D014810:Vitamin E; D011092:Polyethylene Glycols; D000077549:Artemether; D003868:Dequalinium; D017239:Paclitaxel; D008358:Mannose
keywords: Anticancer efficacy; Brain glioma; Cancer stem cells; Functional targeting liposomes; VM channels