title: Enhanced blood-brain barrier penetration and glioma therapy mediated by a new peptide modified gene delivery system.
abstract: Successful glioma gene therapy lays on two important factors, the therapeutic genes and efficient delivery vehicles to cross the blood-brain barrier (BBB) and reach gliomas. In this work, a new gene vector was constructed based on dendrigraft poly-l-lysines (DGL) and polyethyleneglycol (PEG), conjugated with a cell-penetrating peptide, the nucleolar translocation signal (NoLS) sequence of the LIM Kinase 2 (LIMK2) protein (LIMK2 NoLS peptide, LNP), yielding DGL-PEG-LNP. Plasmid DNA encoding inhibitor of growth 4 (ING4) was applied as the therapeutic gene. DGL-PEG-LNP/DNA nanoparticles (NPs) were monodispersed, with a mean diameter of 90.6 ± 8.9 nm. The conjugation of LNP significantly enhanced the BBB-crossing efficiency, cellular uptake and gene expression within tumor cells. Mechanism studies suggested the involvement of energy, caveolae-mediated endocytosis and macropinocytosis in cellular uptake of LNP-modified NPs. MTT results showed that no apparent cytotoxicity was observed when cells were treated with synthesized vectors. Furthermore, LNP-modified NPs mediated strongest and most intensive apoptosis on the tumor site, and the longest median survival time of glioma-bearing mice. All the results demonstrated that LNP is a kind of efficient CPPs especially for BBB-crossing application, and DGL-PEG-LNP/DNA is a potential non-viral platform for glioma gene therapy via intravenous administration.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China.
authors.forename: Kaiyuan
authors.initials: K
authors.lastname: Wang
authors.affiliation: Center of Analysis and Measurement, Fudan University, Shanghai 200433, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, The Ministry of Health, Beijing, China.
authors.forename: Jinning
authors.initials: J
authors.lastname: Lou
authors.affiliation: Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, The Ministry of Health, Beijing, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Ye
authors.affiliation: School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: rqhuang@fudan.edu.cn.
authors.forename: Rongqin
authors.initials: R
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011806:Quinolinium Compounds / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D001583:Benzoxazoles; D010455:Peptides; D011806:Quinolinium Compounds; C075296:1,1'-((4,4,7,7-tetramethyl)-4,7-diazaundecamethylene)bis-4-(3-methyl-2,3-dihydro(benzo-1,3-oxazole)-2-methylidene)quinolinium
keywords: Blood–brain barrier; Cell-penetrating peptide; Gene therapy; Glioma-targeting