title: A non-viral suicide gene delivery system traversing the blood brain barrier for non-invasive glioma targeting treatment.
abstract: Herpes simplex virus type I thymidine kinase gene (HSV-TK) in viral vector is a promising strategy against glioblastoma multiforme (GBM). However, the biosafety risk restricts its application in clinic. In this work, poly (l-lysine)-grafted polyethylenimine (PEI-PLL), which combines the high transfection efficiency of polyethylenimine and the good biodegradability of poly (l-lysine), was adopted as the non-viral vector backbone. Angiopep-2, a blood brain barrier (BBB) crossing and glioma targeting bifunctional peptide was conjugated on PEI-PLL via polyethyleneglycol (PEG) and designated as PPA. The optimal transfection ratio of PPA/DNA complexes nanoparticles (PPA NPs) was firstly characterized. Next, the glioma targeting of the PPA NPs was confirmed through cellular uptake and transfection analysis. The in vivo imaging studies demonstrated that the PPA NPs could not only penetrate BBB but also accumulate in striatum and cortex via systemic administration. Moreover, the PPA/HSV-TK NPs showed remarkably anti-glioma effect and survival benefit in an invasive orthotopic human GBM mouse model through inhibiting proliferation and inducing apoptosis (p<0.05 vs control). This study firstly illustrated that the cationic polymer PPA could be exploited as an efficient gene vector to cross the BBB, and innovatively provided a potential non-viral nanomedicine for noninvasive suicide gene therapy in the glioma treatment.
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China.
authors: Shiqian
authors: S
authors: Gao
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
authors: Huayu
authors: H
authors: Tian
authors: School of Life Science, Northeast Normal University, Changchun 130024, PR China.
authors: Zhenkai
authors: Z
authors: Xing
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
authors: Dawei
authors: D
authors: Zhang
authors: School of Life Science, Northeast Normal University, Changchun 130024, PR China.
authors: Ye
authors: Y
authors: Guo
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
authors: Zhaopei
authors: Z
authors: Guo
authors: School of Life Science, Northeast Normal University, Changchun 130024, PR China. Electronic address: zhuxj720@nenu.edu.cn.
authors: Xiaojuan
authors: X
authors: Zhu
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China. Electronic address: xschen@ciac.ac.cn.
authors: Xuesi
authors: X
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D004247:DNA / Q000008:administration & dosage; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles; D010455:Peptides / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection
chemical_list: C531860:Angiopep-2; D010455:Peptides; D011107:Polylysine; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D004247:DNA; D013937:Thymidine Kinase
keywords: Blood brain barrier; Noninvasive glioma gene therapy; Polyethylenimine; Polylysine; Suicide gene