title: Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration.
abstract: Gene therapy offers great potential for brain glioma. However, therapeutic genes could not reach glioma spontaneously. A glioma-targeting gene delivery system is highly desired to transfer exogenous genes throughout the tumor focus. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the main vector. Chlorotoxin (CTX), which has been demonstrated to bind specifically to receptor expressed in glioma, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG), yielding PAMAM-PEG-CTX. The cellular uptake of CTX itself was observed apparently in C6 glioma cells, almost not in 293 cells. The modification of CTX could significantly increase the cellular uptake of vectors and the DNA-loaded nanoparticles (NPs) in C6 cells. The in vivo distribution of PAMAM-PEG-CTX/DNA NPs in the brain was higher than that of PAMAM/DNA NPs and PAMAM-PEG/DNA NPs. Furthermore, the gene expression of PAMAM-PEG-CTX/DNA NPs was higher and broader in glioma than that of unmodified and PEG-modified counterparts. The TUNEL analysis showed a more wide-extended apoptosis in the CTX-modified group, compared to other groups including commercial temozolomide group. The median survival time of CTX-modified group and temozolomide group was 59.5 and 49 days, respectively, significantly longer than that of other groups. The results suggested that CTX could be exploited as a special glioma-targeting ligand, and PAMAM-PEG-CTX/DNA NPs is a potential non-viral delivery system for gene therapy of glioma via intravenous administration.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Rongqin
authors.initials: R
authors.lastname: Huang
authors.forename: Weilun
authors.initials: W
authors.lastname: Ke
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Shuhuan
authors.initials: S
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000378:metabolism*; D050091:Dendrimers / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D007275:Injections, Intravenous; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000008:administration & dosage* / Q000648:ultrastructure; D051381:Rats; D012604:Scorpion Venoms / Q000008:administration & dosage* / Q000378:metabolism*; D016019:Survival Analysis; D014018:Tissue Distribution
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D050091:Dendrimers; D012604:Scorpion Venoms; C091539:Chlorotoxin; D004247:DNA