title: Dual targeting effect of Angiopep-2-modified, DNA-loaded nanoparticles for glioma.
abstract: Gene therapy offers a promising cure of brain glioma and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to induce cell apoptosis of glioma selectively without affecting the normal cells. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the principal vector. Angiopep-2, which can target to the low-density lipoprotein receptor-related protein-1 (LRP1) expressed on BCECs and glial cells, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG) and then complexed with the DNA, designated as PAMAM-PEG-Angiopep/DNA nanoparticles (NPs). The cellular uptake mechanism explored in glial cells showed that the DNA of PAMAM-PEG-Angiopep/DNA NPs entered into the nuclei through the endosome/lysosome pathway. The in vivo biodistribution of PAMAM-PEG-Angiopep/DNA NPs in the brain especially the tumor site was higher than that of PAMAM-PEG/DNA NPs and PAMAM/DNA NPs. Furthermore, the TUNEL analysis showed a more wide-extended apoptosis in the PAMAM-PEG-Angiopep/pORF-TRAIL NPs treated group, compared to other groups including commercial Temozolomide-treated one. The median survival time of PAMAM-PEG-Angiopep/pORF-TRAIL NPs and Temozolomide treated on brain tumor-bearing mice was 61 and 49 days respectively, significantly longer than that of other groups. Besides, the NPs suggested low cytotoxicity after in vitro transfection. Thus, the results showed that Angiopep-2 could be exploited as a specific ligand to cross the BBB and targeted to glial cells, and PAMAM-PEG-Angiopep/DNA NPs can be a potential non-viral delivery system for gene therapy of glial tumor.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Shixian
authors.initials: S
authors.lastname: Huang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Shuhuan
authors.initials: S
authors.lastname: Liu
authors.forename: Haojun
authors.initials: H
authors.lastname: Ma
authors.forename: Rongqin
authors.initials: R
authors.lastname: Huang
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D050091:Dendrimers / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000628:therapy*; D008297:Male; D008422:Materials Testing; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D015996:Survival Rate; D014162:Transfection / Q000379:methods
chemical_list: C531860:Angiopep-2; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D010455:Peptides; D011092:Polyethylene Glycols; D004247:DNA