title: Co-delivery of TRAIL gene enhances the anti-glioblastoma effect of paclitaxel in vitro and in vivo.
abstract: Co-delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and paclitaxel (PTX) is an attractive strategy to enhance their anti-tumor efficacy. As the most aggressive brain tumor, glioblastoma is sensitive to TRAIL and PTX. However, their therapeutic efficacy for intracranial glioblastoma is significantly impaired by blood-brain barrier (BBB) and blood-tumor barrier (BTB). Previously, we have prepared c(RGDyK)-poly(ethylene glycol)-polyethyleneimine (RGD-PEG-PEI) as a non-viral gene carrier for glioblastoma targeted therapy by employing a cyclic RGD peptide (c(RGDyK), cyclic arginine-glycine-aspartic acid-d-tyrosine-lysine), which binds to integrin α(v)β(3) over-expressed neovasculature and U87 glioblastoma cells with high affinities. In the present work, it was found that low concentration of paclitaxel (10nM) significantly enhanced the gene transfection of RGD-PEG-PEI/pDNA nanoparticle, which, in turn, dramatically elevated the anti-glioblastoma effect of paclitaxel in vitro. The gene transfection was also elevated in vivo. Co-delivery of brain-targeted CDX-PEG-PLA-PTX micelle dramatically enhanced gene transfection efficiency in the intracranial brain tumor. Due to the change of BBB integrity and the formation of BTB, we subsequently investigated the anti-glioblastoma effects of RGD-PEG-PEI/pORF-hTRAIL nanoparticle combined with CDX-PEG-PLA-PTX micelle (paclitaxel loaded CDX-poly(ethylene glycol)-block-poly(lactic acid) micelle). While at the same dosages, the median survival of the intracranial glioblastoma-bearing model mice treated with co-delivery (33.5 days) is significantly longer than those of solely treated mice with CDX-PEG-PLA-PTX (25.5 days), RGD-PEG-PEI/pORF-hTRAIL (24.5 days) or physiological saline (21.5 days). Herein, we verify the high potency of co-delivery of TRAIL gene and paclitaxel in the intervention of intracranial glioblastoma by employing tumor-targeted gene carrier RGD-PEG-PEI and brain-targeted micelle CDX-PEG-PLA, respectively.
authors.affiliation: School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Shanghai 201203, China.
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhan
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wei
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Linglin
authors.initials: L
authors.lastname: Feng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry; D010957:Plasmids; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014162:Transfection / Q000379:methods; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010455:Peptides; D010456:Peptides, Cyclic; D053221:TNF-Related Apoptosis-Inducing Ligand; C507169:cyclic arginine-glycine-aspartic acid peptide; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; C544016:poly(ethylene glycol)-co-poly(ethyleneimine); D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D017239:Paclitaxel