title: The influence of the penetrating peptide iRGD on the effect of paclitaxel-loaded MT1-AF7p-conjugated nanoparticles on glioma cells.
abstract: Low permeability across the blood-brain tumor barrier (BTB) and poor penetration into the glioma parenchyma represent key obstacles for anti-glioblastoma drug delivery. In this study, MT1-AF7p peptide, which presents high binding affinity to membrane type-1 matrix metalloproteinase (MT1-MMP) that over-expressed on both angiogenic blood vessels and glioma cells, was employed to decorate the paclitaxel-loaded PEG-PLA nanoparticles (MT1-NP-PTX) to mediate glioblastoma targeting. Tumor-homing and penetrating peptide iRGD was co-administrated to further facilitate nanoparticles extravasation from the tumor vessels and penetration into the glioma parenchyma. MT1-NP-PTX showed satisfactory encapsulated efficiency, loading capacity and size distribution. In C6 glioma cells, MT1-NP was found to exhibit significantly enhanced cellular accumulation than that of unmodified NP via both energy-dependent macropinocytosis and lipid raft-mediated endocytosis. The anti-proliferative and apoptosis-induction activity of PTX was significantly enhanced following its encapsulation in MT1-NP. In vivo imaging and glioma distribution together confirmed that MT1-AF7p functionalization and iRGD co-administration significantly improved the nanoparticles extravasation across BTB and accumulation in glioma parenchyma. Furthermore, in vitro C6 glioma spheroid assays evidenced that MT1-NP effectively penetrated into the glioma spheroids and significantly improved the growth inhibitory effects of loaded PTX on glioma spheroids. More importantly, the median survival time of those nude mice bearing intracranial C6 glioma received MT1-NP-PTX and iRGD combination regimen was 60 days, significantly longer than that of other groups. The findings suggested that the BTB/glioma cells dual-targeting DDS co-administrated with iRGD peptide might provide a both practical and feasible solution to highly efficient anti-glioblastoma drug delivery.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Gu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.forename: Quanyin
authors.initials: Q
authors.lastname: Hu
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.forename: Zhongyang
authors.initials: Z
authors.lastname: Liu
authors.forename: Mengyin
authors.initials: M
authors.lastname: Jiang
authors.forename: Deyu
authors.initials: D
authors.lastname: Miao
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Song
authors.forename: Lei
authors.initials: L
authors.lastname: Yao
authors.forename: Yifan
authors.initials: Y
authors.lastname: Tu
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003374:Coumarins / Q000378:metabolism; D003952:Diagnostic Imaging; D004705:Endocytosis / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000648:ultrastructure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D057846:Cell-Penetrating Peptides; D003374:Coumarins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; C030123:coumarin; D053511:Matrix Metalloproteinase 14; D017239:Paclitaxel