PEG-co-PCL nanoparticles modified with MMP-2/9 activatable low molecular weight protamine for enhanced targeted glioblastoma therapy.
By taking advantage of the dramatically upregulated expression of matrix metalloproteinases MMP-2 and MMP-9 in glioblastomas and the powerful transport ability of low molecular weight protamine (LMWP), we constructed an activatable low molecular weight protamine (ALMWP) and conjugated it to PEG-PCL nanoparticles (NP) to develop a 'smart' drug delivery system for enhanced targeted glioblastoma therapy. Important parameters such as particle size distribution, zeta potential and surface content were determined, which confirmed the conjugation of ALMWP to the surface of nanoparticle. ALMWP-NP loaded with paclitaxel (PTX) exhibited a desirable pharmacokinetic and biodistribution profiles for anti-glioblastoma drug delivery. Cellular experiments showed that ALMWP-NP exhibited significantly elevated MMP-dependent cellular accumulation in C6 cells via lipid raft-mediated endocytosis and energy-dependent macropinocytosis, and improved the cytotoxicity of PTX. In vitro C6 tumor spheroid uptake confirmed the tumor penetrating ability of ALMWP-NP, in vivo imaging and glioma distribution justified its specific accumulation in the glioma. The improved glioma-targeting and tumor penetration led to an anticipated enhanced in vivo anti-glioblastoma effect: animals (nude mice bearing intracranial C6 glioma) treated with ALMWP-NP-PTX survive significantly longer than those treated with saline, Taxol(®) NP-PTX and LMWP-NP-PTX. The findings here offered strong evidence for the glioblastoma-targeting therapy of ALMWP-NP-PTX, and could also lead to a significant advancement in the application of CPPs for targeted therapy of glioma.
Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
Guangzhi
G
Gu
Huimin
H
Xia
Quanyin
Q
Hu
Zhongyang
Z
Liu
Mengyin
M
Jiang
Ting
T
Kang
Deyu
D
Miao
Yifan
Y
Tu
Zhiqing
Z
Pang
Qingxiang
Q
Song
Lei
L
Yao
Hongzhan
H
Chen
Xiaoling
X
Gao
Jun
J
Chen
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000378:metabolism; D003952:Diagnostic Imaging; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000187:drug effects; D005027:Ethylene Oxide / Q000737:chemistry*; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D053208:Kaplan-Meier Estimate; D007783:Lactones / Q000737:chemistry*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011479:Protamines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution / Q000187:drug effects
D003374:Coumarins; D007783:Lactones; C400421:PLC(20)-b-PEO(44); D011479:Protamines; C030123:coumarin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005027:Ethylene Oxide; D017239:Paclitaxel