LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma

被引:183
|
作者
Zhang, Bo [2 ]
Sun, Xiyang [1 ]
Mei, Heng [2 ]
Wang, Yu [1 ]
Liao, Ziwei [1 ]
Chen, Jun [1 ]
Zhang, Qizhi [1 ]
Hu, Yu [2 ]
Pang, Zhiqing [1 ]
Jiang, Xinguo [1 ]
机构
[1] Fudan Univ, Sch Pharm, Key Lab Smart Drug Delivery, Minist Educ, Shanghai 201203, Peoples R China
[2] Huazhong Univ Sci & Technol, Inst Hematol, Union Hosp, Tongji Med Coll, Wuhan 430022, Hubei, Peoples R China
基金
中国国家自然科学基金;
关键词
Dual targeting; Low-density lipoprotein receptor; Peptide-22; Nanoparticles; Targeting therapy; Brain glioma; LOW-DENSITY-LIPOPROTEIN; CENTRAL-NERVOUS-SYSTEM; PEG-PLA NANOPARTICLES; BLOOD-BRAIN; DRUG-DELIVERY; APOLIPOPROTEIN-E; PHASE-II; RECEPTOR; PACLITAXEL; TUMOR;
D O I
10.1016/j.biomaterials.2013.08.039
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP-PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&E staining showed that PNP-PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications. (C) 2013 Elsevier Ltd. All rights reserved.
引用
收藏
页码:9171 / 9182
页数:12
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