Synergistic targeting tenascin C and neuropilin-1 for specific penetration of nanoparticles for anti-glioblastoma treatment.
The pathological and physiological barriers of glioblastoma multiforme (GBM) lead to insufficient extravasation and penetration of nano-sized therapeutics. As the main driver of interstitial fluid pressure-related drug efflux, the aberrant extracellular matrix (ECM) appears to be a valuable target that plays a crucial role in forming pathological barriers of GBM. Herein, a new Ft peptide was synthesized by coupling FHK and tLyp-1 sequence together via a cysteine to synergistically target glioma-associated tenascin C (extracellular matrix component) and neuropilin-1 on neovasculature and glioma cells to enable specific penetration of nanoparticles for anti-glioblastoma treatment. In vitro, Ft peptide-functionalization not only enabled the internalization of poly (ethyleneglycol)-poly (lactic acid) nanoparticulate system in 2D U87 MG cells and HUVEC cells but also facilitated its deep penetration in 3D glioma spheroids. Similarly, in vivo real-time 2D and 3D imaging clearly showed a substantial accumulation of the Ft-functionalized nanoparticles (Ft-NP) in the glioma foci of intracranial U87 glioma-bearing mice. Glioma distribution assay demonstrated a tenascin C-mediated accumulation in glioma foci and neuropilin-1-mediated transportation through glioma cells. Paclitaxel-loaded Ft-NP (Ft-NP-PTX) induced higher cytotoxic effect and apoptosis rate compared with FHK or tLyp-1-modified ones. The highest anti-glioma efficacy was also achieved following the i.v. administration of Ft-NP-PTX, with a median survival promotion of 269% than that of the saline-treated mice, while only limited life span promotion was obtained after the treatment of other formulations (31.3%, 59.4%, 134.4% and 109.3% respectively for Taxol(®), NP-PTX, tLyp-1-NP-PTX and FHK-NP-PTX). In conclusion, all these evidences together verified the improved therapeutic effect of Ft-NP-PTX for anti-glioma drug delivery via neuropilin-1- and tenascin C-mediated specific penetration of nanoparticles in to glioma parenchyma.
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Ting
T
Kang
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Qianqian
Q
Zhu
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Di
D
Jiang
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Xingye
X
Feng
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Jingxian
J
Feng
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Tianze
T
Jiang
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Jianhui
J
Yao
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Yixian
Y
Jing
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
Qingxiang
Q
Song
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
Xinguo
X
Jiang
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China. Electronic address: shellygao1@sjtu.edu.cn.
Xiaoling
X
Gao
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. Electronic address: chenjun@fudan.edu.cn.
Jun
J
Chen
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D010455:Peptides; D019063:Tenascin; D039942:Neuropilin-1; D017239:Paclitaxel
Drug delivery; Extracellular matrix; Glioma therapy; Penetration; Synergistic effect