Synergistic targeting tenascin C and neuropilin-1 for specific penetration of nanoparticles for anti-glioblastoma treatment
Synergistic targeting tenascin C and neuropilin-1 for specific penetration of nanoparticles for anti-glioblastoma treatment
复制标题
协同靶向 Tenascin C 和 Neuropilin-1，实现纳米颗粒的特异性渗透，用于抗胶质母细胞瘤治疗
DOI：
10.1016/j.biomaterials.2016.05.037
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发表时间：
2016-09-01
期刊：
影响因子：
14
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Kang, Ting;Zhu, Qianqian;Chen, Jun
多形性胶质母细胞瘤（GBM）的病理和生理屏障导致纳米尺寸的治疗剂的外渗和渗透不足。细胞外基质（extracellularmatrix，ECM）是间质液压力相关性药物外排的主要驱动因素，在GBM病理屏障的形成中起着重要作用。在本文中，通过经由半胱氨酸将FHK和tLyp-1序列偶联在一起以协同靶向新血管系统和胶质瘤细胞上的胶质瘤相关生腱蛋白C（细胞外基质组分）和神经纤毛蛋白-1来合成新的Ft肽，以使纳米颗粒能够特异性渗透用于抗胶质母细胞瘤治疗。在体外，Ft肽功能化不仅使聚乙二醇-聚乳酸纳米微粒系统在2D U87 MG细胞和HUVEC细胞中内化，而且促进其在3D胶质瘤球体中的深度渗透。类似地，体内实时2D和3D成像清楚地显示了在颅内U87神经胶质瘤荷瘤小鼠的神经胶质瘤病灶中Ft-功能化纳米颗粒（Ft-NP）的大量积累。胶质瘤分布分析表明，腱生蛋白C介导的积累在胶质瘤灶和神经纤毛蛋白1介导的运输通过胶质瘤细胞。紫杉醇负载的Ft-NP（Ft-NP-PTX）与FHK或tLyp-1修饰的Ft-NP相比诱导更高的细胞毒效应和凋亡率。静脉内给予Ft-NP-PTX后也获得了最高的抗神经胶质瘤功效，与盐水处理的小鼠相比，中位生存期延长了269%，而在其他制剂处理后仅获得有限的寿命延长（对于Taxol（R）、NP-PTX、tLyp-1-NP-PTX和FHK-NP-PTX分别为31.3%、59.4%、134.4%和109.3%）。总之，所有这些证据共同证实了Ft-NP-PTX用于通过神经纤毛蛋白-1和腱生蛋白C介导的纳米颗粒特异性渗透到胶质瘤实质中的抗胶质瘤药物递送的改善的治疗效果。(C)2016爱思唯尔有限公司版权所有
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) nano particulate 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 (R), 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. (C) 2016 Elsevier Ltd. All rights reserved.