Synergistic targeting tenascin C and neuropilin-1 for specific penetration of nanoparticles for anti-glioblastoma treatment.

Abstract

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.

• Authors: Ting Kang, Qianqian Zhu, Di Jiang, Xingye Feng, Jingxian Feng, Tianze Jiang, Jianhui Yao, Yixian Jing, Qingxiang Song, Xinguo Jiang, Xiaoling Gao, Jun Chen
• Journal: Biomaterials (Biomaterials) Vol. 101 Pg. 60-75 (09 2016) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 27267628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Peptides
• Tenascin
• Neuropilin-1
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, therapeutic use)
• Apoptosis (drug effects)
• Brain (drug effects, metabolism, pathology)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Drug Delivery Systems
• Glioblastoma (drug therapy, metabolism, pathology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Male
• Mice, Inbred BALB C
• Nanoparticles (chemistry, metabolism)
• Neuropilin-1 (metabolism)
• Paclitaxel (administration & dosage, therapeutic use)
• Peptides (chemistry, metabolism)
• Tenascin (metabolism)