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Antitumoral Cascade-Targeting Ligand for IL-6 Receptor-Mediated Gene Delivery to Glioma.

Authors
  • Wang, Shanshan1
  • Reinhard, Sören2
  • Li, Chengyi1
  • Qian, Min1
  • Jiang, Huiling1
  • Du, Yilin1
  • Lächelt, Ulrich2
  • Lu, Weiyue1
  • Wagner, Ernst3
  • Huang, Rongqin4
  • 1 Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. , (China)
  • 2 Pharmaceutical Biotechnology, Center for System-Based Drug Research, Center for Nanoscience (CeNS), Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 Munich, Germany. , (Germany)
  • 3 Pharmaceutical Biotechnology, Center for System-Based Drug Research, Center for Nanoscience (CeNS), Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: [email protected] , (Germany)
  • 4 Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Molecular Therapy
Publisher
Elsevier
Publication Date
Jul 05, 2017
Volume
25
Issue
7
Pages
1556–1566
Identifiers
DOI: 10.1016/j.ymthe.2017.04.023
PMID: 28502470
Source
Medline
Keywords
License
Unknown

Abstract

The effective treatment of glioma is largely hindered by the poor transfer of drug delivery systems across the blood-brain barrier (BBB) and the difficulty in distinguishing healthy and tumorous cells. In this work, for the first time, an interleukin-6 receptor binding I6P7 peptide was exploited as a cascade-targeting ligand in combination with a succinoyl tetraethylene pentamine (Stp)-histidine oligomer-based nonviral gene delivery system (I6P7-Stp-His/DNA). The I6P7 peptide provides multiple functions, including the cascade-targeting potential represented by a combined BBB-crossing and subsequent glioma-targeting ability, as well as a direct tumor-inhibiting effect. I6P7-Stp-His/DNA nanoparticles (NPs) mediated higher gene expression in human glioma U87 cells than in healthy human astrocytes and a deeper penetration into glioma spheroids than scrambled peptide-modified NPs. Transport of I6P7-modified, but not the control, NPs across the BBB was demonstrated in vitro in a transwell bEnd.3 cell model resulting in transfection of underlying U87 cells and also in vivo in glioma-bearing mice. Intravenous administration of I6P7-Stp-His/plasmid DNA (pDNA)-encoding inhibitor of growth 4 (pING4) significantly prolonged the survival time of orthotopic U87 glioma-bearing mice. The results denote that I6P7 peptide is a roborant cascade-targeting ligand, and I6P7-modified NPs might be exploited for efficient glioma therapy.

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