Issue 12, 2015

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

Abstract

Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.

Graphical abstract: Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

Supplementary files

Article information

Article type
Paper
Submitted
07 Nov 2014
Accepted
15 Feb 2015
First published
18 Feb 2015
This article is Open Access
Creative Commons BY-NC license

Nanoscale, 2015,7, 5350-5362

Author version available

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

P. Kos, U. Lächelt, A. Herrmann, F. M. Mickler, M. Döblinger, D. He, A. Krhač Levačić, S. Morys, C. Bräuchle and E. Wagner, Nanoscale, 2015, 7, 5350 DOI: 10.1039/C4NR06556E

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