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Cancers 2019, 11(3), 333; https://doi.org/10.3390/cancers11030333

Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model

1
Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, 60528 Frankfurt am Main, Germany
2
Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, 04107 Leipzig, Germany
3
Institute of Human Genetics, Tumor Genetics Group, University of Göttingen, 37073 Göttingen, Germany
4
Department of Neurosurgery, Goethe University Hospital, 60528 Frankfurt am Main, Germany
5
Institute of Neurology (Edinger-Institute), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany
6
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg
7
Laboratoire national de santé (LNS), 3555 Dudelange, Luxembourg
8
Luxembourg Centre of Neuropathology (LCNP), 3555 Dudelange, Luxembourg
9
NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), 1526 Luxembourg, Luxembourg
10
German Cancer Consortium DKTK Partner site Frankfurt/Main, Frankfurt am Main, Germany and German Cancer Research Center DKFZ, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 21 December 2018 / Revised: 25 February 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
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Abstract

Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12–15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. Signal transducer and activator of transcription 3 (Stat3) is a key signaling protein driving major hallmarks of cancer and represents a promising target for the development of targeted glioblastoma therapies. Here we present data showing that the therapeutic application of siRNAs, formulated in nanoscale lipopolyplexes (LPP) based on polyethylenimine (PEI) and the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), represents a promising new approach to target Stat3 in glioma. We demonstrate that the LPP-mediated delivery of siRNA mediates efficient knockdown of Stat3, suppresses Stat3 activity and limits cell growth in murine (Tu2449) and human (U87, Mz18) glioma cells in vitro. In a therapeutic setting, intracranial application of the siRNA-containing LPP leads to knockdown of STAT3 target gene expression, decreased tumor growth and significantly prolonged survival in Tu2449 glioma-bearing mice compared to negative control-treated animals. This is a proof-of-concept study introducing PEI-based lipopolyplexes as an efficient strategy for therapeutically targeting oncoproteins with otherwise limited druggability. View Full-Text
Keywords: STAT3; siRNA/RNAi; polyethylenimine; PEI; lipopolyplex; siRNA delivery; glioma; glioblastoma STAT3; siRNA/RNAi; polyethylenimine; PEI; lipopolyplex; siRNA delivery; glioma; glioblastoma
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Linder, B.; Weirauch, U.; Ewe, A.; Uhmann, A.; Seifert, V.; Mittelbronn, M.; Harter, P.N.; Aigner, A.; Kögel, D. Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model. Cancers 2019, 11, 333.

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