TY  - JOUR
A1  - Linder, Benedikt
A1  - Weirauch, Ulrike
A1  - Ewe, Alexander
A1  - Uhmann, Anja
A1  - Seifert, Volker
A1  - Mittelbronn, Michel Guy André
A1  - Harter, Patrick Nikolaus
A1  - Aigner, Achim
A1  - Kögel, Donat
T1  - Therapeutic targeting of Stat3 using lipopolyplex nanoparticle-formulated siRNA in a syngeneic orthotopic mouse glioma model
T2  - Cancers
N2  - 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.
KW  - STAT3
KW  - siRNA/RNAi
KW  - polyethylenimine
KW  - PEI
KW  - lipopolyplex
KW  - siRNA delivery
KW  - glioma
KW  - glioblastoma
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/49302
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-493024
SN  - 2072-6694
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
VL  - 11
IS  - 3, Art. 333
SP  - 1
EP  - 22
PB  - MDPI
CY  - Basel
ER  -