TY - JOUR
T1 - Repositioning the antihistamine ebastine as an intracellular siRNA delivery enhancer
AU - Muntean, Cristina
AU - Blondeel, Eva
AU - Harinck, Laure
AU - Pednekar, Kunal
AU - Prakash, Jai
AU - De Wever, Olivier
AU - Chain, Jeanne Leblond
AU - De Smedt, Stefaan C.
AU - Remaut, Katrien
AU - Raemdonck, Koen
N1 - Funding Information:
The authors acknowledge the Ghent Light Microscopy Core (GLiM) for use of microscopy facilities and training. K.R. and C.M. acknowledge the Research Foundation Flanders (FWO) for funding through research grant G039419N. K.R. additionally acknowledges the European Research Council (ERC) for funding received under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 101002571).
Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2023/9/25
Y1 - 2023/9/25
N2 - Small interfering RNAs (siRNAs) are promising therapeutics for the treatment of human diseases via the induction of sequence-specific gene silencing. To be functional, siRNAs require cytosolic delivery into target cells. However, state-of-the-art delivery systems mediate cellular entry through endocytosis and suffer from ineffective endosomal escape, routing a substantial fraction of the siRNA towards the lysosomal compartment. Cationic amphiphilic drugs (CADs) have been described to improve cytosolic siRNA delivery by the transient induction of lysosomal membrane permeabilization. In this work, we evaluated ebastine, an antihistamine CAD, for its ability to enhance cytosolic release of siRNA in a non-small cell lung cancer model. In particular, we demonstrated that ebastine can improve the siRNA-mediated gene silencing efficiency of a polymeric nanogel by 40-fold, outperforming other CAD compounds. Additionally, ebastine substantially enhanced gene knockdown of a cholesterol-conjugated siRNA, in two-dimensional (2D) cell culture as well as in three-dimensional (3D) tumor spheroids. Finally, ebastine could strongly promote siRNA delivery of lipid nanoparticles (LNPs) composed of a pH-dependent switchable ionizable lipid and with stable PEGylation, in contrast to state-of-the-art LNP formulations. Altogether, we identified ebastine as a potent and versatile siRNA delivery enhancer in cancer cells, which offers opportunities for drug combination therapy in oncology.
AB - Small interfering RNAs (siRNAs) are promising therapeutics for the treatment of human diseases via the induction of sequence-specific gene silencing. To be functional, siRNAs require cytosolic delivery into target cells. However, state-of-the-art delivery systems mediate cellular entry through endocytosis and suffer from ineffective endosomal escape, routing a substantial fraction of the siRNA towards the lysosomal compartment. Cationic amphiphilic drugs (CADs) have been described to improve cytosolic siRNA delivery by the transient induction of lysosomal membrane permeabilization. In this work, we evaluated ebastine, an antihistamine CAD, for its ability to enhance cytosolic release of siRNA in a non-small cell lung cancer model. In particular, we demonstrated that ebastine can improve the siRNA-mediated gene silencing efficiency of a polymeric nanogel by 40-fold, outperforming other CAD compounds. Additionally, ebastine substantially enhanced gene knockdown of a cholesterol-conjugated siRNA, in two-dimensional (2D) cell culture as well as in three-dimensional (3D) tumor spheroids. Finally, ebastine could strongly promote siRNA delivery of lipid nanoparticles (LNPs) composed of a pH-dependent switchable ionizable lipid and with stable PEGylation, in contrast to state-of-the-art LNP formulations. Altogether, we identified ebastine as a potent and versatile siRNA delivery enhancer in cancer cells, which offers opportunities for drug combination therapy in oncology.
KW - 2023 OA procedure
UR - http://www.scopus.com/inward/record.url?scp=85170061365&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2023.123348
DO - 10.1016/j.ijpharm.2023.123348
M3 - Article
C2 - 37633539
AN - SCOPUS:85170061365
SN - 0378-5173
VL - 644
JO - International journal of pharmaceutics
JF - International journal of pharmaceutics
M1 - 123348
ER -
