2. Academic Validation
  3. Repositioning the over-the-counter antihistamine ebastine as an intracellular siRNA delivery enhancer

Repositioning the over-the-counter antihistamine ebastine as an intracellular siRNA delivery enhancer

  • Int J Pharm. 2023 Aug 24;123348. doi: 10.1016/j.ijpharm.2023.123348.
Cristina Muntean 1,  Eva Blondeel 2,  Laure Harinck 3,  Kunal Pednekar 4,  Jai Prakash 4,  Olivier De Wever 2,  Jeanne Leblond Chain 5,  Stefaan C De Smedt 6,  Katrien Remaut 3,  Koen Raemdonck 1
Affiliations

Affiliations

  • 1 Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
  • 2 Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium; Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, UZ-Gent, 2RTP, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
  • 3 Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
  • 4 Engineered Therapeutics Group, Department of Advanced Organ Bioengineering and Therapeutics, Technical Medical Centre, University of Twente, 7500 AE Enschede, The Netherlands.
  • 5 University of Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212, F-33000 Bordeaux, France.
  • 6 Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Ghent Light Microscopy (GLiM) Core, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
PMID: 37633539 DOI: 10.1016/j.ijpharm.2023.123348
Abstract

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 over-the-counter antihistamine CAD, for its ability to enhance cytosolic release of siRNA in a non-small cell lung Cancer model. In particular, we demonstrate 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.

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