@article{01HHM3PJRCVBTMGYGBM8A8W2Z8,
  abstract     = {{The widespread use of small interfering RNA (siRNA) is limited by the multiple extra- and intracellular barriers upon in vivo administration. Hence, suitable delivery systems, based on siRNA encapsulation in nanoparticles or its conjugation to targeting ligands, have been developed. Nevertheless, at the intracellular level, these state-ofthe-art delivery systems still suffer from a low endosomal escape efficiency. Consequently, the bulk of the endocytosed siRNA drug rapidly accumulates in the lysosomal compartment. We recently reported that a wide variety of cationic amphiphilic drugs (CADs) can promote small nucleic acid delivery from the endolysosomal compartment into the cytosol via transient induction of lysosomal membrane permeabilization. Here, we describe the identification of alternate siRNA delivery enhancers from the NIH Clinical Compound Collection that do not have the typical physicochemical properties of CADs. Additionally, we demonstrate improved endolysosomal escape of siRNA via a cholesterol conjugate and polymeric carriers with the alpha 1-adrenergic antagonist prazosin, which was identified as the best performing delivery enhancer from the compound screen. A more detailed assessment of the mode-of-action of prazosin suggests that a different cellular phenotype compared to typical CAD adjuvants drives cytosolic siRNA delivery. As it has been described in the literature that prazosin also induces cancer cell apoptosis and promotes antigen cross-presentation in dendritic cells, the proof-ofconcept data in this work provides opportunities for the repurposing of prazosin in an anti-cancer combination strategy with siRNA.}},
  author       = {{Van de Vyver, Thijs and Muntean, Cristina and Efimova, Iuliia and Krysko, Dmitri and De Backer, Lynn and De Smedt, Stefaan and Raemdonck, Koen}},
  issn         = {{0168-3659}},
  journal      = {{JOURNAL OF CONTROLLED RELEASE}},
  keywords     = {{Drug repurposing,Cationic amphiphilic drugs,Lysosomal membrane permeabilization,Endosomal escape,Combination therapy,cancer therapy,cancer immunotherapy,BIODEGRADABLE DEXTRAN NANOGELS,CATIONIC AMPHIPHILIC DRUGS,GENE SILENCING POTENCY,IN-VIVO DELIVERY,ENDOSOMAL ESCAPE,LIPID NANOPARTICLES,MEDIATED DELIVERY,SMALL MOLECULES,BINDING-SITE,CELL-DEATH}},
  language     = {{eng}},
  pages        = {{142--158}},
  title        = {{The alpha-adrenergic antagonist prazosin promotes cytosolic siRNA delivery from lysosomal compartments}},
  url          = {{http://doi.org/10.1016/j.jconrel.2023.10.014}},
  volume       = {{364}},
  year         = {{2023}},
}

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