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Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells

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Abstract
Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol. We show that FDA-approved cationic amphiphilic drugs (CADs) significantly improved gene silencing by siRNA-loaded nanogels in cancer cells through simple sequential incubation. CADs induced lysosomal phospholipidosis, leading to transient lysosomal membrane permeabilization and improved siRNA release without cytotoxicity. Of note, the lysosomes could be applied as an intracellular depot for triggered siRNA release by multiple CAD treatments.
Keywords
Drug repurposing, siRNA delivery, Nanogels, Phospholipidosis, Lysosomal membrane permeabilization, Cationic amphiphilic drugs, LOADED DEXTRAN NANOGELS, SMALL INTERFERING RNA, ENDOSOMAL ESCAPE, MEMBRANE PERMEABILIZATION, ACID SPHINGOMYELINASE, LIPID NANOPARTICLES, LUNG-CANCER, DELIVERY, DEATH, VOLUME

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MLA
Joris, Freya, Lynn De Backer, Thijs Van de Vyver, et al. “Repurposing Cationic Amphiphilic Drugs as Adjuvants to Induce Lysosomal siRNA Escape in Nanogel Transfected Cells.” JOURNAL OF CONTROLLED RELEASE 269 (2018): 266–276. Print.
APA
Joris, F., De Backer, L., Van de Vyver, T., Bastiancich, C., De Smedt, S., & Raemdonck, K. (2018). Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells. JOURNAL OF CONTROLLED RELEASE, 269, 266–276.
Chicago author-date
Joris, Freya, Lynn De Backer, Thijs Van de Vyver, Chiara Bastiancich, Stefaan De Smedt, and Koen Raemdonck. 2018. “Repurposing Cationic Amphiphilic Drugs as Adjuvants to Induce Lysosomal siRNA Escape in Nanogel Transfected Cells.” Journal of Controlled Release 269: 266–276.
Chicago author-date (all authors)
Joris, Freya, Lynn De Backer, Thijs Van de Vyver, Chiara Bastiancich, Stefaan De Smedt, and Koen Raemdonck. 2018. “Repurposing Cationic Amphiphilic Drugs as Adjuvants to Induce Lysosomal siRNA Escape in Nanogel Transfected Cells.” Journal of Controlled Release 269: 266–276.
Vancouver
1.
Joris F, De Backer L, Van de Vyver T, Bastiancich C, De Smedt S, Raemdonck K. Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells. JOURNAL OF CONTROLLED RELEASE. 2018;269:266–76.
IEEE
[1]
F. Joris, L. De Backer, T. Van de Vyver, C. Bastiancich, S. De Smedt, and K. Raemdonck, “Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells,” JOURNAL OF CONTROLLED RELEASE, vol. 269, pp. 266–276, 2018.
@article{8548734,
  abstract     = {Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol. We show that FDA-approved cationic amphiphilic drugs (CADs) significantly improved gene silencing by siRNA-loaded nanogels in cancer cells through simple sequential incubation. CADs induced lysosomal phospholipidosis, leading to transient lysosomal membrane permeabilization and improved siRNA release without cytotoxicity. Of note, the lysosomes could be applied as an intracellular depot for triggered siRNA release by multiple CAD treatments.},
  author       = {Joris, Freya and De Backer, Lynn and Van de Vyver, Thijs and Bastiancich, Chiara and De Smedt, Stefaan and Raemdonck, Koen},
  issn         = {0168-3659},
  journal      = {JOURNAL OF CONTROLLED RELEASE},
  keywords     = {Drug repurposing,siRNA delivery,Nanogels,Phospholipidosis,Lysosomal membrane permeabilization,Cationic amphiphilic drugs,LOADED DEXTRAN NANOGELS,SMALL INTERFERING RNA,ENDOSOMAL ESCAPE,MEMBRANE PERMEABILIZATION,ACID SPHINGOMYELINASE,LIPID NANOPARTICLES,LUNG-CANCER,DELIVERY,DEATH,VOLUME},
  language     = {eng},
  pages        = {266--276},
  title        = {Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells},
  url          = {http://dx.doi.org/10.1016/j.jconrel.2017.11.019},
  volume       = {269},
  year         = {2018},
}

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