
Cationic amphiphilic drugs boost the lysosomal escape of small nucleic acid therapeutics in a nanocarrier-dependent manner
- Author
- Thijs Van de Vyver, Bram Bogaert (UGent) , Lynn De Backer (UGent) , Freya Joris (UGent) , Roberta Guagliardo, Jelter Van Hoeck, Pieterjan Merckx (UGent) , Serge Van Calenbergh (UGent) , Srinivas Ramishetti, Dan Peer, Katrien Remaut (UGent) , Stefaan De Smedt (UGent) and Koen Raemdonck (UGent)
- Organization
- Abstract
- Small nucleic acid (NA) therapeutics, such as small interfering RNA (siRNA), are generally formulated in nanoparticles (NPs) to overcome the multiple extra- and intracellular barriers upon in vivo administration. Interaction with target cells typically triggers endocytosis and sequesters the NPs in endosomes, thus hampering the pharmacological activity of the encapsulated siRNAs that occurs in the cytosol. Unfortunately, for most state-of-the-art NPs, endosomal escape is largely inefficient. As a result, the bulk of the endocytosed NA drug is rapidly trafficked toward the degradative lysosomes that are considered as a dead end for siRNA nanomedicines. In contrast to this paradigm, we recently reported that cationic amphiphilic drugs (CADs) could strongly promote functional siRNA delivery from the endolysosomal compartment via transient induction of lysosomal membrane permeabilization. However, many questions still remain regarding the broader applicability of such a CAD adjuvant effect on NA delivery. Here, we report a drug repurposing screen (National Institutes of Health Clinical Collection) that allowed identification of 56 CAD adjuvants. We furthermore demonstrate that the CAD adjuvant effect is dependent on the type of nanocarrier, with NPs that generate an appropriate pool of decomplexed siRNA in the endolysosomal compartment being most susceptible to CAD-promoted gene silencing. Finally, the CAD adjuvant effect was verified on human ovarian cancer cells and for antisense oligonucleotides. In conclusion, this study strongly expands our current knowledge on how CADs increase the cytosolic release of small NAs, providing relevant insights to more rationally combine CAD adjuvants with NA-loaded NPs for future therapeutic applications.
- Keywords
- General Engineering, General Physics and Astronomy, General Materials Science, drug repurposing, cationic amphiphilic drugs, lysosomal membrane permeabilization, nucleic acid therapeutics, cellular delivery, endosomal escape, lipid nanoparticles, BIODEGRADABLE DEXTRAN NANOGELS, MEDIATED SIRNA DELIVERY, ENDOSOMAL ESCAPE, CELL-DEATH, IN-VITRO, PROTEIN-BINDING, HIGH-THROUGHPUT, SMALL MOLECULES, PHOSPHOLIPIDOSIS INDUCTION, INTRACELLULAR DELIVERY
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8671573
- MLA
- Van de Vyver, Thijs, et al. “Cationic Amphiphilic Drugs Boost the Lysosomal Escape of Small Nucleic Acid Therapeutics in a Nanocarrier-Dependent Manner.” ACS NANO, vol. 14, no. 4, 2020, pp. 4774–91, doi:10.1021/acsnano.0c00666.
- APA
- Van de Vyver, T., Bogaert, B., De Backer, L., Joris, F., Guagliardo, R., Van Hoeck, J., … Raemdonck, K. (2020). Cationic amphiphilic drugs boost the lysosomal escape of small nucleic acid therapeutics in a nanocarrier-dependent manner. ACS NANO, 14(4), 4774–4791. https://doi.org/10.1021/acsnano.0c00666
- Chicago author-date
- Van de Vyver, Thijs, Bram Bogaert, Lynn De Backer, Freya Joris, Roberta Guagliardo, Jelter Van Hoeck, Pieterjan Merckx, et al. 2020. “Cationic Amphiphilic Drugs Boost the Lysosomal Escape of Small Nucleic Acid Therapeutics in a Nanocarrier-Dependent Manner.” ACS NANO 14 (4): 4774–91. https://doi.org/10.1021/acsnano.0c00666.
- Chicago author-date (all authors)
- Van de Vyver, Thijs, Bram Bogaert, Lynn De Backer, Freya Joris, Roberta Guagliardo, Jelter Van Hoeck, Pieterjan Merckx, Serge Van Calenbergh, Srinivas Ramishetti, Dan Peer, Katrien Remaut, Stefaan De Smedt, and Koen Raemdonck. 2020. “Cationic Amphiphilic Drugs Boost the Lysosomal Escape of Small Nucleic Acid Therapeutics in a Nanocarrier-Dependent Manner.” ACS NANO 14 (4): 4774–4791. doi:10.1021/acsnano.0c00666.
- Vancouver
- 1.Van de Vyver T, Bogaert B, De Backer L, Joris F, Guagliardo R, Van Hoeck J, et al. Cationic amphiphilic drugs boost the lysosomal escape of small nucleic acid therapeutics in a nanocarrier-dependent manner. ACS NANO. 2020;14(4):4774–91.
- IEEE
- [1]T. Van de Vyver et al., “Cationic amphiphilic drugs boost the lysosomal escape of small nucleic acid therapeutics in a nanocarrier-dependent manner,” ACS NANO, vol. 14, no. 4, pp. 4774–4791, 2020.
@article{8671573, abstract = {{Small nucleic acid (NA) therapeutics, such as small interfering RNA (siRNA), are generally formulated in nanoparticles (NPs) to overcome the multiple extra- and intracellular barriers upon in vivo administration. Interaction with target cells typically triggers endocytosis and sequesters the NPs in endosomes, thus hampering the pharmacological activity of the encapsulated siRNAs that occurs in the cytosol. Unfortunately, for most state-of-the-art NPs, endosomal escape is largely inefficient. As a result, the bulk of the endocytosed NA drug is rapidly trafficked toward the degradative lysosomes that are considered as a dead end for siRNA nanomedicines. In contrast to this paradigm, we recently reported that cationic amphiphilic drugs (CADs) could strongly promote functional siRNA delivery from the endolysosomal compartment via transient induction of lysosomal membrane permeabilization. However, many questions still remain regarding the broader applicability of such a CAD adjuvant effect on NA delivery. Here, we report a drug repurposing screen (National Institutes of Health Clinical Collection) that allowed identification of 56 CAD adjuvants. We furthermore demonstrate that the CAD adjuvant effect is dependent on the type of nanocarrier, with NPs that generate an appropriate pool of decomplexed siRNA in the endolysosomal compartment being most susceptible to CAD-promoted gene silencing. Finally, the CAD adjuvant effect was verified on human ovarian cancer cells and for antisense oligonucleotides. In conclusion, this study strongly expands our current knowledge on how CADs increase the cytosolic release of small NAs, providing relevant insights to more rationally combine CAD adjuvants with NA-loaded NPs for future therapeutic applications.}}, author = {{Van de Vyver, Thijs and Bogaert, Bram and De Backer, Lynn and Joris, Freya and Guagliardo, Roberta and Van Hoeck, Jelter and Merckx, Pieterjan and Van Calenbergh, Serge and Ramishetti, Srinivas and Peer, Dan and Remaut, Katrien and De Smedt, Stefaan and Raemdonck, Koen}}, issn = {{1936-0851}}, journal = {{ACS NANO}}, keywords = {{General Engineering,General Physics and Astronomy,General Materials Science,drug repurposing,cationic amphiphilic drugs,lysosomal membrane permeabilization,nucleic acid therapeutics,cellular delivery,endosomal escape,lipid nanoparticles,BIODEGRADABLE DEXTRAN NANOGELS,MEDIATED SIRNA DELIVERY,ENDOSOMAL ESCAPE,CELL-DEATH,IN-VITRO,PROTEIN-BINDING,HIGH-THROUGHPUT,SMALL MOLECULES,PHOSPHOLIPIDOSIS INDUCTION,INTRACELLULAR DELIVERY}}, language = {{eng}}, number = {{4}}, pages = {{4774--4791}}, title = {{Cationic amphiphilic drugs boost the lysosomal escape of small nucleic acid therapeutics in a nanocarrier-dependent manner}}, url = {{http://dx.doi.org/10.1021/acsnano.0c00666}}, volume = {{14}}, year = {{2020}}, }
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