Show simple item record

dc.contributor.authorOsborn, Maire F.
dc.contributor.authorColes, Andrew H.
dc.contributor.authorBiscans, Annabelle
dc.contributor.authorHaraszti, Reka A
dc.contributor.authorRoux, Loic
dc.contributor.authorDavis, Sarah M
dc.contributor.authorLy, Socheata
dc.contributor.authorEcheverria, Dimas
dc.contributor.authorHassler, Matthew R.
dc.contributor.authorGodinho, Bruno M D C
dc.contributor.authorNikan, Mehran
dc.contributor.authorKhvorova, Anastasia
dc.date2022-08-11T08:10:52.000
dc.date.accessioned2022-08-23T17:22:55Z
dc.date.available2022-08-23T17:22:55Z
dc.date.issued2019-02-20
dc.date.submitted2019-06-03
dc.identifier.citation<p>Nucleic Acids Res. 2019 Feb 20;47(3):1070-1081. doi: 10.1093/nar/gky1232. <a href="https://doi.org/10.1093/nar/gky1232">Link to article on publisher's site</a></p>
dc.identifier.issn0305-1048 (Linking)
dc.identifier.doi10.1093/nar/gky1232
dc.identifier.pmid30535404
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48847
dc.description.abstractEfficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in liver (65%), adrenal gland (37%), ovary (35%), and kidney (78%). Interestingly, siRNA internalization may not be completely driven by lipoprotein endocytosis, but the extent of siRNA phosphorothioate modifications may also be a factor. Although biomimetic lipoprotein nanoparticles have been explored for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30535404&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectsmall interfering RNAs
dc.subjectsiRNAs
dc.subjectlipid transport
dc.subjecthydrophobicity
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleHydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways
dc.typeJournal Article
dc.source.journaltitleNucleic acids research
dc.source.volume47
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1054&amp;context=rti_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/rti_pubs/55
dc.identifier.contextkey14647627
refterms.dateFOA2022-08-23T17:22:55Z
html.description.abstract<p>Efficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in liver (65%), adrenal gland (37%), ovary (35%), and kidney (78%). Interestingly, siRNA internalization may not be completely driven by lipoprotein endocytosis, but the extent of siRNA phosphorothioate modifications may also be a factor. Although biomimetic lipoprotein nanoparticles have been explored for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.</p>
dc.identifier.submissionpathrti_pubs/55
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentRNA Therapeutics Institute
dc.contributor.departmentMorningside Graduate School of Biomedical Sciences
dc.source.pages1070-1081
dc.contributor.studentSarah M. Davis
dc.description.thesisprogramInterdisciplinary


Files in this item

Thumbnail
Name:
gky1232.pdf
Size:
3.521Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Copyright The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as Copyright The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.