Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways
Autor: | Andrew H. Coles, Annabelle Biscans, Maire F. Osborn, Bruno M.D.C. Godinho, Loic Roux, Anastasia Khvorova, Mehran Nikan, Socheata Ly, Matthew R. Hassler, Dimas Echeverria, Reka A. Haraszti, Sarah M. Davis |
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Rok vydání: | 2018 |
Předmět: |
Small interfering RNA
media_common.quotation_subject 02 engineering and technology Biology Kidney Endocytosis Mice 03 medical and health sciences 0302 clinical medicine Chemical Biology and Nucleic Acid Chemistry Genetics Distribution (pharmacology) Animals Humans Gene silencing Tissue Distribution RNA Small Interfering Internalization Lipid Transport 030304 developmental biology media_common 0303 health sciences Chemistry RNA Kidney metabolism Blood Proteins 021001 nanoscience & nanotechnology Lipids Cell biology Lipoproteins LDL Receptors LDL Hepatocytes Female RNA Interference lipids (amino acids peptides and proteins) 0210 nano-technology Hydrophobic and Hydrophilic Interactions 030217 neurology & neurosurgery HeLa Cells Lipoprotein |
Zdroj: | Nucleic Acids Research |
ISSN: | 1362-4962 0305-1048 |
Popis: | 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. |
Databáze: | OpenAIRE |
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