دورية أكاديمية
Delivery of MicroRNAs by Chitosan Nanoparticles to Functionally Alter Macrophage Cholesterol Efflux in Vitro and in Vivo.
| العنوان: | Delivery of MicroRNAs by Chitosan Nanoparticles to Functionally Alter Macrophage Cholesterol Efflux in Vitro and in Vivo. |
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| المؤلفون: | Nguyen MA; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada., Wyatt H; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada., Susser L; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada., Geoffrion M; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada., Rasheed A; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada., Duchez AC; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada., Cottee ML; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada., Afolayan E; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine , University of Ottawa , Ottawa , Ontario K1H 8M5 , Canada., Farah E; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine , University of Ottawa , Ottawa , Ontario K1H 8M5 , Canada., Kahiel Z; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine , University of Ottawa , Ottawa , Ontario K1H 8M5 , Canada., Côté M; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine , University of Ottawa , Ottawa , Ontario K1H 8M5 , Canada., Gadde S; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine , University of Ottawa , Ottawa , Ontario K1H 8M5 , Canada., Rayner KJ; University of Ottawa Heart Institute , Ottawa , Ontario K1Y 4W7 , Canada.; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine , University of Ottawa , Ottawa , Ontario K1H 8M5 , Canada. |
| المصدر: | ACS nano [ACS Nano] 2019 Jun 25; Vol. 13 (6), pp. 6491-6505. Date of Electronic Publication: 2019 Jun 12. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101313589 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1936-086X (Electronic) Linking ISSN: 19360851 NLM ISO Abbreviation: ACS Nano Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington D.C. : American Chemical Society |
| مواضيع طبية MeSH: | Chitosan/*analogs & derivatives , Cholesterol/*metabolism , Macrophages, Peritoneal/*metabolism , MicroRNAs/*genetics , Nanoparticles/*chemistry , RNAi Therapeutics/*methods, ATP Binding Cassette Transporter 1/genetics ; ATP Binding Cassette Transporter 1/metabolism ; Animals ; Cells, Cultured ; Cholesterol/blood ; Gene Transfer Techniques ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; MicroRNAs/metabolism |
| مستخلص: | The prevention and treatment of cardiovascular diseases (CVD) has largely focused on lowering circulating LDL cholesterol, yet a significant burden of atherosclerotic disease remains even when LDL is low. Recently, microRNAs (miRNAs) have emerged as exciting therapeutic targets for cardiovascular disease. miRNAs are small noncoding RNAs that post-transcriptionally regulate gene expression by degradation or translational inhibition of target mRNAs. A number of miRNAs have been found to modulate all stages of atherosclerosis, particularly those that promote the efflux of excess cholesterol from lipid-laden macrophages in the vessel wall to the liver. However, one of the major challenges of miRNA-based therapy is to achieve tissue-specific, efficient, and safe delivery of miRNAs in vivo. We sought to develop chitosan nanoparticles (chNPs) that can deliver functional miRNA mimics to macrophages and to determine if these nanoparticles can alter cholesterol efflux and reverse cholesterol transport in vivo. We developed chNPs with a size range of 150-200 nm via the ionic gelation method using tripolyphosphate (TPP) as a cross-linker. In this method, negatively charged miRNAs were encapsulated in the nanoparticles by ionic interactions with polymeric components. We then optimized the efficiency of intracellular delivery of different formulations of chitosan/TPP/miRNA to mouse macrophages. Using a well-defined miRNA with roles in macrophage cholesterol metabolism, we tested whether chNPs could deliver functional miRNAs to macrophages. We find chNPs can transfer exogenous miR-33 to naïve macrophages and reduce the expression of ABCA1, a potent miR-33 target gene, both in vitro and in vivo, confirming that miRNAs delivered via nanoparticles can escape the endosomal system and function in the RISC complex. Because miR-33 and ABCA1 play a key role in regulating the efflux of cholesterol from macrophages, we also confirmed that macrophages treated with miR-33-loaded chNPs exhibited reduced cholesterol efflux to apolipoprotein A1, further confirming functional delivery of the miRNA. In vivo, mice treated with miR33-chNPs showed decreased reverse cholesterol transport (RCT) to the plasma, liver, and feces. In contrast, when efflux-promoting miRNAs were delivered via chNPs, ABCA1 expression and cholesterol efflux into the RCT pathway were improved. Over all, miRNAs can be efficiently delivered to macrophages via nanoparticles, where they can function to regulate ABCA1 expression and cholesterol efflux, suggesting that these miRNA nanoparticles can be used in vivo to target atherosclerotic lesions. |
| فهرسة مساهمة: | Keywords: chitosan; cholesterol; macrophage; microRNA; nanoparticle |
| المشرفين على المادة: | 0 (ABCA1 protein, mouse) 0 (ATP Binding Cassette Transporter 1) 0 (MicroRNAs) 0 (Mirn33 microRNA, mouse) 9012-76-4 (Chitosan) 97C5T2UQ7J (Cholesterol) |
| تواريخ الأحداث: | Date Created: 20190525 Date Completed: 20200827 Latest Revision: 20200827 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1021/acsnano.8b09679 |
| PMID: | 31125197 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1936-086X |
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| DOI: | 10.1021/acsnano.8b09679 |