Receptor-Mediated Uptake of Phosphorothioate Antisense Oligonucleotides in Different Cell Types of the Liver

Miller, Colton M.; Tanowitz, Michael; Donner, Aaron J; Prakash, Thazha P.; Swayze, Eric E.; Harris, Edward N.; Seth, Punit P.

doi:10.1089/nat.2017.0709

Cited by 49 publications

(30 citation statements)

References 80 publications

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“…In contrast, first-generation PTO can interact with albumin and other serum proteins, extending their circulation from minutes to a few hours and their tissue distribution [61]. Studies suggest that PTO-modified ASOs can also interact with a large number of proteins on the cell surface and in the extracellular matrix and can be endocytosed into intracellular vesicles [62][63][64] After that, they bind to proteins that transport them into the nucleus and perhaps promote the hybridization to RNAs [64][65][66]. The clearance and elimination of PTO are facilitated by enzymatic degradation mediated by endo-and exonucleases that results in small-molecular-weight fragments that are easily eliminated in urine [58].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement

et al. 2020

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Antisense oligonucleotides (ASOs) are synthetically prepared short single-stranded deoxynucleotide sequences that have been validated as therapeutic agents and as a valuable tool in molecular driving biology. ASOs can block the expression of specific target genes via complementary hybridization to mRNA. Due to their high specificity and well-known mechanism of action, there has been a growing interest in using them for improving vaccine efficacy. Several studies have shown that ASOs can improve the efficacy of vaccines either by inducing antigen modification such as enhanced expression of immunogenic molecules or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extended use, some problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe ASO-based vaccines. In this review, we analyze the molecular bases and the research that has been conducted to demonstrate the potential use of ASOs in vaccines.

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Section: Pharmacokineticsmentioning

confidence: 99%

Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement

et al. 2020

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“…Thus, differences in the endosomal release kinetics for each endocytic pathway, in addition to uptake, may result in the differences in siRNA activity we observed among the different endocytic pathways and cell types. Differences in release kinetics may also explain why the active endocytic pathway for uptake of drugs and other molecules differs depending on the cell type [42,[57][58][59][60].…”

Section: Figmentioning

confidence: 99%

Endocytosis Controls siRNA Efficiency: Implications for siRNA Delivery Vehicle Design and Cell-Specific Targeting

Vocelle

Chan

Walton

2020

Nucleic Acid Therapeutics

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While small interfering RNAs (siRNAs) are commonly used for laboratory studies, development of siRNA therapeutics has been slower than expected, due, in part, to a still limited understanding of the endocytosis and intracellular trafficking of siRNA-containing complexes. With the recent characterization of multiple clathrin-/ caveolin-independent endocytic pathways, that is, those mediated by Graf1, Arf6, and flotillin, it has become clear that the endocytic mechanism influences subsequent intracellular processing of the internalized cargo. To explore siRNA delivery in light of these findings, we developed a novel assay that differentiates uptake by each of the endocytic pathways and can be used to determine whether endocytosis by a pathway leads to the initiation of RNA interference (RNAi). Using Lipofectamine 2000 (LF2K), we determined the endocytosis pathway leading to active silencing (whether by clathrin, caveolin, Arf6, Graf1, flotillin, or macropinocytosis) across multiple cell types (HeLa, H1299, HEK293, and HepG2). We showed that LF2K is internalized by Graf1-, Arf6-, or flotillin-mediated endocytosis for the initiation of RNAi, depending on cell type. In addition, we found that a portion of siRNA-containing complexes is internalized by pathways that do not lead to initiation of silencing. Inhibition of these pathways enhanced intracellular levels of siRNAs with concomitant enhancement of silencing.

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“…Single-stranded PS oligonucleotides can interact with the stabilin class of scavenger receptors (66), which are highly expressed in the spleen, liver, LNs, and BM (67) -tissues corresponding to sites of higher accumulation of PS ASOs (25). The stabilins bind and internalize large polyanionic components of the extracellular matrix like hyaluronic acid, chondroitin and dermatan sulfates, and other glycosaminoglycans, suggesting a common pharmacophore with polyanionic PS ASOs (68). HEK293 cells expressing stabilin-2 showed 3-to 5-fold enhanced uptake of single-stranded PS ASOs (66).…”

Section: Promoting Plasma Protein Interaction and Peripheral Tissue Dmentioning

confidence: 99%