Efficient In Vivo Delivery of siRNA to the Liver by Conjugation of α-Tocopherol

Nishina, Kazutaka; Unno, Toshinori; Uno, Yoshitaka; Kubodera, Takayuki; Kanouchi, Tadashi; Mizusawa, Hidehiro; Yokota, Takanori

doi:10.1038/sj.mt.6300420

Cited by 122 publications

(193 citation statements)

References 27 publications

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“…The results indicated that the introduction of the lipophilic ligands to ASOs increased the binding to serum albumin and lipoprotein, compared with those of unconjugated ASO, as reported. 4,5 Also, GalNAc-ASO, which has a hydrophilic ligand, showed no affinity, as observed for unconjugated ASO. This reason would be due to no increasing lipophilicity of molecular by introduction of the hydrophilic ligand to ASO.…”

Section: Regeneration Of Ligand Immobilized On the Sensor Chipmentioning

confidence: 92%

“…Recently, it was reported that ASOs conjugated with cholesterol, tocopherol (vitamin E), and triantennary N-acetyl galactosamine (GalNAc) were especially available for delivery of ASOs to the liver. [4][5][6][7][8] ASOs conjugated with cholesterol and tocopherol as lipophilic ligands could improve their uptake by the liver via receptor-mediated endocytosis after interaction with albumin and lipoproteins, such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in circulation. The liver takes up most of the LDL via LDL receptor-mediated endocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Surface Plasmon Resonance Assay of Binding Properties of Antisense Oligonucleotides to Serum Albumins and Lipoproteins

et al. 2015

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In the present study, we developed an assay to evaluate the kinetic binding properties of the unconjugated antisense oligonucleotide (ASO) and lipophilic and hydrophilic ligands conjugated ASOs to mouse and human serum albumin, and lipoproteins using surface plasmon resonance (SPR). The lipophilic ligands conjugated ASOs showed clear affinity to the albumins and lipoproteins, while the unconjugated and hydrophilic ligand conjugated ASOs showed no interaction. The SPR method showed reproducible immobilization of albumins and lipoproteins as ligands on the sensor chip, and reproducible affinity kinetic parameters of interaction of ASOs conjugated with the ligands could be obtained. The kinetic binding data of these ASOs to albumin and lipoproteins by SPR were related with the distributions in the whole liver in mice after administration of these conjugated ASOs. The results demonstrated that our SPR method could be a valuable tool for predicting the mechanism of the properties of delivery of conjugated ASOs to the organs.

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Section: Regeneration Of Ligand Immobilized On the Sensor Chipmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Surface Plasmon Resonance Assay of Binding Properties of Antisense Oligonucleotides to Serum Albumins and Lipoproteins

et al. 2015

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“…The cholesterol moiety enhances retention of the conjugated siRNA in the circulation by binding to albumin, low-density lipoprotein and highdensity lipoprotein particles, as well as uptake in hepatocytes by binding to low-density lipoprotein receptors and uptake in the liver, gut, kidney and steroidogenic organs by binding to the scavenger receptor class B, type I receptors, which take up high-density lipoprotein. 40 Conjugation of cholesterol, as well as a-tocopherol, 41 lithocholic acid or lauric acid 42 to ApoB-siRNAs reduces serum cholesterol and ApoB mRNA levels in the liver after intravenous injection. Another example of this approach is 'siRNA dynamic polyconjugates' .…”

Section: Introductionmentioning

confidence: 99%

Special delivery: targeted therapy with small RNAs

2011

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Harnessing RNA interference using small RNA-based drugs has great potential to develop drugs designed to knock down expression of any disease-causing gene, thereby greatly expanding the universe of possible drug targets. However, delivering small RNAs into specific tissues and cells is still a hurdle. Here, we review recent progress in overcoming systemic, local and cellular barriers to RNA drug delivery, focusing on strategies for targeted uptake.

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“…Many kinds of systemic siRNA delivery techniques have been successfully achieved by conjugating compounds such as cholesterol (Soutschek J et al, 2004), polymers (Rozema DB et al, 2007), and targeted ligands (Nishina K et al, 2008) to siRNA, by forming stable nucleic acid-lipid nanoparticles (SNALP) of siRNA (Zimmermann TS et al, 2006;Semple SC et al, 2010), and by assembling lipid-siRNA complexes (Santel A et al, 2006). Carbon nanotubes have also been used to systemically deliver siRNA (McCarrol J et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Cell penetrating peptide-mediated systemic siRNA delivery to the liver

Hayashi

Yamauchi

Khalil

et al. 2011

International Journal of Pharmaceutics

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Footnote:Yasuhiro Hayashi and Jun Yamauchi equally contributed to this study. These authors are listed alphabetically in accordance with family name. AbstractThe Cell-penetrating peptide (CPP) is one of the most attractive tools for efficiently delivering biomolecules to a target organnelle. Here, we describe the use of octaarginine (R8)-modified lipid nanoparticles for the efficient and targeted in vivo delivery of siRNA to the liver. In this study, SR-BI (a scavenger receptor class B, member 1) was targeted by this nanoparticle. Our results demonstrate that R8-modified lipid nanoparticles can be used for the efficient and targeted delivery of liver siRNA to induce the specific knock-down of an endogenous gene with minimum liver toxicity and immune response, and that this CPP based technology holds considerable promise for further in vivo biological applications of siRNA.

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Efficient In Vivo Delivery of siRNA to the Liver by Conjugation of α-Tocopherol

Cited by 122 publications

References 27 publications

Surface Plasmon Resonance Assay of Binding Properties of Antisense Oligonucleotides to Serum Albumins and Lipoproteins

Surface Plasmon Resonance Assay of Binding Properties of Antisense Oligonucleotides to Serum Albumins and Lipoproteins

Special delivery: targeted therapy with small RNAs

Cell penetrating peptide-mediated systemic siRNA delivery to the liver

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