Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents

Shokrzadeh, Nasrin; Winkler, Anna-Maria; Dirin, Mehrdad; Winkler, Johannes

doi:10.1016/j.bmcl.2014.10.045

Cited by 26 publications

(20 citation statements)

References 18 publications

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“…Depending on the size of the attached ligand, renal elimination is a threat. This can be avoided by increasing the molecular size, for example by PEGylation [178][179][180]. In contrast to particle systems, bioconjugates are more readily distributed into organs, since they are not depending on endothelial fenestrations.…”

Section: Bioconjugates For Targeted Deliverymentioning

confidence: 96%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

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254

204

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Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

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Section: Bioconjugates For Targeted Deliverymentioning

confidence: 96%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

Self Cite

254

204

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“…As demonstrated for siRNAs, short PEG 12 chains do not reduce the efficiency of antisense oligonucleotides [61]. Superior efficacy was found after lipoplex mediated application of both wild-type and phosphorothioate backbone modified antisense oligonucleotides in 100 nM concentrations targeted at bcl-2 in a cell culture reporter assay.…”

Section: Key Termmentioning

confidence: 94%

“…Recent reports indicate that the use of slightly longer PEG chains positively influence cellular uptake, but only together with a transfection enhancing system [61]. Attachment at the 2´-position would enable a sequence-wide distribution of PEG substituents, and could potentially increase membrane permeability of antisense oligonucleotides, the precise challenge that currently limits a wider thera-peutic use.…”

Section: Review Winklermentioning

confidence: 99%

Therapeutic Oligonucleotides with Polyethylene Glycol Modifications

Winkler

2015

Future Med. Chem.

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In the field of oligonucleotide drugs, the attachment of PEG is a well-established strategy to prevent enzymatic degradation and avoid renal elimination. Pegaptanib and other oligonucleotides in clinical development utilize the attachment of linear or branched high molecular weight PEG chains for increase of accumulation and duration of the effect after local or systemic application. The length of PEG chains is decisive for the pharmacokinetic and pharmacodynamic effects. Longer chains increase circulation times, but generally decrease gene-silencing efficiencies for antisense and siRNA agents and binding affinities for aptamers. Shorter chains are less efficient in preventing renal filtration, but have also less impact on the gene-silencing machinery and binding kinetics.

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“…In contrast, Park et al have PEGylated double-stranded siRNA at all possible termini (5′ sense/antisense or 3′ sense/antisense), and discovered that gene silencing activity was not affected by the conjugation site [80]. Similarly, Winkler et al have also reported nearly identical knockdown efficacies using two PEGylated antisense strands at either 5′ or 3′ [81]. Internal positions (often via 2′-O) are also used.…”

Section: Pegylation Of Ons Using Linear or Slightly Branched Pegmentioning

confidence: 99%

PEGylation of therapeutic oligonucletides: From linear to highly branched PEG architectures

Zhang

2018

Nano Res.

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PEGylation, the attachment of poly(ethylene glycol) (PEG), has been adopted to improve the pharmacokinetic properties of oligonucleotide therapeutics for nearly 30 years. Prior efforts mainly focused on the investigation of linear or slightly branched PEG having different molecular weights, terminal functional groups, and possible oligonucleotide sites for functionalization. Recent studies on highly branched PEG (including brush, star, and micellar structures) indicate superior properties in several areas including cellular uptake, gene regulation efficacy, reduction of side effects, and biodistribution. This review focuses on comparing the effects of PEG architecture on the physiochemical and biological properties of the PEGylated oligonucleotide.

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Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents

Abstract: Graphical abstract

Cited by 26 publications

References 18 publications

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Therapeutic Oligonucleotides with Polyethylene Glycol Modifications

PEGylation of therapeutic oligonucletides: From linear to highly branched PEG architectures

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