Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect

Gaziova, Zuzana; Baumann, Volker; Winkler, Anna-Maria; Winkler, Johannes

doi:10.1016/j.bmc.2014.02.004

Cited by 29 publications

(23 citation statements)

References 31 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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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

View full text Add to dashboard Cite

show abstract

“…The target was chosen to be the mRNA of bcl‐2 gene. The PEGylated siRNA produced 70% gene silencing, and the circulation time was prolonged by reducing the renal filtration rate …”

Section: Modification To the Termini And Conjugate Groupsmentioning

confidence: 99%

Therapeutic potential of chemically modified siRNA: Recent trends

et al. 2017

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Small Interfering RNAs (siRNAs) are one of the valuable tools to investigate the functions of genes, and are also used for gene silencing. It has a wide scope in drug discovery through in vivo target validation. siRNA therapeutics are not optimal drug-like molecules due to poor bioavailability, immunogenic and off-target effects. In order to overcome the challenges associated with siRNA therapeutics, identification of appropriate chemical modifications that improves the stability, specificity and potency of siRNA is essential. This review focuses on the various chemical modifications and their implications in siRNA therapy.

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“…Adding a PEG 12 chain (molecular weight ca. 500 Da) to the 3´-end of either sense or antisense strand, siRNA mediated silencing of endogenous bcl-2 did not significantly differ from the effect found for the unmodified parent compound [53]. Efficient down regulations of >90% were found for 10 nM concentrations after lipoplex mediated transfections.…”

Section: Pegylated Oligonucleotidesmentioning

confidence: 46%

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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Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect

Abstract: Graphical abstract

Cited by 29 publications

References 31 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 potential of chemically modified siRNA: Recent trends

Therapeutic Oligonucleotides with Polyethylene Glycol Modifications

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