Click-Modified Anandamide siRNA Enables Delivery and Gene Silencing in Neuronal and Immune Cells

Willibald, Julian; Harder, Johannes; Sparrer, Konstantin M. J.; Conzelmann, Karl‐Klaus; Carell, Thomas

doi:10.1021/ja303251f

Cited by 68 publications

(71 citation statements)

References 49 publications

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“…Trivalent but not monovalent conjugates provided effective delivery of the SSO. Anandamide, a ligand for cannabinoid receptors, was conjugated to siRNA via click chemistry (242). These conjugates provided effective functional delivery of siRNA to several cell types.…”

Section: Approaches To Deliverymentioning

confidence: 99%

The delivery of therapeutic oligonucleotides

2016

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The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.

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Section: Approaches To Deliverymentioning

confidence: 99%

The delivery of therapeutic oligonucleotides

2016

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“…Anandamide recognizes the cannabinoid receptor which is highly expressed on neuronal and immune cells. A corresponding siRNA conjugate was successfully taken up in these cultured cells and resulted in down regulation of the siRNA-targeted gene, although high concentrations were required [145].…”

Section: Targets and Ligands For Tumorsmentioning

confidence: 99%

“…transferrin-antibody transferrin-targeted fusion peptide transferrin receptor  liposomes [110]  peptide/siRNA complexes [112] rabies virus glycoprotein (RVG) not identified nAChR, NCAM, and p75NTR are possible targets  peptide/siRNA complexes [113]  polyethyleneimine complexes [115]  liposomes [116]  PAMAM nanoparticles [117]  targeted exosomes [114] LEUKOCYTES integrin-antibody integrins  protamine-antibody/siRNA complexes [126]  liposomes [127] TUMOR TISSUES folate folate-receptor  polythyleneimine complexes [135][136][137]  PEG-siRNA conjugate [138]  self-assembled nanoparticles [145] hyaluronic acid CD44  hyaluronic acid-graft-poly(dimethylaminoethyl methacrylate) (HPD) conjugate complexes [140] …”

Section: Blood-brain-barriermentioning

confidence: 99%

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

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

241

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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“…Much work has been carried out on modifying cationic lipids for use in gene transfection, to determine if there is a ‘best’ chain length. 31 However, solid conclusions are rarely obtained, for the conclusions of these studies are frequently contradictory. In this study, CDL14 and CDO14 showed superior siRNA delivery.…”

Section: Resultsmentioning

confidence: 99%

Tri-peptide cationic lipids for gene delivery

Zhao

Zhang

et al. 2015

J. Mater. Chem. B

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Several novel tri-peptide cationic lipids were designed and synthesized for delivering DNA and siRNA. They have tri-lysine and tri-ornithine as head groups, carbamate group as linker and 12 and 14 carbon atom alkyl groups as tails. These tri-peptide cationic lipids were prepared into cationic liposomes for the study of the physicochemical properties and gene delivery. Their particle size, Zeta potential and DNA-binding were characterized to show that they were suitable for gene transfection. The further results indicate that these lipids can transfer DNA and siRNA very efficiently into NCI-H460 and Hep-2 tumor cells. The selected lipid, CDO14, was able to deliver combined siRNAs against c-Myc and VEGF for silencing distinct oncogenic pathways in lung tumors of mice, with little in vitro and in vivo toxicity.

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Click-Modified Anandamide siRNA Enables Delivery and Gene Silencing in Neuronal and Immune Cells

Cited by 68 publications

References 49 publications

The delivery of therapeutic oligonucleotides

The delivery of therapeutic oligonucleotides

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

Tri-peptide cationic lipids for gene delivery

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