Receptors, endocytosis, and trafficking: the biological basis of targeted delivery of antisense and siRNA oligonucleotides

Juliano, Rudolph L.; Carver, Kyle; Cao, Canhong; Xin, Ming

doi:10.3109/1061186x.2012.740674

Cited by 72 publications

(49 citation statements)

References 157 publications

(196 reference statements)

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“…A lot of data has been generated and discussed regarding this last and maybe most difficult hurdle [88,89]. It seems clear that the endocytosis pathway is dominating siRNA uptake, whether in naked or conjugated form, or in a delivery system.…”

Section: Cellular Uptake and Intracellular Traffickingmentioning

confidence: 98%

“…Phagocytosis is restricted to specialized cells, such as macrophages, granulocytes and Kupffer cells. All these uptake mechanisms have been reviewed in depth elsewhere [89,94]. Although there are small, but important differences between these mechanisms, in nearly all cases of functional uptake, the siRNA agent ends up in an endosomal vesicle [89].…”

Section: Cellular Uptake and Intracellular Traffickingmentioning

confidence: 99%

See 1 more Smart Citation

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

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

245

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: Cellular Uptake and Intracellular Traffickingmentioning

confidence: 98%

Section: Cellular Uptake and Intracellular Traffickingmentioning

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

245

204

View full text Add to dashboard Cite

show abstract

“…Cell selective delivery through ligand conjugation depends on the binding affinity of the ligands to their receptors and the density of the receptors on the target cell surface [32]. Besides, the intrinsic uptake rate of the ONs also plays a role.…”

Section: Molecular Conjugatesmentioning

confidence: 99%

Bioconjugates for targeted delivery of therapeutic oligonucleotides

Xin

Laing

2015

Advanced Drug Delivery Reviews

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Bioconjugates have been used to deliver therapeutic oligonucleotides to their pharmacological targets in diseased cells. Molecular-scale conjugates can be prepared by directly linking targeting ligands with oligonucleotides and the resultant conjugates can selectively bind to cell surface receptors in target cells in diseased tissues. Besides targeted delivery, additional functionality can be incorporated in the conjugates by utilization of carrier molecules, and these larger conjugates are called carrier-associated conjugates. Both molecular and carrier-associated conjugates have achieved initial successes in clinical trials for treating liver diseases; therefore, currently the greater challenge is to deliver oligonucleotides to extrahepatic tissues such as tumors. This review will provide an update on the application of oligonucleotide conjugates for targeted delivery during the last decade. By identifying key elements for successful delivery, it is suggested that oligonucleotide conjugates with intermediate size, cell targeting ability, and endosomal release functionality are superior systems to advance oligonucleotides to achieve their full therapeutic potentials.

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“…In recent years, a variety of chemical molecules have been covalently conjugated to siRNA to improve its stability, specificity and correspondence: Zhenjun Yang; Yun Wu state Key laboratory of Natural and Biomimetic Drugs, school ofDifferent siRNA conjugates possess their unique biological properties and characteristics, and cell-targeting peptides which specifically bind to overexpressed target proteins on the surface of certain cells can achieve specific endocytosis. 8 A common cell-targeting peptide is Arg-Gly-Asp peptide sequence (cRGD), which implement endocytosis by binding to overexpressed integrin αvβ3 receptors on tumor cell surface. 9 Many reports have demonstrated that the transport capacity of siRNAs was significantly improved when siRNAs were covalently conjugated with cRGD peptides.…”

Section: Introductionmentioning

confidence: 99%

Reductive nanocomplex encapsulation of cRGD-siRNA conjugates for enhanced targeting to cancer cells

Zhou¹,

Liu²,

Zhang³

et al. 2017

IJN

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In this study, through covalent conjugation and lipid material entrapment, a combined modification strategy was established for effective delivery of small interfering RNA (siRNA). Single strands of siRNA targeting to BRAF V600E gene (siMB3) conjugated with cRGD peptide at 3′-terminus or 5′-terminus via cleavable disulfide bond was synthesized and then annealed with corresponding strands to obtain single and bis-cRGD-siRNA conjugates. A cationic lipid material (CLD) developed by our laboratory was mixed with the conjugates to generate nanocomplexes; their uniformity and electrical property were revealed by particle size and zeta potential measurement. Compared with CLD/siBraf, CLD/cRGD-siBraf achieved higher cell uptake and more excellent tumor-targeting ability, especially 21 (sense-5′/antisense-3″-cRGD-congjugate) nanocomplex. Moreover, they can regulate multiple pathways to varying degree and reduce acidification of endosome. Compared with the gene silencing of different conjugates, single or bis-cRGD-conjugated siRNA showed little differences except 22 (5/5) which cRGD was conjugated at 5′-terminus of antisense strand and sense strand. However bis-cRGD conjugate 21 nanocomplex exhibited better specific target gene silencing at multiple time points. Furthermore, the serum stabilities of the bis-cRGD conjugates were higher than those of the single-cRGD conjugates. In conclusion, all these data suggested that CLD/bis-conjugates, especially CLD/ 21 , can be an effective system for delivery of siRNA to target BRAF V600E gene for therapy of melanoma.

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Receptors, endocytosis, and trafficking: the biological basis of targeted delivery of antisense and siRNA oligonucleotides

Cited by 72 publications

References 157 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

Bioconjugates for targeted delivery of therapeutic oligonucleotides

Reductive nanocomplex encapsulation of cRGD-siRNA conjugates for enhanced targeting to cancer cells

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