Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras

McNamara, James O; Andrechek, Eran R.; Wang, Yong; Viles, Kristi D.; Rempel, Rachel E.; Gilboa, Eli; Sullenger, Bruce A.; Giangrande, Paloma H.

doi:10.1038/nbt1223

Cited by 922 publications

(778 citation statements)

References 34 publications

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“…Aptamer-siRNA chimeras that utilize an aptamer that recognizes prostate surface membrane antigen specifically deliver siRNAs and inhibit tumor outgrowth in a xenograft model of human prostate cancer. 45,46 Similarly, a chimeric RNA containing an aptamer to HIV env protein specifically delivers siRNAs to HIV-infected CD4 + cells, which are otherwise refractory to transfection, and when joined with siRNAs that target viral genes can be used to inhibit HIV replication in vitro. 47,48 An siRNA-aptamer encoding a CD4 aptamer knocks down gene expression specifically in human CD4+ T cells, macrophages and dendritic cells.…”

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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Section: Introductionmentioning

confidence: 99%

Special delivery: targeted therapy with small RNAs

2011

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“…However, the delivery efficiency (desired dose), uncontrollable biodistribution and delivery-related toxicitities must be carefully analyzed. Recently, the cell type-specific delivery of siRNAs has been achieved using aptamer-siRNA chimeras 25 . In this system, the aptamer portion mediated binding to the prostate-specific membrane antigen (PSAM), a cell-surface receptor and the siRNAs linked to the aptamer was selectively delivered into PSMA expressing cells resulting in silencing of target transcripts both in cell culture and in vivo following intratumoral delivery.…”

Section: Discussionmentioning

confidence: 99%

Novel Cell type-specific aptamer-siRNA delivery system for HIV-1 therapy

Zhou

et al. 2007

Nat Prec

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SummaryThe successful use of small interfering RNAs (siRNAs) for therapeutic purposes requires safe and efficient delivery to specific cells and tissues. Here we demonstrate cell type-specific delivery of anti-HIV siRNAs via fusion to an anti-gp120 aptamer. The envelope glycoprotein is expressed on the surface of HIV-1 infected cells, allowing binding and interalization of the aptamer-siRNA chimeric molecules. We demonstrate that the anti-gp120 aptamer-siRNA chimera is specifically taken up by cells expressing HIV-1 gp120, and the appended siRNA is processed by Dicer, releasing an anti-tat/rev siRNA which in turn inhibits HIV replication. We show for the first time a dual functioning aptamer-siRNA chimera in which both the aptamer and the siRNA portions have potent anti-HIV activities and that gp120 expressed on the surface of HIV infected cells can be used for aptamer mediated delivery of anti-HIV siRNAs.RNA interference (RNAi) is a process of sequence-specific post-transcriptional gene silencing triggered by small interfering RNAs (siRNA). The silencing is sequence specific and one of the two strands of the siRNA guides the RNA induced silencing complex (RISC) to the complementary target, resulting in cleavage and subsequent destruction of the target RNA 1 . RNAi is rapidly becoming one of the methods of choice for gene function studies, and is also being exploited for therapeutic applications 2, 3 . The

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“…Aptamers, peptide molecules that bind to specific target molecules, can be synthesised and subsequently utilised for the cell specific delivery of siRNAs [109,110] . Both components can be chemically synthesised so aptamer-siRNA conjugates have the potential to be applied to a wide range of diseases.…”

Section: "Ad" System -Based Deliverymentioning

confidence: 99%

“…Chu et al [109] demonstrated that an anti-prostate specific aptamer (PSMA) coupled via a streptavidin bridge with siRNA against lamin A/C, could be used to specifically and efficiently deliver functional siRNA to PSMA positive cells in vitro. Similarly PMSA conjugated siRNA targeting the survival gene PLK1 has been used in vivo to induce regression of PMSA expressing LNCaP induced prostate tumours [110] .…”

Section: "Ad" System -Based Deliverymentioning

confidence: 99%

“…Using a previously designed AD delivery system appended with a PEG moiety [110] , a novel ACD particle has recently been successfully developed [121] . Researchers have enhanced the silencing activity and specificity of the aptamer-siRNA chimera by incorporating modifications that enable more efficient processing of the siRNA by the cellular machinery.…”

Section: "Acd" System -Based Deliverymentioning

confidence: 99%

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Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

et al. 2010

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Access to the full text of the published version may require a subscription. Rights AbstractGene silencing using RNA-interference, first described in mammalian systems almost a decade ago, is revolutionizing therapeutic target validation efforts both in vitro and in vivo. Moreover, the potential for using short interfering RNA (siRNA) as a therapy in its own right is also progressing at a significant pace. However, the widespread use of such approaches is contingent on having appropriate delivery systems to achieve clinically appropriate, safe, and efficient delivery of siRNA. There are many physicochemical and biological barriers to such delivery, and a growing emphasis on the design and characterisation of non-viral technologies that will overcome these barriers and expedite targeted delivery. This review discusses the considerations and challenges associated with use of siRNA-based therapeutics, including stability and off-target effects. Speculation is made on the properties of an ideal delivery system and the non-viral delivery approaches used to date, both in vitro and in vivo, are classified and discussed. Moreover, the ability of cyclodextrin-based delivery vectors to fulfil many of the criteria of an ideal delivery construct is also elaborated.3 Introduction:

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Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras

Cited by 922 publications

References 34 publications

Special delivery: targeted therapy with small RNAs

Special delivery: targeted therapy with small RNAs

Novel Cell type-specific aptamer-siRNA delivery system for HIV-1 therapy

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

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