Systemic Leukocyte-Directed siRNA Delivery Revealing Cyclin D1 as an Anti-Inflammatory Target

Peer, Dan; Park, Eun Jeong; Morishita, Yoshiyuki; Carman, Christopher V.; Shimaoka, Motomu

doi:10.1126/science.1149859

Cited by 456 publications

(385 citation statements)

References 21 publications

Supporting

Mentioning

379

Contrasting

Order By: Relevance

“…Stabilized liposomes (termed I-tsNP) can deliver siRNAs into leukocytes involved in gut inflammation to inhibit colitis in a mouse model. 60 I-tsNPs are B80 nm neutral liposomes loaded with siRNAs precondensed with protamine. Each liposome carries a high payload (B4000 siRNAs per particle), allowing therapeutic efficacy at a low dose (B2.5 mg kg À1 ).…”

Section: Introductionmentioning

confidence: 99%

Special delivery: targeted therapy with small RNAs

2011

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Special delivery: targeted therapy with small RNAs

2011

View full text Add to dashboard Cite

show abstract

“…Advances are made, both in the area of siRNA design [5][6][7][8][9] and siRNA delivery. New formulation strategies emerge, designed to overcome intra-and extracellular hurdles and to improve the fraction of the administered siRNA dose that eventually reaches the cytoplasm of the target cell [3,[10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Prolonged gene silencing by combining siRNA nanogels and photochemical internalization

Raemdonck

Naeye

Høgset

et al. 2010

Journal of Controlled Release

View full text Add to dashboard Cite

Small interfering RNAs (siRNAs) show potential for the treatment of a wide variety of pathologies with a known genetic origin through sequence-specific gene silencing. However, siRNAs do not have favorable drug-like properties and need to be packaged into nanoscopic carriers that are designed to guide the siRNA to the cytoplasm of the target cell. In this report biodegradable cationic dextran nanogels are used to deliver siRNA across the intracellular barriers. For the majority of non-viral siRNA carriers studied so far, endosomal confinement is identified as the most prominent hurdle, limiting the full gene silencing potential. Thus, there is a major interest in methods that are able to enhance endosomal escape of siRNA to improve its intracellular bioavailability. Photochemical internalization (PCI) is a method that employs amphiphilic photosensitizers to destabilize endosomal vesicles. We show that applying PCI at a later time-point post-transfection significantly prolonged the knockdown of the target protein only in case the siRNA was carried by nanogels and not when a liposomal carrier was used. Combining siRNA nanogels and PCI creates new possibilities to prolong gene silencing by using intracellular vesicles as depots for siRNA and applying PCI at the time when maintaining the RNAi effect becomes critical. Graphical abstractCombining siRNA nanogels and photochemical internalization (PCI) creates new possibilities to prolong gene silencing by using intracellular vesicles as depots and applying PCI at the time when maintaining the RNAi effect becomes critical.

show abstract

“…Integrins, adhesion molecules that bind to components of the extracellular matrix and act as sensor/signalling molecules, can also be used as targeting moieties [68][69][70] . In particular, the integrin lymphocyte function-associated antigen-1 (LFA-1) expressed on all leukocytes, which mediates heterotypic adhesion to intercellular adhesion molecules on other immune cells, undergoes remarkable conformational changes in response to stimulation [68] .…”

Section: Serum Stabilitymentioning

confidence: 99%

“…On the other hand, antibodies targeting the β7 integrin, found on the surface of inflammation associated helper T cells, were covalently attached to lipid-based nanoparticles and used to selectively deliver siRNA specific for the cyclin D (CyD1) (a cell cycle regulatory molecule) gene to the target cells to knock down the protein [69] . Following intravenous administration this approach resulted in a reduction of intestinal inflammation in a mouse model [69] .…”

Section: Serum Stabilitymentioning

confidence: 99%

“…In addition, as described earlier Peer et al [69] developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Liposomes were grafted with a spacer namely hyaluronan (a high-molecular-mass polysaccharide) to the outer surface, thus stabilizing the particles both during subsequent siRNA entrapment and during systemic circulation in vivo.…”

Section: "Abcd" System -Based Deliverymentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2010

View full text Add to dashboard Cite

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:

show abstract

Systemic Leukocyte-Directed siRNA Delivery Revealing Cyclin D1 as an Anti-Inflammatory Target

Cited by 456 publications

References 21 publications

Special delivery: targeted therapy with small RNAs

Special delivery: targeted therapy with small RNAs

Prolonged gene silencing by combining siRNA nanogels and photochemical internalization

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

Contact Info

Product

Resources

About