In vivo efficacy and off-target effects of Locked Nucleic Acid (LNA) and Unlocked Nucleic Acid (UNA) modified siRNA and small internally segmented interfering RNA (sisiRNA) in mice bearing human tumor xenografts

Mook, Olaf R.F.; Vreijling, Jeroen; Wengel, Suzy L.; Wengel, Jesper; Zhou, Chuanzheng; Chattopadhyaya, J.; Baas, Frank; Fluiter, Kees

doi:10.4161/adna.1.1.12204

Cited by 38 publications

(36 citation statements)

References 30 publications

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“…Improving siRNA transport into cells is an active area of research today [29]. Several studies have shown that modification of siRNA molecules with small chemical groups greatly enhances cellular uptake and efficacy [30,31], and we hypothesize that the incorporation of such small chemical groups to improve siRNA cellular uptake efficiency would not significantly influence release kinetics from our composite material.…”

Section: Discussionmentioning

confidence: 99%

Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery

Strong

Dahotre

West

2014

Journal of Controlled Release

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A poly(N-isopropylacrylamide-co-acrylamide) (NIPAAm-co-AAm) hydrogel with near-infrared (NIR) absorbing silica-gold nanoshells was designed as a platform for pulsatile delivery of cancer therapeutics. This hydrogel was designed to have a lower critical solution temperature (LCST) above physiologic temperature, such that the material will transition from a hydrated state to a collapsed state above ~40 °C. Additionally, the silica-gold nanoshells used were designed to have a peak extinction coefficient in the NIR, where penetration of light through tissue is maximal. This heat-triggered material phase transition of the composite was found to follow exposure of NIR light, indicating the ability of the NIR absorption by the nanoshells to sufficiently drive this transition. The composite material was loaded with either doxorubicin or a DNA duplex (a model nucleic acid therapeutic), two cancer therapeutics with differing physical and chemical properties. Release of both therapeutics was dramatically enhanced by NIR light exposure, causing 2-5x increase in drug release. Drug delivery profiles were influenced by both the molecular size of the drug as well as its chemical properties. The DNA therapeutic showed slower rates of nonspecific delivery by passive diffusion due to its larger size. Additionally, only 70% of the more hydrophobic doxorubicin was released from the material, whereas the more hydrophillic DNA showed over 90% release. Further, hydrogel composites were used to deliver the doxorubicin to CT.26-WT colon carcinoma cells, eliciting a therapeutic response. This work validates the potential application for this material in site-specific cancer therapeutic delivery.

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Section: Discussionmentioning

confidence: 99%

Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery

Strong

Dahotre

West

2014

Journal of Controlled Release

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“…Tritium radiolabeling procedures of oligonucleotides have also been reported in the literature, for example, internal labeling of deprotected phosphorothioate oligodeoxynucleotides randomly labeled at the unstable C8‐position of the purines by exchange with tritiated water as described by Graham et al . This procedure has been adapted to siRNAs but has limitations in biological assays because of radiolytic degradation and formation of tritiated water. Sands et al .…”

Section: Introductionmentioning

confidence: 99%

Tritium labeling of full‐length small interfering RNAs

Christensen

Natt

Hunziker

et al. 2012

Labelled Comp Radiopharmac

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A simple procedure is described for full‐length single internal [3H]‐radiolabeling of oligonucleotides. Previous labeling strategies have been applied to large molecular weight compounds such as proteins and oligonucleotides, for example, iodination and 111In labeling via covalently bounded chelators. However, a procedure has not yet been reported for single internal radiolabeling of oligonucleotides that preserves the molecular structure (3H replacing a 1H). In following our strategy, the radiolabel can be strategically placed within a stable and predetermined internal position of the siRNA. This placement was accomplished by placing a 5‐bromouridine or 5‐bromo‐2′‐O‐methyluridine phosphoramidite building block into the middle of the antisense strand using standard phosphoramidite chemistry. The deprotected full‐length antisense strand was tritium labeled by bromine/tritium exchange, catalyzed by palladium on charcoal in the predetermined 5‐position of either uridine or 2′‐O‐methyluridine. Internal placement of the building block within the oligonucleotide sequence and label placement at 5‐position decreases the likelihood of the label to be readily cleaved from the oligonucleotide in vivo, and loss of the label by spontaneous tritium/hydrogen exchange. The tritiated single‐stranded and double‐stranded RNAs were also shown to be radio and chemically stable for at least 6 months at −80 °C. This allows more than sufficient time to conduct pharmaceutical formulation and pharmacokinetic studies. Copyright © 2012 John Wiley & Sons, Ltd.

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“…In addition, for the [ 3 H]siRNA, significant distribution of radioactivity was observed in the salivary gland and spleen (8.9% and 2.4% ID/g, respectively). The salivary gland, contrary to the spleen (Mook et al, 2007;Mook et al, 2010), has not before been reported as an organ of distribution of total radiolabeled components after siRNA administration.…”

mentioning

confidence: 99%

“…Nevertheless, the labeling methods applied in those studies had potential drawbacks. Typically, siRNAs were 3 H-labeled at chemically unstable positions (Mook et al, 2007;Sonoke et al, 2008;Mook et al, 2010) or at problematic sites at the end of the oligonucleotide, such as by addition of a […”

Section: Introductionmentioning

confidence: 99%

Metabolism Studies of Unformulated Internally [³H]-Labeled Short Interfering RNAs in Mice

et al. 2013

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Absorption, distribution, metabolism, and excretion properties of two unformulated model short interfering RNA (siRNAs) were determined using a single internal [ Syndrome antigen B) siRNA, respectively). After an initial rapid decrease, concentrations of total radiolabeled components in dried blood decreased at a much slower rate. A nearly complete mass balance was obtained for the [ 3 H]SSB siRNA, and renal excretion was the main route of elimination (38%). The metabolism of the two model siRNAs was rapid and extensive. Five minutes after administration, no parent compound could be detected in plasma. Instead, radiolabeled nucleosides resulting from nuclease hydrolysis were observed. In the metabolism profiles obtained from various tissues, only radiolabeled nucleosides were found, suggesting that siRNAs are rapidly metabolized and that the distribution pattern of total radiolabeled components can be ascribed to small molecular weight metabolites.

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In vivo efficacy and off-target effects of Locked Nucleic Acid (LNA) and Unlocked Nucleic Acid (UNA) modified siRNA and small internally segmented interfering RNA (sisiRNA) in mice bearing human tumor xenografts

Cited by 38 publications

References 30 publications

Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery

Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery

Tritium labeling of full‐length small interfering RNAs

Metabolism Studies of Unformulated Internally [³H]-Labeled Short Interfering RNAs in Mice

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In vivo efficacy and off-target effects of Locked Nucleic Acid (LNA) and Unlocked Nucleic Acid (UNA) modified siRNA and small internally segmented interfering RNA (sisiRNA) in mice bearing human tumor xenografts

Cited by 38 publications

References 30 publications

Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery

Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery

Tritium labeling of full‐length small interfering RNAs

Metabolism Studies of Unformulated Internally [3H]-Labeled Short Interfering RNAs in Mice

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Metabolism Studies of Unformulated Internally [³H]-Labeled Short Interfering RNAs in Mice