Pharmacokinetic Properties of Phosphorothioates in Animals — Absorption, Distribution, Metabolism and Elimination

Nicklin, Paul; Craig, S. J.; Phillips, J. A.

doi:10.1007/978-3-642-58785-6_4

Cited by 17 publications

(11 citation statements)

References 30 publications

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“…Although systemic administration of CpG ODN has shown efficacy in some studies [21–23], untargeted immunostimulation may have limited impact on anti-tumor immunity while CpG ODN accumulation in the liver and kidney may induce problematic toxicities [24]. A common strategy to obtain preferential delivery to tumors is to take advantage of the Enhanced Permeability and Retention (EPR) effect [25, 26], whereby circulating macromolecules and nanoparticles leak through endothelial gaps in the disordered tumor vasculature.…”

Section: Introductionmentioning

confidence: 99%

Radiation-enhanced delivery of systemically administered amphiphilic-CpG oligodeoxynucleotide

Appelbe

Moynihan

Flor

et al. 2017

Journal of Controlled Release

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Along with vaccines and checkpoint blockade, immune adjuvants may have an important role in tumor immunotherapy. Oligodeoxynucleotides containing unmethylated cytidyl guanosyl dinucleotide motifs (CpG ODN) are TLR9 ligands with attractive immunostimulatory properties, but intratumoral administration has been required to induce an effective anti-tumor immune response. Following on recent studies with radiation-targeted delivery of nanoparticles, we examined enhanced tumor-specific delivery of amphiphile-CpG, an albumin-binding analog of CpG ODN, following systemic administration 3 days after tumor irradiation. The combination of radiation and CpG displayed superior tumor control over either treatment alone. Intravital imaging of fluorescently labeled amphiphilic-CpG revealed increased accumulation in irradiated tumors along with decreased off-target accumulation in visceral organs. Within 48 hrs after amphiphile-CpG administration, immune activation could be detected by increased Granzyme B and Interferon gamma activity in the tumor as well as in circulating monocytes and activated CD8+ T cells. Using radiotherapy to enhance the targeting of CpG to tumors may help advance this once promising therapy to clinical relevance.

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Section: Introductionmentioning

confidence: 99%

Radiation-enhanced delivery of systemically administered amphiphilic-CpG oligodeoxynucleotide

Appelbe

Moynihan

Flor

et al. 2017

Journal of Controlled Release

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“…Under pharmacokinetics, we discuss the kinetics of antisense drugs, clearance of drugs from the site of action, and its ultimate pharmacological activity. Because phosphorothioate oligonucleotides are the most widely studied, we discuss the AS ODN kinetics with respect to the pharmacokinetics of phosphorothioate oligonucleotides [135,136]. miRNA is synthesized from an unmatched segment of RNA precursor featuring a hairpin foldback structure.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

“…To elucidate the safety of AS ODNs, their biological activity as a function of dose, rate of distribution, and mechanism of clearance from the body must be established. Because phosphorothioate oligonucleotides were the first synthetically prepared antisense nucleotides, their pharmacokinetics, and hence their efficacy and safety, has been widely studied and reported [134][135][136]. Their pharmacokinetics has been found to be independent of their physical and chemical properties.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Following injection, AS ODNs bind to various proteins, distribute to various tissues, and finally get cleared from the body. The kidney, liver, and other organs of the RES are the major organs of distribution for AS ODNs and siRNA [135][136][137], and have benefitted from their ability to target to these sites. Certain siRNA formulations also accumulate in subcutaneous tumors through enhanced permeability and retention due to their leaky vasculature [135].…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Antisense Oligonucleotides and RNA Interference

Kher

Trehan

Misra

2011

Challenges in Delivery of Therapeutic Genomics and Proteomics

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“…In the liver, most of ODNs could be detected in nonparenchymal cells (NPCs) including KCs and SECs; lower levels were localized in the cytoplasm of hepatocytes (458,459). Graham et al (460) reported that almost 80% of injected PS-ODNs were taken up by KCs and SECs equivalently using nonlabeling method, capillary gel electrophoresis (CGE).…”

Section: Biodistributionmentioning

confidence: 99%

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

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Pharmacokinetic Properties of Phosphorothioates in Animals — Absorption, Distribution, Metabolism and Elimination

Cited by 17 publications

References 30 publications

Radiation-enhanced delivery of systemically administered amphiphilic-CpG oligodeoxynucleotide

Radiation-enhanced delivery of systemically administered amphiphilic-CpG oligodeoxynucleotide

Antisense Oligonucleotides and RNA Interference

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

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