Characterization of Binding Sites, Extent of Binding, and Drug Interactions of Oligonucleotides with Albumin

Srinivasan, Shashi K.; Tewary, Hemant K.; Iversen, Patrick L.

doi:10.1089/ard.1995.5.131

Cited by 108 publications

(47 citation statements)

References 46 publications

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“…PSODNs bind to plasma proteins, which is likely to affect their disposition (Cossum et al, 1993;Srinivasan et al, 1995;Nolting et al, 1997). We found that the association of cholesteryl-derivatized ISIS-9388 with plasma proteins differs from that of nonconjugated ISIS-3082 (Bijsterbosch et al, 3 H]ISIS-9389 was incubated with rat plasma (at 20 g/ml; the concentration immediately after injection).…”

Section: Resultsmentioning

confidence: 99%

bis-Cholesteryl-Conjugated Phosphorothioate Oligodeoxynucleotides Are Highly Selectively Taken Up by the Liver

Bijsterbosch¹,

Manoharan²,

Dorland³

et al. 2002

J Pharmacol Exp Ther

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We previously modulated, by conjugating a single cholesterol, plasma protein binding and liver cell uptake of a phosphorothioate oligodeoxynucleotide (PS-ODN). In this study, we investigated the biological fate of a PS-ODN, denoted ISIS-9389 (3Ј,5Ј-bis-cholesteryl-conjugated ISIS 3082), provided with two cholesteryl moieties. After intravenous injection of into rats, [ 3 H]ISIS-9389 was cleared from plasma with a half-life of 23.6 Ϯ 0.3 min. After 90 min (approximately 95% cleared), the liver contained 83.0 Ϯ 0.8% of the dose. Spleen and bone (marrow), which constitute with the liver the reticuloendothelial system, contained 3.1 Ϯ 0.3 and 4.3 Ϯ 0.2%, respectively. All other tissues accumulated together Ͻ5% of the dose. The hepatic uptake of [ 3 H]ISIS-9389 occurred mainly by endothelial cells (51.9 Ϯ 6.4% of the liver uptake). Parenchymal and Kupffer cells were responsible for 24.9 Ϯ 7.7 and 23.3 Ϯ 2.5%, respectively. Preinjected polyinosinic acid and polyadenylic acid reduced hepatic uptake, albeit the latter was less effective. This finding suggests implication of (multiple) scavenger receptors in liver uptake of ISIS-9389. The interaction of ISIS-9389 with plasma proteins, analyzed by size exclusion chromatography, differs from that of unconjugated PS-ODN and PS-ODN with a single cholesterol. Plasma-incubated ISIS-9389 was mainly recovered as a high molecular weight complex. In conclusion, conjugation of PS-ODNs with two cholesteryl moieties results in almost quantitative uptake by the liver. The liver targeting exceeds the already impressive gain in liver uptake achieved by conjugation of a single cholesterol, and is expected to increase the therapeutic activity against liver-associated targets and reduce side effects in nonhepatic tissues.

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Section: Resultsmentioning

confidence: 99%

bis-Cholesteryl-Conjugated Phosphorothioate Oligodeoxynucleotides Are Highly Selectively Taken Up by the Liver

Bijsterbosch¹,

Manoharan²,

Dorland³

et al. 2002

J Pharmacol Exp Ther

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“…The apparent a nity for albumin is quite low (200 ± 400 mM) and comparable to the low a nity binding observed for a number of drugs, e.g. aspirin, penicillin (Crooke et al, 1996;Joos and Hall, 1969;Srinivasan et al, 1995). Serum protein binding, therefore, provides a repository for these drugs and prevents rapid renal excretion.…”

Section: Properties Of Phosphorothioate Oligodeoxynucleotidesmentioning

confidence: 58%

“…In contrast, in a study in which an equilibrium dissociation constant was derived from an assay using albumin loaded on a CH-sephadex column, the Km ranged from 1 ± 5610 75 M for bovine serum albumin and 2 ± 3610 74 M for human serum albumin. Moreover, warfarin and indomethacin were reported to compete for binding to serum albumin (Srinivasan et al, 1995). Clearly, much more work is required before de®nitive conclusions can be drawn.…”

Section: Properties Of Phosphorothioate Oligodeoxynucleotidesmentioning

confidence: 99%

Potential roles of antisense technology in cancer chemotherapy

Crooke

2000

Oncogene

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IntroductionProgress in sequencing the human genome has resulted in optimism that we will shortly have a much better understanding of health and disease and the factors that contribute to both at the molecular level. Armed with these insights, we will then be able to rapidly e ect dramatic improvement in the prevention and treatment of many diseases and enhance the productivity of the drug discovery and development process. For no disease is there a greater need, and therefore more hope, that genomic information will result in revolutionary advances than cancer.Nevertheless, to achieve the full bene®t of the genomic revolution, investment in technologies that can convert genomic information into therapeutic gains and enhanced drug discovery and development productivity is a must. Again, for no disease is this more apparent than cancer. Speci®cally, technologies that can take genomic information directly and rapidly and e ciently create gene-speci®c inhibitors that can be used to functionalize and validate as good drug targets various genes are required. Development technologies that can result in dramatically more speci®c drugs, classes of drugs that can be more easily used in combination and for which the failure rates in preclinical and early clinical trials are much lower also musts.Antisense technology is arguably the most advanced genomically-based drug discovery technology. It has been shown to be capable of generating very speci®c inhibitors and a signi®cant number of antisense drugs are in development as anticancer agents.In this review I will brie¯y summarize the current state of antisense technology, the pharmacodynamic, pharmacokinetic and toxicological properties of antisense drugs, and the current applications of antisense technology in cancer, including gene functionalization and therapeutic target validation.

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“…Hepatocytes and KCs were responsible for 24.9% and 23.3%, respectively. The increased retention in plasma is possibly due to the increased serum protein binding (486). However, it is not clear whether the increased hepatic uptake is due to an active transport of the lipophilic conjugates or whether the effects were simply due to the changes in lipophilicity.…”

Section: Conjugation With Lipophilic Molecules-mentioning

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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Characterization of Binding Sites, Extent of Binding, and Drug Interactions of Oligonucleotides with Albumin

Cited by 108 publications

References 46 publications

bis-Cholesteryl-Conjugated Phosphorothioate Oligodeoxynucleotides Are Highly Selectively Taken Up by the Liver

bis-Cholesteryl-Conjugated Phosphorothioate Oligodeoxynucleotides Are Highly Selectively Taken Up by the Liver

Potential roles of antisense technology in cancer chemotherapy

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

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