Covalent Protein−Oligonucleotide Conjugates for Efficient Delivery of Antisense Molecules

Rajur, Sharanabasava B.; Roth, Charles M.; Morgan, Jeffrey R.; Yarmush, Martin L.

doi:10.1021/bc970172u

Cited by 60 publications

(40 citation statements)

References 15 publications

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“…To avoid the use of polycations, Rajur et al (28) conjugated ODNs to asialoglycoprotein via a disulfide bond. Direct conjugation of molecules to the TFO often tends to disturb the triplex forming ability of the TFOs, which is essential for transcription inhibition.…”

Section: Discussionmentioning

confidence: 99%

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Cheng

Guntaka

et al. 2006

Bioconjugate Chem.

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Excessive production of extracellular matrix, predominantly type I collagen results in liver fibrosis. Earlier we synthesized mannose 6-phosphate-bovine serum albumin (M6P-BSA) and conjugated to the type I collagen specific triplex forming oligonucleotide (TFO) for its enhanced delivery to hepatic stellate cells (HSCs), which is the principle liver fibrogenic cell. In this report, we demonstrate a time-dependent cellular uptake of M6P-BSA-33 P-TFO by HSC-T6 cells. Both cellular uptake and nuclear deposition of M6P-BSA-33 P-TFO were significantly higher than those of 33 P-TFO, leading to enhanced inhibition of type I collagen transcription. Following systemic administration into rats, hepatic accumulation of M6P-BSA-33 P-TFO increased from 55% to 68% with the number of M6P per BSA from 14 to 27. Unlike 33 P-TFO, there was no significant decrease in the hepatic uptake of (M6P) 20 -BSA-33 P-TFO in fibrotic rats. Prior administration of excess M6P-BSA decreased the hepatic uptake of (M6P) 20 -BSA-33 P-TFO from 66% to 40% in normal rats, and from 60% to 15% in fibrotic rats, suggesting M6P/insulin-like growth factor II (M6P/IGF-II) receptor-mediated endocytosis of M6P-BSA-33 P-TFO by HSCs. Almost 82% of the total liver uptake in fibrotic rats was contributed by HSCs. In conclusion, by conjugation with M6P-BSA, the TFO could be potentially used for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Cheng

Guntaka

et al. 2006

Bioconjugate Chem.

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“…Rajur et al conjugated ODNs to ASGP by a disulfide linkage (556). Six ODN molecules could be conjugated to each ASGP molecule.…”

Section: Proteins As Carriersmentioning

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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“…Among these non-viral gene carriers, using natural or artificial polypeptides such as polylysine (PLL), 4 polyarginine, 5 polyhistidine 6 and polyornithine (PO) 7 is considered as promising approach. Polylysine is one of the first gene transfer polymers to be used, but polyornithine is more effective in the gene transfer into mammalian cells in vitro.…”

mentioning

confidence: 99%

In vitro Gene Delivery to HepG2 Cells with a Novel Galactosylated Polyornithine

2009

Bulletin of the Korean Chemical Society

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Covalent Protein−Oligonucleotide Conjugates for Efficient Delivery of Antisense Molecules

Cited by 60 publications

References 15 publications

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

In vitro Gene Delivery to HepG2 Cells with a Novel Galactosylated Polyornithine

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