Receptor-mediated hepatic uptake of M6P-BSA-conjugated triplex-forming oligonucleotides in rats

Zhaoyang Ye, Kun Cheng, Ramareddy Guntaka, Ram I. Mahato

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 principal 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 MoP-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 MoP-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.

Original languageEnglish (US)
Pages (from-to)823-830
Number of pages8
JournalBioconjugate Chemistry
Volume17
Issue number3
DOIs
StatePublished - May 1 2006

Fingerprint

Oligonucleotides
Bovine Serum Albumin
Rats
Phosphates
Liver
Hepatic Stellate Cells
Collagen Type I
Collagen
Liver Cirrhosis
mannose-6-phosphate
IGF Type 2 Receptor
Insulin
Transcription
Endocytosis
Extracellular Matrix

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Receptor-mediated hepatic uptake of M6P-BSA-conjugated triplex-forming oligonucleotides in rats. / Ye, Zhaoyang; Cheng, Kun; Guntaka, Ramareddy; Mahato, Ram I.

In: Bioconjugate Chemistry, Vol. 17, No. 3, 01.05.2006, p. 823-830.

Research output: Contribution to journalArticle

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abstract = "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 principal 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 MoP-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 MoP-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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AB - 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 principal 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 MoP-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 MoP-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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