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

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

Research output: Contribution to journalArticle

21 Scopus citations

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- 33P-TFO by HSC-T6 cells. Both cellular uptake and nuclear deposition of MoP-BSA-33P-TFO were significantly higher than those of 33P-TFO, leading to enhanced inhibition of type I collagen transcription. Following systemic administration into rats, hepatic accumulation of MoP-BSA-33P-TFO increased from 55% to 68% with the number of M6P per BSA from 14 to 27. Unlike 33P-TFO, there was no significant decrease in the hepatic uptake of (M6P)20-BSA-33P-TFO in fibrotic rats. Prior administration of excess M6P-BSA decreased the hepatic uptake of (M6P)20-BSA-33P-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- 33P-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 2006

ASJC Scopus subject areas

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

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