Journal
BIOCONJUGATE CHEMISTRY
Volume 17, Issue 3, Pages 823-830Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bc060006z
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Funding
- NIBIB NIH HHS [R01 EB003922] Funding Source: Medline
- NIDDK NIH HHS [R01 DK064366, R01 DK064633] Funding Source: Medline
- PHS HHS [47379] Funding Source: Medline
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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 principal liver fibrogenic cell. In this report, we demonstrate a time-dependent cellular uptake of M6P-BSA-P-33-TFO by HSC-T6 cells. Both cellular uptake and nuclear deposition of M6P-BSA-P-33-TFO were significantly higher than those of P-33-TFO, leading to enhanced inhibition of type I collagen transcription. Following systemic administration into rats, hepatic accumulation of M6P-BSA-P-33-TFO increased from 55% to 68% with the number of M6P per BSA from 14 to 27. Unlike P-33-TFO, there was no significant decrease in the hepatic uptake of (M6P)(20)-BSA-P-33-TFO in fibrotic rats. Prior administration of excess M6P-BSA decreased the hepatic uptake of (M6P)(20)-BSA-P-33-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-P-33-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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