Journal
JOURNAL OF CONTROLLED RELEASE
Volume 155, Issue 2, Pages 326-330Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2011.06.037
Keywords
Bioconjugation; HPMA; TFO; Liver fibrosis
Funding
- NIBIB NIH HHS [R01 EB003922, R01 EB003922-04] Funding Source: Medline
- NIDDK NIH HHS [DK69968, R01 DK069968] Funding Source: Medline
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Triplex-forming oligonucleotides (TFOs) represent an antigene approach for gene regulation through direct interaction with genomic DNA. While this strategy holds great promise owing to the fact that only two alleles need silencing to impact gene regulation, delivering TFOs to target cells in vivo is still a challenge. Our recent efforts have focused on conjugating TFOs to carrier molecules like cholesterol to enhance their cellular uptake and mannose-6-phosphate-bovine serum albumin (M6P-BSA) to target TFO delivery to hepatic stellate cells (HSCs) for treating liver fibrosis. These approaches however are rendered less effective owing to a lack of targeted delivery, as seen with lipid-conjugates, and the potential immune reactions due to repeated dosing with high molecular weight BSA conjugated TFO. In this review, we discuss our latest efforts to enhance the effectiveness of TFO for treating liver fibrosis. We have shown that conjugation of TFOs to M6P-HPMA can enhance TFO delivery to HSCs and has the potential to treat liver fibrosis by inhibiting collagen synthesis. This TFO conjugate shows negligible immunogenicity owing to the use of HPMA, one of the least immunogenic copolymers, thereby making it a suitable and more effective candidate for antifibrotic therapy. (C) 2011 Elsevier B.V. All rights reserved.
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