Synthesis and characterization of a hemoglobin-ribavirin conjugate for targeted drug delivery

Bioconjugate Chemistry
Steve BrookesGord Adamson

Abstract

A novel conjugate of human hemoglobin (Hb) and the nucleoside analogue ribavirin (RBV) was synthesized to demonstrate the utility of Hb as a biocompatible drug carrier for improved drug delivery in the treatment of liver disease. RBV is used in combination with interferon for the treatment of hepatitis C, but its side effects can result in dose limitation or discontinuation of treatment. Targeted delivery of RBV may help to prevent or minimize its toxicity. The hemoglobin-ribavirin conjugate (Hb-RBV) was designed to release bioactive drug upon endocytosis by cells and tissues involved in extracellular Hb catabolism and clearance. Ribavirin-5'-monophosphate (RBV-P) was prepared from RBV and activated as the 5'-monophosphorimidazolide (RBV-P-Im) for reaction with carbonmonoxyhemoglobin to yield Hb-RBV consisting of multiple RBV drugs covalently attached as physiologically labile phosphoramidates via their 5'-hydroxyl groups. A molar drug ratio of six to eight RBV molecules per Hb tetramer was obtained with near complete haptoglobin (Hp) binding of the drug modified Hb maintained. The conjugate complex (Hp-Hb-RBV) was selectively taken up in vitro by cells that express the hemoglobin-haptoglobin receptor, CD163. Recovered ribaviri...Continue Reading

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Citations

Sep 26, 2015·Pharmaceutics·Kazuaki TaguchiMasaki Otagiri
Oct 21, 2011·Biotechnology and Bioengineering·Ning Zhang, Andre F Palmer
Feb 18, 2011·Biotechnology and Bioengineering·Ning Zhang, Andre F Palmer
Apr 18, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Haiyan GuoYanjiao Wang
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Oct 17, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hanadi SinokrotRafik Karaman
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Jun 17, 2020·Biomaterials Science·Chris E CooperBrandon J Reeder
Jul 19, 2020·International Journal of Molecular Sciences·Łukasz KiragaMagdalena Król

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