Macromolecular Prodrugs for Controlled Delivery of Ribavirin

• Published in: Macromolecular bioscience Vol. 14; no. 2; pp. 173 - 185
• Main Authors: Kryger, Mille B. L., Smith, Anton A. A., Wohl, Benjamin M., Zelikin, Alexander N.
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 01.02.2014; Wiley Subscription Services, Inc
• Subjects: Acrylic Resins - chemistry; Antiviral Agents - administration & dosage; antiviral therapy; Cell Survival - drug effects; Chemical compounds; Chemistry Techniques, Synthetic; Conjugation; Copolymers; Dose-Response Relationship, Drug; Drugs; Effectiveness; Erythrocytes - drug effects; Hep G2 Cells - drug effects; hepatitis; Humans; inflammation; Macrophages - drug effects; Nitric oxide; Nitric Oxide - metabolism; polymer therapeutics; Polymers; Polyvinyls - chemistry; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Pyrrolidinones - chemistry; Retarding; ribavirin; Ribavirin - administration & dosage; Side effects; ribavirin; hepatitis; polymer therapeutics; inflammation; antiviral therapy
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.201300244

Ribavirin (RBV)‐containing polymers are synthesized based on poly(N‐vinylpyrrolidone) and poly(acrylic acid), two polymers with extensive characterization in biomedicine. The copolymers are shown to exhibit a minor to negligible degree of association with erythrocytes, thus effectively eliminating the origin of the main side effects of RBV. The therapeutic benefit of macromolecular RBV prodrugs is illustrated by matched efficacy in suppressing production of nitric oxide by stimulated cultured macrophages as compared to pristine RBV with no associated cytotoxicity, which is in stark contrast to an RBV‐based treatment which results in a significant decrease in cell viability. These results contribute to the development of antiviral polymer therapeutics and delivery of RBV in particular. Conjugation to carrier polymers significantly improves the pharmacokinetics of ribavirin and delivers pronounced therapeutic benefit. Polymer‐conjugated ribavirin exhibits minimal association with red blood cells, demonstrates no cytotoxicy in hepatic cells, yet reveals a pronounced intracellular activity through inhibition of production of nitric oxide.