title: Macromolecular (pro)drugs with concurrent direct activity against the hepatitis C virus and inflammation.
abstract: Macromolecular prodrugs (MPs) are a powerful tool to alleviate side-effects and improve the efficacy of the broad-spectrum antiviral agent ribavirin. In this work, we sought an understanding of what makes an optimal formulation within the macromolecular parameter space--nature of the polymer carrier, average molar mass, drug loading, or a good combination thereof. A panel of MPs based on biocompatible synthetic vinylic and (meth)acrylic polymers was tested in an anti-inflammatory assay with relevance to alleviating inflammation in the liver during hepatitis C infection. Pristine polymer carriers proved to have a pronounced anti-inflammatory activity, a notion which may prove significant in developing MPs for antiviral and anticancer treatments. With conjugated ribavirin, MPs revealed enhanced activity but also higher toxicity. Therapeutic windows and therapeutic indices were determined and discussed to reveal the most potent formulation and those with optimized safety. Polymers were also tested as inhibitors of replication of the hepatitis C viral RNA using a subgenomic viral replicon system. For the first time, negatively charged polymers are revealed to have an intracellular activity against hepatitis C virus replication. Concerted activity of the polymer and ribavirin afforded MPs which significantly increased the therapeutic index of ribavirin-based treatment. Taken together, the systematic investigation of the macromolecular space identified lead candidates with high efficacy and concurrent direct activity against the hepatitis C virus and inflammation.
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus C 8000, Denmark; iNANO Interdisciplinary Nanoscience Centre, Aarhus University, Aarhus C 8000, Denmark.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Wohl
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus C 8000, Denmark.
authors.forename: Anton A A
authors.initials: AA
authors.lastname: Smith
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus C 8000, Denmark.
authors.forename: Bettina E B
authors.initials: BE
authors.lastname: Jensen
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus C 8000, Denmark; iNANO Interdisciplinary Nanoscience Centre, Aarhus University, Aarhus C 8000, Denmark. Electronic address: zelikin@chem.au.dk.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Zelikin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D066298:In Vitro Techniques; D046911:Macromolecular Substances / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D011355:Prodrugs / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D004337:Drug Carriers; D046911:Macromolecular Substances; D011355:Prodrugs; D012367:RNA, Viral; D012254:Ribavirin
keywords: Antiviral; Drug delivery; Hepatitis C; Macromolecular prodrugs; Poly(N-(2-hydroxypropyl) methacrylamide) (PubChem CID: 38622); Poly(N-vinylpyrrolidone) (PubChem CID: 6917); Poly(acrylic acid) (PubChem CID: 6581); Poly(methacrylic acid) (PubChem CID: 3255932); Polymer therapeutics; Ribavirin; Ribavirin (PubChem CID: 37542)