Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs

Camilla Kaas Frich, Franziska Krüger, Raoul Walther, Cecilie Domar, Anna H.F. Andersen, Anne Tvilum, Frederik Dagnæs-Hansen, Paul W. Denton, Martin Tolstrup, Søren R. Paludan, Jan Münch, Alexander N. Zelikin

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Albumin is a highly successful tool of drug delivery providing drastically extended body and blood residence time for the associated cargo, but it only traffics single drug copies at a time. In turn, macromolecular prodrugs (MP) are advantaged in carrying a high drug payload but offering only a modest extension of residence time to the conjugated drugs. In this work, we engineer MP to contain terminal groups that bind to albumin via non-covalent association and reveal that this facile measure affords a significant protraction for the associated polymers. This methodology is applied to MP of acyclovir, a successful drug against herpes simplex virus infection but with poor pharmacokinetics. Resulting albumin-affine MP were efficacious agents against herpes simplex virus type 2 (HSV-2) both in vitro and in vivo. In the latter case, sub-cutaneous administration of MP resulted in local (vaginal) antiviral effects and a systemic protection. Presented benefits of non-covalent association with albumin are readily transferrable to a wide variety of MP in development for drug delivery as anticancer, anti-inflammatory, and anti-viral measures.

Original languageEnglish (US)
Pages (from-to)298-310
Number of pages13
JournalJournal of Controlled Release
Volume294
DOIs
StatePublished - Jan 28 2019
Externally publishedYes

Keywords

  • Acyclovir
  • Albumin
  • Herpes simplex virus
  • Macromolecular prodrugs

ASJC Scopus subject areas

  • Pharmaceutical Science

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