Cathepsin B-Cleavable Voriconazole Macromolecular Prodrugs for Intracellular Release
Abstract Invasive aspergillosis is a life-threatening fungal infection starting in the lungs of immunocompromised patients. After inhalation, the conidia (spores) of this mold are phagocytosed by epithelial and immune cells. The fungus has developed mechanisms to survive intracellularly in phagolysosomes. This way, the conidia hide from the residual immune system and also medication for some time, as antifungal drugs need to cross two membranes, i.e., the cytoplasmic and phagolysosomal membranes. A macromolecular prodrug (MPD) has therefore been designed and successfully synthesized for the intraphagosomal delivery of voriconazole, the primary antibiotic for treatment of invasive aspergillosis. The drug was attached as a benzylazolium salt to a cathepsin B-cleavable substrate, which was then linked to an N-(2-hydroxypropyl)methacrylate-analogous polymer. The intracellular colocalization of the MPD with conidia in phagolysosomes was demonstrated, and approximately 45% of voriconazole was released within three days, demonstrating the successful linkage of azole antifungals to enzyme-cleavable substrates.
Authors
- Thomas Orasch (ORCID: https://orcid.org/0000-0003-4653-4932)
- Carlos Guerrero‐Sánchez (ORCID: https://orcid.org/0000-0001-6772-4765)
- Nicole C. Roesner (ORCID: https://orcid.org/0000-0002-5133-775X)
- Sophie Dietz (ORCID: https://orcid.org/0000-0002-5350-6625)
- Julien Alex (ORCID: https://orcid.org/0000-0002-4486-2839)
- Maira Rosin (ORCID: https://orcid.org/0000-0002-4263-4541)
- Axel A. Brakhage (ORCID: https://orcid.org/0000-0002-8814-4193)
- Katherine González (ORCID: https://orcid.org/0000-0001-8549-9741)
- Peter Bellstedt (ORCID: https://orcid.org/0000-0002-5131-8452)
- Hans F. Ulrich (ORCID: https://orcid.org/0000-0001-6228-1838)
- Ulrich S. Schubert (ORCID: https://orcid.org/0000-0003-4978-4670)
- Maria Cristina Stroe (ORCID: https://orcid.org/0000-0003-4049-1062)
- Christine Weber (ORCID: https://orcid.org/0000-0003-0712-5255)
- Derya Nur Coemert
- Nils E. Schlörer (ORCID: https://orcid.org/0000-0002-0990-9582)
- Sophie Tröger-Görler
- Melanie Haendel
- Henrik Schweder
- Thorsten Heinekamp
Institutions
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Friedrich Schiller University Jena (DE)
Publication Details
- Journal
- Biomacromolecules
- Published
- 2026-11-11
- DOI
- https://doi.org/10.1021/acs.biomac.6c01503
- Primary Topic
- Advanced Drug Delivery Systems
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung