Cathepsin B-Cleavable Voriconazole Macromolecular Prodrugs for Intracellular Release

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.