Cathepsin B cleavable voriconazole macromolecular prodrugs for intracellular release

Invasive aspergillosis is a life-threatening fungal infection starting in lungs of immunocompromised patients and associated with mortality rates up to 95%. After inhalation, the conidia (spores) of this mold are phagocytosed by epithelial and immune cells including alveolar macrophages. The fungus has developed mechanisms to survive intracellularly in phagolysosomes (PLs). This way the conidia hide from the residual immune system and also medication for some time, as antifungal drugs need to cross two membranes for effective treatment, i.e., the cytoplasmic and the phagolysosomal membrane. Thus, targeting PLs with specific antifungal drugs could provide high local concentrations of the drug and prolonged retention in the PLs.. 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. Cathepsin B was previously found to be located in PLs and the intracellular colocalization of the MPD with conidia in PLs was demonstrated. Approximately 45% of voriconazole was released within three days demonstrating the successful linkage of azole antifungals to enzyme-cleavable substrates.