Tumor-Targeted Delivery of an EGFR Inhibitor Prodrug via Site-Specific Albumin Conjugation

Albumin is a promising vehicle for anticancer drug delivery due to its high plasma concentration, long half-life and known tumor accumulation. Drugs can be covalently conjugated to albumin via the free thiol at Cys³⁴, using maleimide chemistry. Interestingly, such strategies have not yet been applied to tyrosine kinase inhibitors (TKIs), e.g. crucial in lung cancer treatment. This study investigates a prodrug delivery system for a derivative of the approved epidermal growth factor receptor (EGFR) inhibitor osimertinib, incorporating a maleimide for albumin binding and a cathepsin B-cleavable valine-citrulline (ValCit) dipeptide for selective drug release. In silico and in vitro studies confirmed the prodrug nature. Additionally, selective albumin-binding and efficient cathepsin B-mediated drug release were demonstrated. In non-small cell lung cancer (NSCLC) xenografts, the prodrug exhibited enhanced anticancer activity compared to osimertinib and a noncleavable glycine-glycine (GlyGly) control. These results highlight covalent albumin-binding as a promising strategy for TKI delivery.