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.