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

Federa, Anja and Pitek, Rastislav and Dömötör, Orsolya and Enyedy, Éva Anna and Terenzi, Alessio and Caban, Monika and Stefanelli, Alessia and D’Anna, Luisa and White, Faye and Heffeter, Petra and Kowol, Christian R. (2026) Tumor-Targeted Delivery of an EGFR Inhibitor Prodrug via Site-Specific Albumin Conjugation. JOURNAL OF MEDICINAL CHEMISTRY, 69 (3). pp. 2554-2574. ISSN 0022-2623

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Abstract

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.

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