2. Academic Validation
  3. Tumor-Targeted Delivery of an EGFR Inhibitor Prodrug via Site-Specific Albumin Conjugation

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

  • J Med Chem. 2026 Feb 12;69(3):2554-2574. doi: 10.1021/acs.jmedchem.5c02536.
Anja Federa 1 2,  Rastislav Pitek 3,  Orsolya Dömötör 4,  Éva A Enyedy 4,  Alessio Terenzi 5,  Monika Caban 3,  Alessia Stefanelli 3,  Luisa D'Anna 5,  Faye White 3,  Petra Heffeter 3 6,  Christian R Kowol 1 6
Affiliations

Affiliations

  • 1 Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
  • 2 Vienna Doctoral School in Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria.
  • 3 Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
  • 4 Department of Molecular and Analytical Chemistry, University of Szeged, Dóm tér 7-8, H-6720 Szeged, Hungary.
  • 5 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze, Edificio 17, 90128 Palermo, Italy.
  • 6 Research Cluster "Translational Cancer Therapy Research", 1090 Vienna, Austria.
PMID: 41575354 DOI: 10.1021/acs.jmedchem.5c02536
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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