Design, synthesis, and biological evaluation of a dual tumor-specific motive containing integrin-targeted plasmin-cleavable doxorubicin prodrug

Franciscus M H De Groot, Henk J. Broxterman, Hans P H M Adams, Alexandra Van Vliet, Godefridus I. Tesser, Yvonne W. Elderkamp, Astrid J. Schraa, Robbert Jan Kok, Grietje Molema, Herbert M. Pinedo, Hans W. Scheeren

Research output: Contribution to journalArticle

Abstract

The design, synthesis, and initial biological evaluation of a doxorubicin prodrug that contains a dual tumor specific moiety, which allows enhanced tumor recognition potential, is reported. Both a tumor-specific recognition site and a tumor selective enzymatic activation sequence are incorporated in the prodrug. The first tumor-specific sequence is the bicyclic CDCRGDCFC (RGD-4C) peptide that selectively binds αvβ3 and αvβ5 integrins. These integrins are highly overexpressed on invading tumor endothelial cells. The second tumor-specific sequence is a D-Ala-Phe-Lys tripeptide that is selectively recognized by the tumor-associated protease plasmin, which is involved in tumor invasion and metastasis. An aminocaproyl residue was incorporated as a spacer between the two peptide sequences, whereas a self-eliminating 4-aminobenzyl alcohol spacer was inserted between the plasmin substrate and doxorubicin. Although the prodrug showed a decreased binding affinity as compared with the unconjugated reference peptide, it was still a potent ligand for αvβ3 and αvβ5 integrin receptors. The synthesized construct also possessed plasmin substrate properties as demonstrated by doxorubicin release from 1 upon incubation with plasmin. The release of doxorubicin from 1 was not complete, possibly related to low prodrug solubility. In vitro prodrug 1 showed plasmin-dependent cytotoxicity for endothelial cells and HT1080 fibrosarcoma cells. On the basis of these in vitro results, derivatives of 1 with improved water solubility are considered good candidates for additional development and in vivo evaluation of this dual targeting concept.

Original languageEnglish (US)
Pages (from-to)901-911
Number of pages11
JournalMolecular Cancer Therapeutics
Volume1
Issue number11
StatePublished - Sep 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

De Groot, F. M. H., Broxterman, H. J., Adams, H. P. H. M., Van Vliet, A., Tesser, G. I., Elderkamp, Y. W., Schraa, A. J., Kok, R. J., Molema, G., Pinedo, H. M., & Scheeren, H. W. (2002). Design, synthesis, and biological evaluation of a dual tumor-specific motive containing integrin-targeted plasmin-cleavable doxorubicin prodrug. Molecular Cancer Therapeutics, 1(11), 901-911.