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

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 alpha v beta 3 and alpha v beta 5 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 alpha v beta 3 and alpha v beta 5 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.

• Authors: 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, Robert Jan Kok, Grietje Molema, Herbert M Pinedo, Hans W Scheeren
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 11 Pg. 901-11 (Sep 2002) ISSN: 1535-7163 [Print] United States
• PMID: 12481411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzyl Alcohols
• Integrin alphaVbeta3
• Integrins
• Ligands
• Oligopeptides
• Peptides
• Prodrugs
• Receptors, Vitronectin
• integrin alphaVbeta5
• 4-aminobenzyl alcohol
• arginyl-glycyl-aspartic acid
• Doxorubicin
• Fibrinolysin

Topics

• Amino Acid Sequence
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Benzyl Alcohols (pharmacology)
• Binding Sites
• Cell Adhesion
• Chromatography, High Pressure Liquid
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Design
• Endothelium (cytology)
• Endothelium, Vascular (cytology)
• Fibrinolysin (chemistry, metabolism)
• Humans
• Inhibitory Concentration 50
• Integrin alphaVbeta3 (metabolism)
• Integrins (chemistry, metabolism)
• Ligands
• Models, Chemical
• Molecular Sequence Data
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Oligopeptides
• Peptides (chemistry)
• Prodrugs (chemical synthesis, pharmacology)
• Protein Binding
• Protein Structure, Tertiary
• Receptors, Vitronectin (metabolism)