This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Groot, F. M. H. Articles by Scheeren, H. W. Search for Related Content PubMed PubMed Citation Articles by de Groot, F. M. H. Articles by Scheeren, H. W.

Department of Organic Chemistry, NSR-Center for Molecular Structure, Design and Synthesis, University of Nijmegen, 6525 ED Nijmegen [F. M. H. d. G., H. P. H. M. A., G. I. T., H. W. S.]; Department of Medical Oncology, Academic Hospital Vrije Universiteit, 1007 MB Amsterdam [H. J. B., Y. W. E., H. M. P.]; Ansynth Service B.V., 4703 LE Roosendaal [A. v. V.]; Department of Pathology and Laboratory Medicine, Medical Biology Section, Tumor Immunology Laboratory, 9713 GZ Groningen [A. J. S., G. M.]; and Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, 9713 AV Groningen, [R. J. K.], the Netherlands

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 _vß₃ and _vß₅ 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 _vß₃ and _vß₅ 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.

This article has been cited by other articles:

				D. J. Burkhart, B. T. Kalet, M. P. Coleman, G. C. Post, and T. H. Koch Doxorubicin-formaldehyde conjugates targeting {alpha}v{beta}3 integrin Mol. Cancer Ther., December 1, 2004; 3(12): 1593 - 1604. [Abstract] [Full Text] [PDF]

				G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF]

				C. Pan, P. M. Cardarelli, M. H. Nieder, L. B. Pickford, S. Gangwar, D. J. King, G. T. Yarranton, D. Buckman, W. Roscoe, F. Zhou, et al. CD10 Is a Key Enzyme Involved in the Activation of Tumor-activated Peptide Prodrug CPI-0004Na and Novel Analogues: Implications for the Design of Novel Peptide Prodrugs for the Therapy of CD10+ Tumors Cancer Res., September 1, 2003; 63(17): 5526 - 5531. [Abstract] [Full Text] [PDF]