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Research Articles: Therapeutics, Targets, and Development

Synthesis and biological activity of stable branched neurotensin peptides for tumor targeting

Department of Molecular Biology, Laboratory of Molecular Biotechnology, University of Siena, Siena, Italy

Requests for reprints: Chiara Falciani, Department of Molecular Biology, University of Siena, Siena, Italy 53100. Phone: 39-0577-234928. E-mail: chiarafalciani{at}unisi.it

Abstract

Receptors for endogenous regulatory peptides, like the neuropeptide neurotensin, are overexpressed in several human cancers and can be targets for peptide-mediated tumor-selective therapy. Peptides, however, have the main drawback of an extremely short half-life in vivo. We showed that neurotensin and other endogenous peptides, when synthesized as dendrimers, retain biological activity and become resistant to proteolysis. Here, we synthesized the neurotensin functional fragment NT(8-13) in a tetrabranched form linked to different units for tumor therapy or diagnosis. Fluorescent molecules were used to monitor receptor binding and internalization in HT29 human adenocarcinoma cells and receptor binding in HT29 tumor xenografts in nude mice. Linking of chemotherapic molecules like chlorin e6 and methotrexate to dendrimers resulted in a dramatic increase in drug selectivity, uptake of which by target cells became dependent on peptide receptor binding. When nude mice carrying human tumor xenografts were treated with branched NT(8-13)-methotrexate, a 60% reduction in tumor growth was observed with respect to mice treated with the free drug. [Mol Cancer Ther 2007;6(9):2441–8]

Grant support: Associazione Italiana per la Ricerca sul Cancro regional grant 2004-2006, the Italian Ministry of University and Research (PRIN 2005), and the Italian Consortium for Biotechnology and the University of Siena (PAR project).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 7/07; revised 5/24/07; accepted 7/18/07.