title: Synthesis and biological activity of stable branched neurotensin peptides for tumor targeting.
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.
authors.affiliation: Department of Molecular Biology, University of Siena, Siena, Italy 53100. chiarafalciani@unisi.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Falciani
authors.forename: Monica
authors.initials: M
authors.lastname: Fabbrini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.forename: Luisa
authors.initials: L
authors.lastname: Lozzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Lelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Pileri
authors.forename: Jlenia
authors.initials: J
authors.lastname: Brunetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Bindi
authors.forename: Silvia
authors.initials: S
authors.lastname: Scali
authors.forename: Luisa
authors.initials: L
authors.lastname: Bracci
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D019073:HT29 Cells; D006801:Humans; D008727:Methotrexate / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D009496:Neurotensin / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use*; D018028:Receptors, Neurotensin / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; D009496:Neurotensin; D008727:Methotrexate