Synthesis and biological activity of stable branched neurotensin peptides for tumor targeting.
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.
Falciani
Chiara
C
Department of Molecular Biology, University of Siena, Siena, Italy 53100. chiarafalciani@unisi.it
Fabbrini
Monica
M
Pini
Alessandro
A
Lozzi
Luisa
L
Lelli
Barbara
B
Pileri
Silvia
S
Brunetti
Jlenia
J
Bindi
Stefano
S
Scali
Silvia
S
Bracci
Luisa
L
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
D000964:Antimetabolites, Antineoplastic; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; D009496:Neurotensin; D008727:Methotrexate