Branched peptides as targeting agents for tumor imaging and therapy

4072 Membrane receptors for endogenous peptides like Somatostatin, Neurotensin, Bombesin and many others, are over-expressed in different human cancers and might be targeted as tumor-specific antigens. Efficiency of peptide-receptor targeting depends on the presence and concentration of receptors on neoplastic tissues. Receptor-specific diagnostic tools would be extremely useful to predict the efficacy of a treatment aimed at the same receptors, provided that molecules used for receptor tracing have similar binding efficiency than those used for therapy.
 Our goal is producing peptide molecules that can be used for both a specific receptor-tracing test and for therapy or in vivo imaging, by delivering radio or chemotherapeutic moieties to the same receptors on tumor cells. Branched peptide molecules can be used for both purposes with no modification of the tumor targeting moiety, but only by addition of different functional units, like chromophores, radio or chemotherapic moieties, to the conserved branched core. Moreover, branched peptides have the additional advantage of a longer half-life caused by a much higher resistance to proteolysis, compared to linear peptides (1, 2).
 We previously demonstrated that neurotensin (NT), when synthesized as a tetra-branched dendrimer, retains biological activity and becomes resistant to proteases (1).
 Tetrabranched NT conjugated to fluorophores was synthesized and tested for receptor binding on different human tumor cell lines. Once verified that conjugation to functional units did not reduce receptor binding of branched peptides, we tested our molecules on samples from surgical resection of colon and pancreas adenocarcinoma, in comparison with healthy tissues from the same patients. Confocal images show a general good staining of most tumor samples by branched NT and a much lower staining of healthy tissue from the same patients, indicating a good selectivity of the peptide. The same tetrabranched peptide was conjugated to different chemotherapic drugs and tested for cytotoxicity toward tumor cells in vitro and in animal models (3). Results indicate very promising features of branched NT for selective tumor targeting.