Abstract
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Objectives Radiolabeled octreotide-analogs are most successfully being applied for tumor visualization and treatment. However, translation of this paradigm to other radiopeptide ligands has been often hampered by their poor metabolic stability. We have recently shown that single co-injection of phosphoramidon (PA) promotes the bioavailability and tumor uptake of radiopeptides. PA is a potent (IC50 34 nM) and reversible competitive inhibitor of neutral endopeptidase (NEP). We herein provide further evidence on the efficacy of this novel approach in a wider range of radiopeptide analogs, based on somatostatin, gastrin, bombesin and gastrin-releasing-peptide ligands.
Methods In our studies, test radiopeptide was injected without (control) or with PA (0.3 mg) in mice and in vivo stability was compared by HPLC analysis of blood collected 5 min post injection (pi). Biodistribution studies as well as dynamic and static animal SPECT/CT imaging studies were performed in SCID mice bearing tumors expressing the respective receptor-target to assess uptake changes induced by PA. Peptide ligands were labeled with 99mTc or trivalent radiometals suitable for diagnosis and therapy, like 111In or 177Lu.
Results We could provoke a remarkable rise (up to 40 times the control values) in the percentage of circulating intact radiolabeled peptide analogs in healthy mice after PA co-injection. Most importantly, this strategy resulted in an unprecedented increase of radiolabel accumulation (up to 14 times the control values) in the different types of tumors xenografted in the mice. The improved tumor uptake could be clearly visualized by SPECT/CT as well.
Conclusions Our findings open exciting new opportunities for the application of biodegradable peptide-drugs of either natural or synthetic origin as well as for the rationale design of in vivo stable analogs. They also provide a versatile tool for elucidating enzyme - peptide interactions.