Synthesis and evaluation of radiolabeled peptide multimers for tumor targeting

Many cancer types express specific receptors on their cellular surface onto which regulatory peptides bind with high affinity. This mechanism can be exploited by labeling the peptide with a radionuclide and using the radiolabeled peptide as a vehicle to guide the radioactivity to receptor-rich cells, thus enabling the non-invasive imaging of cancerous tissues (for diagnostic purposes) or their selective irradiation with suitable short-range, high-energy ?-emitting isotopes (in therapeutic applications). Development of multimeric peptides have attracted much attention, because they may have enhanced receptor affinity compared to monomeric analogs. The aim of this thesis is to explore this concept in the design, synthesis and biological evaluation of multimeric peptides as agents for tumor targeting and nuclear imaging. Analogs of somatostatin (a cyclic peptide) are of particular interest, because their receptors are overexpressed on the cellular surface of neuroendocrine tumors, such as pancreas-, lung- and brain cancers. One peptide analog of somatostatin is the [Tyr3]octreotide, which is used in the clinic. In this thesis, DOTA-conjugated [Tyr3]octreotide multimers were synthesized using a two-stage ‘Click’ chemistry approach, more specifically: a combination of Cu-catalyzed azide/alkyne ‘copper-Click’ cycloaddition (to facilitate [Tyr3]octreotide multimer formation) followed by thio acid/sulfonyl azide ‘sulfo-Click’ amidation (to induce metal-free coupling of DOTA-moiety). These DOTA-conjugated [Tyr3]octreotide multimers were radiolabeled (with 111In) and their receptor binding properties were determined in a competitive binding assay using a tumor cell line. Tumor targeting and pharmacokinetic properties were evaluated in animal models. Radiolabeled dimeric [Tyr3]octreotide analogs showed high and prolonged tumor uptake. These promising results can be exploited for radiotherapeutic application using radiolabeled dimeric peptide analogs