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Novel Radiolabelled Peptidomimetics for Tumor Targeting
| Third-party funded project |
| Project title |
Novel Radiolabelled Peptidomimetics for Tumor Targeting |
| Principal Investigator(s) |
Mindt, Thomas L.
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| Co-Investigator(s) |
Walter, Martin
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| Organisation / Research unit |
Bereich Querschnittsfächer (Klinik) / Radiologische Chemie (Mindt) |
| Project start |
01.03.2011 |
| Probable end |
28.02.2013 |
| Status |
Completed |
| Abstract |
Background: Radiolabelled peptides which target receptors that are over expressed by malignant tumors and metastases hold great promise for the development of radiodiagnostics and -therapeutics useful in oncology for the management of the disease. Regulatory peptides represent a class of high affinity ligands with ideal characteristics for the development of targeted radiopharmaceuticals. The major drawback of vectors based on regulatory peptides for the selective delivery of attached radionuclides to tumors and metastasis is their short biological half life as the result of rapid in vivo degradation by intra- and extracellular peptidases. Substantial research efforts have been made in the past years in order to stabilize regulatory peptides against enzymatic degradation while not impacting their high affinity to the receptors and favorable biological properties. For example, the introduction of stabilizing structural elements such as unnatural amino acids has yielded somatostatin analogues (octreotide) suitable for clinical use. However, application of the same strategy to other peptides has been of limited success so far because degradation by cleavage of amide bond still occurs in vivo. Employment of surrogates of amide bonds which are not prone to enzymatic hydrolysis could provide a solution.
Methods: We will establish libraries of stabilized regulatory peptides by systematic replacement of amide bonds known to be susceptible to enzymatic cleavage with novel amide bond surrogates. The peptidomimetics will be modified with a chelator for the labeling with radiometals. The radioconjugates obtained will be evaluated in vitro and in vivo and their stability, receptor affinity and pharmacokinetics will be compared with unstabilized, analogous reference compounds.
Significance: If successful, the new radiotracers derived from the novel analogues of regulatory peptides will display improved characteristics in vivo and lead to the development of a new generation of peptide-based radiopharmaceuticals for the diagnosis and therapy of cancer. |
| Financed by |
Swiss National Science Foundation (SNSF)
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07/05/2024
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