Tumor targeting with radiolabeled ligands that bind selectively to receptors overexpressed on cancer cells is valuable for tumor imaging and therapy. Yet, current ligands typically suffer from either low internalization into tumor cells (agonists) or high wash-out since they only bind to the receptors (antagonists).
We use azidoproline containing oligoprolines as functionalizable molecular scaffolds that allow for combining agonists with antagonists in defined distances. Our group showed that hybrid ligands consisting of a bombesin-based agonist and antagonist as recognition motifs exhibit extraordinary tumor uptake properties in prostate carcinoma. The oligoproline scaffold allowed for distance control between the agonist and the antagonist and revealed that hybrid ligands with 20 Å spacing have significantly higher tumor uptakes in vitro and in vivo compared to monovalent and divalent controls.
Based on these findings we are now designing oligoproline-based ligands to expand the method to targeting other cancer types and to achieve a deeper understanding of how the uptake takes place on the molecular and cellular level.
- C. Kroll, R. Mansi, F. Braun, S. Dobitz, H. Maecke, H. Wennemers, "Hybrid Bombesin Analogues – Combining an Agonist and an Antagonist in Defined Distances for Optimized Tumor Targeting"
J. Am. Chem. Soc. 2013, 135, 16793–16796
- P. Wilhelm, B. Lewandowski, N. Trapp, H. Wennemers, "A Crystal Structure of an Oligoproline PPII-Helix, at Last"
J. Am. Chem. Soc. 2014, 136, 15829–15832
- M. Kuemin, Y. A. Nagel, S. Schweizer, F. W. Monnard, C. Ochsenfeld, H. Wennemers, "Tuning the cis:trans Conformer Ratio of Xaa-Pro Amide Bonds by Intramolecular Hydrogen Bonds – Effect on the Stability of the PPII Helix"
Angew. Chem. Int. Ed. 2010, 49, 6324–6327
- M. Kuemin, L.-S. Sonntag, H. Wennemers, "Azidoproline Containing Helices – Stabilization of the Polyproline II Structure by a Functionalizable Group"
J. Am. Chem. Soc. 2007, 129, 466–467