Molecularly targeted cancer imaging is critical for fundamental improvements in cancer patient care, and image quality and diagnostic accuracy rely heavily on the affinity/specificity between the targeted receptor and targeting ligand (small molecules, peptides and antibodies). A heterodimeric ligand that simultaneously associates two linked ligands with two different targeting receptors provides a broadly applicable approach to convert low affinity ligands (Kdaffinity ~ mM - M) to the one with high avidity/specificity (Kdavidity ~ nM). Such high avidity heterodimers are usually pursued by: 1) synthesizing a number of heterodimers with different linkers; and 2) measuring their in vitro avidities individually. However, once the receptor of interest changes, repeating the entire procedure (including new heterodimer library synthesis and avidity measurement) is required for linker optimization. Even more disappointing is the fact that even by prudently selecting dual-receptor pairs where a potent heterodimer may be applied to a variety of tumors, in a particular lab using particular cell lines(s) where receptor distance(s) varied significantly, heterodimer library synthesis and avidity measurements needs to be conducted again. Therefore, the lack of a generic and rapid linker optimization platform has been considered as one of the major barriers for the widespread and routine utilization of heterodimeric ligand for preclinical and/or clinical studies. In order to overcome this problem, utilizing two bioorthogonal ligations, we propose the first, high-throughput, in vitro screening platform for easy preparation of high avidity heterodimers, which can be broadly applied to various dual-receptor combinations and different tumors. Such widespread applicable technology will significantly accelerate and/or enhance receptor-targeted cancer imaging using heterodimers, particularly in the following situations: 1) when targeted receptor(s) are expressed in low abundance; and 2) situations where no high affinity (and/or specificity) monovalent ligands are available.
With the success and the influx of targeted cancer imaging and therapy, the development of high affinity/specificity targeting probe is extremely desirable. Heterodimeric ligand that simultaneously associates two linked ligands with two different biomarkers provides a broadly applicable approach to convert the low affinity ligands to the one with high avidity/specificity. Although there has been a considerable effort in the development of heterodimeric ligands, optimization of linkers for bivalency still remains as one major unresolved issue since it has been widely observed that the linker dramatically affects the avidity of bivalency. Therefore, utilizing two bioorthogonal ligations, we propose the first, high-throughput, in vitro screening platform for easy preparation of high avidity heterodimers, which can be broadly applied to various dual- receptor combinations and different tumors. Such widespread applicable technology can significantly accelerate and/or enhance receptor-targeted cancer imaging using heterodimers, particularly in the following situations: 1) targeted receptor(s) which are expressed in low abundance; and 2) situations where no high affinity (and/or specificity) monovalent ligands are available. In this proposal, two peptide ligands, targeting uPAR and Plectin-1 biomarkers respectively, are selected to pursue the corresponding high avidity heterodimer used for PET imaging of pancreatic cancer at early stage.
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