Metal Chelating Conjugate Peptides
Cancer cells that express or overexpress specific receptors has lead to the development of synthetic peptides that target these receptors. Peptides conjugated to metal chelates (e.g, DOTA, NOTA, etc.) offer an attractive approach for both imaging of cancer tissues and as therapies that deliver cytotoxic cargo to cancer cells. The interleukin-13 receptor alpha 2 (IL13RA2) is a receptor that is abundantly overexpressed in most GBMs but not present in heathy brain cells. Ligands that specifically target this receptor may offer new approaches to treatment of GBM. Because IL13RA2 is internalized upon binding IL13, this receptor is an attractive target for therapies involving the delivery of cytotoxic cargo to Glioblastoma (GBM) cells. Peptide-1 linear (Pep-1L) has been evaluated for its ability to localize at IL13RA2 and deliver cytotoxic alpha-particle emitters (Actinium-225, Ac-225) to GBM cells (right).
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An immune checkpoint protein called programmed cell death ligand (PD-L1) is a common biomarker for cancer because it is over-expressed in many tumor cells as an adaptive immune response to cytotoxic T-cells. Binding of PD-L1 to programmed cell death protein 1 (PD-1) receptors of infiltrating host immune cells triggers deactivation and immune suppression. Rapid and non-invasive positron emission topography (PET) imaging that can monitor PD-L1 expression levels and distribution would enable more efficient treatment options for cancer patients. Current immunotherapies rely on radiolabeled anti-PD-L1 antibodies to determine PD-L1 expression levels non-invasively in human tumors. Radiolabeled antibody conjugates, however, have long clearance times that limits the amount of imaging agents that can be injected and increases diagnoses time. Peptide-based PET tracers, on the other hand, have lower molecular weights compared to proteins and show enhanced clearance rates.
Chatterjee and co-workers hypothesized that PD-L1 binding peptides would more efficiently and rapidly detect PD-L1 expression levels in tumors. From a library of PD-L1 binding peptides, peptide WL12 (right) was selected to test their hypothesis. The peptide has several structural features that make it more resistant to proteolytic metabolism, namely: (1) macrocyclization (thioether), (2) N-methylated substituents and (3) the incorporation of unnatural amino acids. The single primary amine of the ornithine side chain provides a relatively easy method in which to conjugate a DOTA chelator for radiolabeling with 64Cu.