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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).

peptide chelate conjugates
ACRONYM FULL CHELATE NAME
DOTA 1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid
NOTA 1,4,7-triazacyclononane-N,N,N-triacetic acid
TETA 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid
DTPA diethylenetriaminepentaacetic acid
IDA Iminodiacetic acid
CB-TE2A 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane
DiAmSar 1,8-Diamino-3,6,10,13,16,19-hexaazabicyclo[6,6,6]-eicosane

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.

Custom Peptide Synthesis NOTA chelate

Sai, Kiran Kumar Solingapuram, et al. "Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker." Oncotarget 5 (2017).

Metal-Chelate Peptide Citations

"For Ac-225 labeling, the prepared DOTA-Pep-1L (CPC-scientific, San Jose, CA) was incubated with Ac-225 at 70°C for 50 minutes. The TLC plates were scanned on a BioScan Imaging Scanner. Cu-64 was purchased from Washington University in St. Louis. The custom peptide specific to IL13RA2 and a scrambled peptide were conjugated with NOTA by CPC scientific Inc (San Jose, CA). Both the peptides, Pep-1L and scrambled peptide-NOTA were radiolabeled with Cu-64 according to the previously reported methods [15]."

1. Sattiraju, Anirudh, et al. "IL13RA2 targeted alpha particle therapy against glioblastomas." Oncotarget 8.26 (2017): 42997.Learn More »

"Synthesis, Labeling, and Stability of ECL1i. The ECL1i peptide (LGTFLKC) was synthesized from d-form amino acids by CPC Scientific (Sunnyvale, Calif)."

2. Liu, Yongjian, et al. "PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation." Radiology (2017): 161409.Learn More »

"Pep-1L was conjugated with NOTA, a chelator that can form a six-coordinate complex with Cu-64 that results in a high stability constant (log K=21.6) by CPC scientific Inc. [34]… The sequence of the Pep-1L peptide was as follows: H-Ala-Cys-GlyGlu-Met-Gly-Trp-Val-Arg-Cys-Gly-Gly- Gly-Ser-LCLys-Lys(biotin)-NH2. Pep-1L conjugated to NOTA was purchased from CPC scientific ltd, Sunnyvale, CA... The custom Peptide- NOTA was conjugated by CPC scientific Inc."

3. Sai, Kiran Kumar Solingapuram, et al. "Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker." Oncotarget 5 (2017).Learn More »

"Synthesis was conducted at CPC Scientific Inc. Ac-Asp(OtBu)-Thr(tBu)-His(Trt)-Phe-Pro-Ile-Cys(Trt)-Ile-PhePEG3-Arg(Pbf)-Arg(Pbf)-Lys(Boc)-wang resin (2)… Ac-Asp-Thr-His-Phe-Pro-Ile-Cys-Ile-Phe-PEG3-Arg-Arg-Lys(BODIPY_TMR_C6)."

4. Skerratt, Sarah, et al. "Identification of a novel BODIPY minihepcidin tool for the high content analysis of Ferroportin (SLC40A1) pharmacology." MedChemComm (2016).Learn More »

"[RGD-Glu-(DO3A)-6-Ahx-RM2], [Cyclo-(Arg-Gly-Asp-D-Tyr- Lys)-(DO3A)-Glu-(6-Ahx-D-Phe-Gln-Trp-Ala-Val-Gly-His- Sta-Leu-NH2)], was purchased from CPC Scientific (Sunny- vale, CA, USA)."

5. Jiang, Zongrun, et al. "Molecular imaging investigations of a 67Ga/64Cu labeled bivalent ligand,[RGD-Glu-(DO3A)-6-Ahx-RM2], targeting GRPR/αvβ3 biomarkers: a comparative study." Radiochimica Acta. (2016).Learn More »

"Here, we report the design and characterization of a dually radiolabeled peptide [ 64 Cu]c(RGDfE)K(DOTA)PLGVRY[ 123 I] for targeting cancer cells ... All peptides were purchased from CPC scientific (San Jose, CA.)"

6. Mebrahtu, Efrem, et al. "Initial characterization of a dually radiolabeled peptide for simultaneous monitoring of protein targets and enzymatic activity." Nuclear Medicine and Biology 40.2 (2013): 190-196.Learn More »

"DOTA-c(RGDyK) was purchased from CPC Scientific, Inc. (Sunnyvale, CA), and its purity and mass were confirmed at Wake Forest using HPLC and electrospray ionization (ESI) mass spectrometry as described below."

7. Pandya, Darpan N., et al. "Preliminary Therapy Evaluation of 225Ac-DOTA-c (RGDyK) Demonstrates that Cerenkov Radiation Derived from 225Ac Daughter Decay Can Be Detected by Optical Imaging for In Vivo Tumor Visualization." Theranostics 6.5 (2016): 698.Learn More »

"Two versions of the peptide L19K were synthesized by CPC Scientific (Sunnyvale, CA) consisting of the sequence DO3A- or NO2A-PEG4-GGNECDIARMWEWECFERK-CONH2, with a Cys-Cys disulfide bridge and polyethylene glycol (PEG) as a spacer between peptide and chelate."

8. Mastren, Tara, et al. "Cyclotron Production of High–Specific Activity 55 Co and In Vivo Evaluation of the Stability of 55 Co Metal-Chelate-Peptide Complexes." Molecular Imaging 14.10 (2015): 11-22.Learn More »

"DOTA-[Tyr3]octreotide and NO2A-[Tyr3]octreotide were purchased from CPC Scientific (Sunnyvale, CA)."

9. Lin, Mai, Michael J. Welch, and Suzanne E. Lapi. "Effects of Chelator Modifications on 68Ga-Labeled [Tyr3] Octreotide Conjugates." Molecular Imaging and Biology 15.5 (2013): 606-613.Learn More »

"NOTA-conjugated peptide was commercially purchased from CPC scientific ltd. The conjugated ligand was radiolabeled with 64 Cu with high purity and reaction progress was monitored by radio-TLC…"

10. Sai, Kiran Kumar Solingapuram, et al. "Radiolabeling and initial biological evaluations of [64Cu] NOTA-Pep-1L for imaging Glioblastoma (GBM)." Journal of Nuclear Medicine 57.supplement 2 (2016): 1100-1100.Learn More »

DOTA WL12 PD-L1 binding peptide

Chatterjee, Samit, et al. "Rapid PD-L1 detection in tumors with PET using a highly specific peptide." Biochemical and Biophysical Research Communications 483.1 (2017): 258-263.