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Targeting of CCK-2 receptor-expressing tumors using a radiolabeled divalent gastrin peptide
Jane K Sosabowski1, Torkjel Matzow, Julie M Foster
1Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom. j.k.sosabowski@qmul.ac.uk
Unlabelled:
Gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) are overexpressed in several tumor types and are, thus, a potential target for peptide receptor radionuclide therapy (PRRT) of cancer. To improve the in vivo performance of CCK-2R binding peptides, we have previously synthesized and screened a series of divalent gastrin peptides for improved biochemical and biologic characteristics. In this study, we explore in more detail the most promising of these compounds and compare its performance with a previously described monomeric peptide.
Methods:
From six (111)In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-conjugated divalent gastrin peptides based on the C-terminal sequence of minigastrin, the maleimide-linked compound DOTA-GSC(succinimidopropionyl-EAYGWNleDF-NH(2))-EAYGWNleDF-NH(2) (MGD5) was selected. The in vitro stability, receptor binding, and internalization of (111)In-MGD5 were studied and compared with those of monomer compound (111)In-APH070. In vivo biodistribution and imaging using a SPECT/CT camera were also performed.
Results:
More than 90% of the labeled divalent peptide remained intact after 20 h of incubation in plasma. The inhibitory concentration of 50% of the divalent peptide was 1.0 versus 5.6 nM for the monomer, and the dissociation constant was 0.7 versus 2.9 nM. The rate of internalization of the divalent peptide was twice that of the monomer. Tumor uptake of the divalent peptide in vivo was about 6 times that of the monomer. The rate of washout of the divalent peptide from the tumor was lower than that of the monomer.
Conclusion:
Dimerization of the CCK-2R binding site results in an increase in binding affinity and an increase in tumor uptake both in vitro and in vivo. It is likely that these increases would result in improved tumor-targeting efficiency in patients with CCK-2R-positive tumors.
Insights
Divalent gastrin peptides targeting gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) show enhanced binding and tumor uptake compared to monomeric versions. This suggests improved potential for peptide receptor radionuclide therapy (PRRT) in CCK-2R-positive cancers.
Area of Science:
- Oncology
- Radiopharmaceutical Chemistry
- Molecular Imaging
Background:
- Gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) are overexpressed in various cancers, making them a target for cancer therapy.
- Peptide receptor radionuclide therapy (PRRT) utilizes targeted peptides to deliver radionuclides for cancer treatment.
- Previous research synthesized divalent gastrin peptides to enhance CCK-2R binding and in vivo performance.
Purpose of the Study:
- To further investigate the most promising divalent gastrin peptide.
- To compare its performance against a previously developed monomeric peptide.
- To evaluate its potential for improved cancer targeting in PRRT.
Main Methods:
- Selected a maleimide-linked DOTA-conjugated divalent gastrin peptide (MGD5) from six (111)In-labeled compounds.
- Assessed in vitro stability, receptor binding (IC50, Kd), and cellular internalization of (111)In-MGD5 compared to a monomeric peptide ((111)In-APH070).
- Performed in vivo biodistribution and SPECT/CT imaging studies.
Main Results:
- The divalent peptide (MGD5) demonstrated high plasma stability (>90% intact after 20h).
- MGD5 exhibited significantly higher binding affinity (1.0 nM vs 5.6 nM IC50; 0.7 nM vs 2.9 nM Kd) and twice the internalization rate compared to the monomer.
- In vivo studies showed approximately 6-fold higher tumor uptake and slower washout for the divalent peptide.
Conclusions:
- Dimerization of the CCK-2R binding site enhances binding affinity and in vitro/in vivo tumor uptake.
- The divalent peptide MGD5 demonstrates superior tumor targeting efficiency compared to the monomer.
- These findings suggest improved therapeutic potential for CCK-2R-positive tumors using this divalent peptide in PRRT.
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