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Toward the Optimization of Bombesin-Based Radiotracers for Tumor Targeting
Ibai E Valverde1, Sandra Vomstein1, Thomas L Mindt1,2
1Division of Radiopharmaceutical Chemistry, University of Basel Hospital , Petersgraben 4, 4031 Basel, Switzerland.
Abstract:
The peptide bombesin (BBN) is a peptide with high affinity for the gastrin-releasing peptide receptor (GRPr), a receptor that is overexpressed by, for example, breast and prostate cancers. Thus, GRPr agonists can be used as cancer-targeting vectors to shuttle diagnostic and therapeutic agents into tumor cells. With the aim of optimizing the tumor targeting properties of a radiolabeled [Nle(14)]BBN(7-14) moiety, novel BBN(7-14)- and BBN(6-14)-based radioconjugates were synthesized, labeled with Lu-177, and fully evaluated in vitro and in vivo. The effect of residue and backbone modification on several parameters such as the internalization of the radiolabeled peptides into PC3 and AR42J tumor cells, their affinity toward the human GRPr, metabolic stability in blood plasma, and biodistribution in mice bearing GRPr-expressing PC3 xenografts was studied. As a result of our investigations, a novel radiolabeled GRPr agonist with a high tumor uptake and a high tumor-to-kidney ratio was identified.
Insights
Novel bombesin (BBN) analogs targeting gastrin-releasing peptide receptors (GRPr) were developed for cancer therapy. A new radiolabeled GRPr agonist showed high tumor uptake and improved tumor-to-kidney ratio in preclinical models.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Oncology
Background:
- The peptide bombesin (BBN) binds to the gastrin-releasing peptide receptor (GRPr).
- GRPr is overexpressed in cancers like breast and prostate, making it a target for cancer therapy.
- GRPr agonists can serve as vectors for delivering diagnostic and therapeutic agents to tumors.
Purpose of the Study:
- To optimize tumor targeting of radiolabeled BBN analogs.
- To synthesize and evaluate novel BBN(7-14)- and BBN(6-14)-based radioconjugates.
- To investigate the impact of modifications on radioconjugate properties for improved cancer targeting.
Main Methods:
- Synthesis of novel BBN(7-14)- and BBN(6-14)-based radioconjugates.
- Radiolabeling with Lutetium-177 (Lu-177).
- In vitro and in vivo evaluation, including cell internalization, receptor affinity, metabolic stability, and biodistribution studies in PC3 xenografts.
Main Results:
- Several novel radiolabeled GRPr agonists were synthesized and characterized.
- Modifications influenced internalization, affinity, stability, and biodistribution.
- A novel radiolabeled GRPr agonist demonstrated high tumor uptake and a favorable tumor-to-kidney ratio.
Conclusions:
- Optimized BBN analogs can effectively target GRPr-expressing tumors.
- The identified radioconjugate shows promise as a theranostic agent for GRPr-positive cancers.
- Further development of these targeted radiopharmaceuticals is warranted for clinical application.
