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Evaluation of cleavable (Tyr3)-octreotate derivatives for longer intracellular probe residence
Paul A Whetstone1, Hiromichi Akizawa, Claude F Meares
1Department of Chemistry, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Abstract:
Radioligand targeting of somatostatin receptor subtype 2 (sstr2)-positive tumors with synthetic somatostatin analogues such as octreotide is subject to improvement in tumor to nontumor biodistribution, in part because internalization of such somatostatin analogues is limited by sstr2 recycling to the cell surface. We reasoned that it might be possible to prepare probe-carrying somatostatin analogues that would escape recycling, efficiently depositing probe molecules inside cells and ultimately increasing their intracellular concentration. We have incorporated cathepsin-B-cleavable linkers into (Tyr3)-octreotate chelate conjugates and examined these constructs as to cellular uptake, externalization, subcellular localization, and cleavage in the rat pancreatic tumor cell line AR42J in culture. Comparison of the cleavable radioligands with a noncleavable control indicates that scission of the constituent cathepsin B substrate occurs at a rate faster than ligand externalization, depositing virtually all internalized cleaved radiochelates within lysosomal compartments.
Insights
New radioligands targeting somatostatin receptor subtype 2 (sstr2) tumors show improved delivery. By using cathepsin-B-cleavable linkers, these probes avoid receptor recycling, concentrating imaging agents within tumor cells.
Area of Science:
- Biomedical imaging
- Radiopharmaceutical chemistry
- Molecular imaging
Background:
- Somatostatin receptor subtype 2 (sstr2) targeted radioligands like octreotide face challenges in tumor biodistribution due to sstr2 recycling.
- Limited internalization of current somatostatin analogues hinders optimal tumor imaging and therapy.
Purpose of the Study:
- To develop novel somatostatin analogues that evade sstr2 recycling for enhanced intracellular probe deposition.
- To investigate the efficacy of cathepsin-B-cleavable linkers in radioligand design for improved tumor targeting.
Main Methods:
- Synthesis of (Tyr3)-octreotate chelate conjugates incorporating cathepsin-B-cleavable linkers.
- Evaluation of cellular uptake, externalization, subcellular localization, and linker cleavage in AR42J rat pancreatic tumor cells.
- Comparison of cleavable radioligands with a noncleavable control.
Main Results:
- Cathepsin-B-mediated cleavage of the linker occurred rapidly, faster than ligand externalization.
- Internalized cleaved radiochelates were predominantly localized within lysosomal compartments.
- This strategy effectively increased intracellular probe concentration by preventing receptor recycling.
Conclusions:
- Incorporating cathepsin-B-cleavable linkers into somatostatin analogues offers a promising strategy to overcome sstr2 recycling.
- This approach enhances radioligand internalization and intracellular accumulation, potentially improving tumor imaging and therapy.
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