Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy

Abstract

Over the past few years, an approach emerged that combines different receptor-specific peptide radioligands able to bind different target structures on tumor cells concomitantly or separately. The reason for the growing interest in this special field of radiopharmaceutical development is rooted in the fact that bispecific peptide heterodimers can exhibit a strongly increased target cell avidity and specificity compared to their corresponding monospecific counterparts by being able to bind to two different target structures that are overexpressed on the cell surface of several malignancies. This increase of avidity is most pronounced in the case of concomitant binding of both peptides to their respective targets but is also observed in cases of heterogeneously expressed receptors within a tumor entity. Furthermore, the application of a radiolabeled heterobivalent agent can solve the ubiquitous problem of limited tumor visualization sensitivity caused by differential receptor expression on different tumor lesions. In this article, the concept of heterobivalent targeting and the general advantages of using radiolabeled bispecific peptidic ligands for tumor imaging or therapy as well as the influence of molecular design and the receptors on the tumor cell surface are explained, and an overview is given of the radiolabeled heterobivalent peptides described thus far.

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

“…In addition to multimeric probes carrying multiple identical integrin ligands, heterodimeric probes combining integrin ligands with ligands directed to other target structures have been explored (e.g., reviewed in [ 395 ]). The rationale behind this strategy is to benefit from the increased affinity and tumor retention of peptide dimers and to tackle the heterogeneity of target expression in distinct tumor types by dual receptor targeting, enabling imaging tumors that express either or both targets [ 396 ]. A F-18 labeled construct targeting αvβ3 and NRP-1 via an RGD-ATWLPPR heterodimer showed higher uptake and tumor-to-background ratios in a glioblastoma model than the respective monomers [ 397 ].…”

“…These recent clinical evaluations showed a very good correlation between the PET signal and the expression of αvβ3 and the respective other target determined by immunohistochemistry on tumor cells. Additional heterodimeric/heterobivalent ligands at the preclinical evaluation stage, including PET and SPECT tracers targeting GRPR/αvβ3 or PSMA/αvβ3 [ 401 ], were recently reviewed [ 396 , 402 ].…”

Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?

“…Furthermore, peptides exhibit low toxicity and immunogenicity, are easily synthetically accessible and can be chemically modified at defined sites. Their pharmacokinetics prove to be very advantageous due to rapid tissue penetration, target accumulation and elimination from non-target tissues [9,10]. Therefore, numerous radiolabeled peptides have been developed for both the diagnosis and therapy of malignancies over the last decades [11,12].…”

“…The prerequisite for an HBPL with high tumor visualization potential is at least a moderate binding affinity of each of the included peptides to their target receptors. Ideally, both receptor types should be present in high density to achieve a concomitant binding of both peptide binders of the HBPL; however, the presence of only one target receptor is sufficient to achieve a high tumor uptake [9,[15][16][17], resulting in an overall improved imaging sensitivity.…”

“…This results in an insufficient sensitivity of the peptides' tumor delineation (Figure 1A). In contrast, HBPLs have the advantage of binding to more than one receptor type and thus exhibit a high tumor visualization efficiency (Figure 1B) [9,20]. Schematic depiction of the concept of HBPL application exemplified by a comparison of a radiolabeled monospecific (A) or heterobivalent peptidic ligand (B) binding to tumor entities overexpressing different receptor types.…”