Design, synthesis and in vitro evaluation of heterobivalent peptidic radioligands targeting both GRP- and VPAC1-Receptors concomitantly overexpressed on various malignancies – Is the concept feasible?

Lindner, Simon; Fiedler, Luise; Wängler, Björn; Bartenstein, Peter; Schirrmacher, Ralf; Wängler, Carmen

doi:10.1016/j.ejmech.2018.05.047

Cited by 15 publications

(13 citation statements)

References 29 publications

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“…The branched bis -amines 7 − 11 and bis -aldehydes 12 − 16 ( Scheme 1 ) were synthesized following a published procedure [ 22 ] with minor modifications (see Supplementary Materials for detailed description). In the following, these NODA-GA-modified branched bis -aldehyde scaffolds 12 − 16 were efficiently reacted with aminooxy-PESIN ( 1 ) and aminooxy-PESIN scrambled ( 5 ) to the monovalent intermediates 17 − 21 and 19a .…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis, In Vitro, and Initial In Vivo Evaluation of Heterobivalent Peptidic Ligands Targeting Both NPY(Y1)- and GRP-Receptors—An Improvement for Breast Cancer Imaging?

et al. 2018

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Heterobivalent peptidic ligands (HBPLs), designed to address two different receptors independently, are highly promising tumor imaging agents. For example, breast cancer has been shown to concomitantly and complementarily overexpress the neuropeptide Y receptor subtype 1 (NPY(Y1)R) as well as the gastrin-releasing peptide receptor (GRPR). Thus, radiolabeled HBPLs being able to bind these two receptors should exhibit an improved tumor targeting efficiency compared to monospecific ligands. We developed here such bispecific HBPLs and radiolabeled them with 68Ga, achieving high radiochemical yields, purities, and molar activities. We evaluated the HBPLs and their monospecific reference peptides in vitro regarding stability and uptake into different breast cancer cell lines and found that the 68Ga-HBPLs were efficiently taken up via the GRPR. We also performed in vivo PET/CT imaging and ex vivo biodistribution studies in T-47D tumor-bearing mice for the most promising 68Ga-HBPL and compared the results to those obtained for its scrambled analogs. The tumors could easily be visualized by the newly developed 68Ga-HBPL and considerably higher tumor uptakes and tumor-to-background ratios were obtained compared to the scrambled analogs in and ex vivo. These results demonstrate the general feasibility of the approach to use bispecific radioligands for in vivo imaging of breast cancer.

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Section: Resultsmentioning

confidence: 99%

“…Bis -amines 7 – 11 and bis -aldehydes 12 – 16 were synthesized according to published procedures [ 22 ] with minor modifications of the synthesis protocols. Details of these syntheses can be found in the supplementary information .…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, In Vitro, and Initial In Vivo Evaluation of Heterobivalent Peptidic Ligands Targeting Both NPY(Y1)- and GRP-Receptors—An Improvement for Breast Cancer Imaging?

et al. 2018

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“…On the other hand, highly rigid linkers could limit the motility of the molecule, impeding the first peptide to bind although the second binder might be forced to stay near the cell surface, increasing its binding probability. However, an effect of linker rigidity on the peptide-receptor interaction of peptide homo-or heterodimers-although having been investigated in some studies-could not be shown thus far [59,62,66,68].…”

Section: Influence Of Molecular Design On Target Interactionmentioning

confidence: 97%

“…On the other hand, very long linkers increase the entropy of the system and decrease the local concentration of the second binder in terms of monovalent binding and thus the forced proximity effect, resulting in a decreased avidity of the whole heterodimer, limiting its tumor accumulation. This important effect related to the linker length between peptide binders was shown for several peptide homo-and heterodimers and resulted in drastic differences in tumor cell uptakes and binding avidities of the studied radioligands [30,31,59,61,63,66]. Unfortunately, an appropriate linker length can only be determined experimentally and depends on the tumor model used as the distance between receptors varies with receptor density and thus tumor type.…”

Section: Influence Of Molecular Design On Target Interactionmentioning

confidence: 99%

“…An alternative attempt was made recently, aiming at the bispecific targeting of the GRPR and the VPAC 1 R [66]. The reason for this is that the latter is overexpressed by virtually all PCa primaries and metastases [125,126] and furthermore plays an important role in upregulation of EGFR (epidermal growth factor receptor) and VEGF (vascular endothelial growth factor) [127,128].…”

Section: Further Heterobivalent Agents For Pca Imaging or Therapymentioning

confidence: 99%

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

et al. 2020

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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.

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Functional Hybrid Molecules for the Visualization of Cancer: PESIN‐Homodimers Combined with Multimodal Molecular Imaging Probes for Positron Emission Tomography and Optical Imaging: Suited for Tracking of GRPR‐Positive Malignant Tissue**

Hübner

Cheng

Wängler

et al. 2020

Chemistry A European J

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We describe multimodali maging probesf or gastrin-releasingp eptide receptor (GRPR)-specifict argeting suited for positrone mission tomographya nd opticali maging (PET/OI), consistingo fP ESIN (PEG 3-BBN 7-14)d imers connected to multimodali magingsubunits.T hese multimodal agents comprise af luorescentd ye for OI and the chelator ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutarica cid) (NODA-GA) for PET radiometali sotope labelling. Special focus was puto nt he influenceo ft he used dyes on the properties of the whole bioconjugates. For this, several compoundsw ith different fluorescent dyes and non-dye carrying subunits were synthesized and investigated.A sf luorescent dyes, dansyl, NBD, derivatives of fluorescein,c oumarin and rhodamine as well as three pyrilium-based dyes were employed. Considerable influence of the chargeo ft he colored unit on hydrophilicity as well as in vitro target receptor binding was observed and classified. High radiochemical yields and purities were found during radiolabeling of the multimodali maging subunits as well as their GRPR-specific bioconjugates with 68 Ga. Examinationso ft he photophysical properties of both molecule species displayedn ol oss or alteration of fluorescence characteristics.

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Design, synthesis and in vitro evaluation of heterobivalent peptidic radioligands targeting both GRP- and VPAC1-Receptors concomitantly overexpressed on various malignancies – Is the concept feasible?

Cited by 15 publications

References 29 publications

Design, Synthesis, In Vitro, and Initial In Vivo Evaluation of Heterobivalent Peptidic Ligands Targeting Both NPY(Y1)- and GRP-Receptors—An Improvement for Breast Cancer Imaging?

Design, Synthesis, In Vitro, and Initial In Vivo Evaluation of Heterobivalent Peptidic Ligands Targeting Both NPY(Y1)- and GRP-Receptors—An Improvement for Breast Cancer Imaging?

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

Functional Hybrid Molecules for the Visualization of Cancer: PESIN‐Homodimers Combined with Multimodal Molecular Imaging Probes for Positron Emission Tomography and Optical Imaging: Suited for Tracking of GRPR‐Positive Malignant Tissue**

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