Multimerization Improves Targeting of Peptide Radio-Pharmaceuticals

Carlucci, Giuseppe; Ananias, H. J. K.; Yu, Zilin; Wiele, Christophe Van de; Dierckx, Rudi; Jong, Igle J. de; Elsinga, Philip H.

doi:10.2174/13816128112092501

Cited by 17 publications

(30 citation statements)

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“…This could increase the probability of receptor target interaction and therefore increase receptor avidity [ 10 , 11 ] as well as promoting the formation of metabolites able to rebind to the receptor. By this, increased apparent stability tumour uptake and therefore improved imaging contrast would be achieved as has been proposed by Carlucci and coworkers [ 12 ]. Sosabowski and coworkers were, to the best of our knowledge, the only group so far reporting on a divalent probe (MGD5) for nuclear imaging of CCK2R expression.…”

Section: Introductionmentioning

confidence: 75%

Exploiting the Concept of Multivalency with ⁶⁸Ga- and ⁸⁹Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Summer

Rangger

Klingler

et al. 2018

Contrast Media & Molecular Imaging

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Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (log⁡D, IC50, and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the 68Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with 89Zr-labelled counterparts showed a clearly enhanced imaging contrast of the trimeric probe compared to the mono- and dimer. Furthermore, in vivo stability studies showed a higher metabolic stability for multimeric probes compared to the monomeric bioconjugate. In summary, we could show that FSC can be utilized as suitable scaffold for novel mono- and multivalent imaging probes for CCK2R-related malignancies with partly improved targeting properties for multivalent conjugates. The increased tumour accumulation of the trimer 24 h postinjection (p.i.) can be explained by slower clearance and increased metabolic stability of multimeric conjugates.

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Section: Introductionmentioning

confidence: 75%

Exploiting the Concept of Multivalency with ⁶⁸Ga- and ⁸⁹Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Summer

Rangger

Klingler

et al. 2018

Contrast Media & Molecular Imaging

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“…The synthetic and radiosynthetic aspects of this approach along with the resulting in vivo PET data and ex vivo fluorescent data are reported. In terms of a bioconjugation strategy, we sought a facile and modular construction for generating a tracer that comprises a peptide-dimer for increased affinity, 25,26 a bright fluorophore of choice, and an 18 F-radioprosthesis. In terms of a radioprosthesis, we sought one that would afford an efficient late-stage labeling that would proceed in a single, aqueous step via a userfriendly method that obviates both drying of the [ 18 F]-fluoride ion prior to labeling and HPLC purification following.…”

Section: ■ Introductionmentioning

confidence: 99%

Dual Mode Fluorescent ¹⁸F-PET Tracers: Efficient Modular Synthesis of Rhodamine-[cRGD]₂-[¹⁸F]-Organotrifluoroborate, Rapid, and High Yielding One-Step ¹⁸F-Labeling at High Specific Activity, and Correlated in Vivo PET Imaging and ex Vivo Fluorescence

Liu

Radtke

Wong³

et al. 2014

Bioconjugate Chem.

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The design of dual mode fluorescent-PET peptidic tracers that can be labeled with [(18)F]fluoride at high specific activity and high yield has been challenged by the short half-life of (18)F and its aqueous indolence toward nucleophilic displacement, that often necessitates multistep reactions that start with punctiliously dry conditions. Here we present a modular approach to constructing a fluorescent dimeric peptide with a pendant radioprosthesis that is labeled in water with [(18)F]fluoride ion in a single, user-friendly step. The modular approach starts with grafting a new zwitterionic organotrifluoroborate radioprosthesis onto a pentaerythritol core with three pendent alkynes that enable successive grafting of a bright fluorophore (rhodamine) followed by two peptides (cylcoRGD). The construct is labeled with [(18)F]fluoride via isotope exchange within 20 min in a single step at high specific activity (>3 Ci/μmol) and in good yield to provide 275 mCi and high radiochemical purity. Neither drying of the [(18)F]fluoride ion solution nor HPLC purification of the labeled tracer is required. Facile chemical synthesis of this dual mode tracer along with a user-friendly one-step radiolabeling method affords very high specific activity. In vivo PET images of the dual mode tracer are acquired at both high and low specific activities. At very high specific activity, i.e., 3.5 Ci/μmol, tumor uptake is relatively high (5.5%ID/g), yet the associated mass is below the limits of fluorescent detection. At low specific activity, i.e., 0.01 Ci/μmol, tumor uptake in the PET image is reduced by approximately 50% (2.9%ID/g), but the greater associated mass enables fluorescence detection in the tumor. These data highlight a facile production of a dual mode fluorescent-PET tracer which is validated with in vivo and ex vivo images. These data also define critical limitations for the use of dual mode tracers in small animals.

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“…Cyclische Arginin‐Glycin‐Asparaginsäure‐Sequenzen (cRGDs) sind an der Zelladhäsion über α V β 3 ‐Integrinrezeptoren beteiligt und haben Anwendungen in den Bereichen Wirkstofftransport, Gentransport, Bildgebung und Krebstherapie gefunden. cRGD‐Peptide sind eingesetzt worden, um mehrästige synthetische Gerüste zu dekorieren, um so die Zelladhäsion und die Tumoraufnahme zu verbessern . Die Amidbindungskonjugation ist die am häufigsten eingesetzte Form der Verknüpfung von cyclischem RGD mit verschiedenartigen Dendrimerplattformen .…”

Section: Pdd‐synthesenunclassified

Mit Peptiden dekorierte Dendrimere und ihre biotechnologische Nutzung

Wan

Alewood

2016

Angewandte Chemie

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Peptid‐dekorierte Dendrimere (PDDs) bilden eine Klasse kugelförmiger, regulärer, verzweigter Polymere, die an ihren Oberflächen kovalent durch Peptide modifiziert sind. PDDs sind als Proteinmimetika, neuartige Biomaterialien sowie für ein breites Spektrum biomedizinischer Anwendungen zum Einsatz gekommen. Seit ihrer Konzeption und Entwicklung in den späten 1980er Jahren ist Poly‐l‐lysin die bevorzugte Kernstruktur für PDDs. Jüngst haben zahlreiche Innovationen in der Polymer‐ und Ligationschemie das Feld neu belebt. Dies hat dazu geführt, dass heute wohldefinierte Dendrimere mit vielfältigeren Strukturen und Funktionen vorliegen. Dieser Kurzaufsatz beleuchtet die Entwicklung von PDDs als Produkte einer signifikant verbesserten Ligationschemie unter Einbeziehung strukturell wohldefinierter Peptide sowie erste Anwendungen von PDDs in den Bereichen Bildgebung und Wirkstoffentwicklung.

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Multimerization Improves Targeting of Peptide Radio-Pharmaceuticals

Cited by 17 publications

References 0 publications

Exploiting the Concept of Multivalency with ⁶⁸Ga- and ⁸⁹Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Exploiting the Concept of Multivalency with ⁶⁸Ga- and ⁸⁹Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Dual Mode Fluorescent ¹⁸F-PET Tracers: Efficient Modular Synthesis of Rhodamine-[cRGD]₂-[¹⁸F]-Organotrifluoroborate, Rapid, and High Yielding One-Step ¹⁸F-Labeling at High Specific Activity, and Correlated in Vivo PET Imaging and ex Vivo Fluorescence

Mit Peptiden dekorierte Dendrimere und ihre biotechnologische Nutzung

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Multimerization Improves Targeting of Peptide Radio-Pharmaceuticals

Cited by 17 publications

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Exploiting the Concept of Multivalency with 68Ga- and 89Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Exploiting the Concept of Multivalency with 68Ga- and 89Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Dual Mode Fluorescent 18F-PET Tracers: Efficient Modular Synthesis of Rhodamine-[cRGD]2-[18F]-Organotrifluoroborate, Rapid, and High Yielding One-Step 18F-Labeling at High Specific Activity, and Correlated in Vivo PET Imaging and ex Vivo Fluorescence

Mit Peptiden dekorierte Dendrimere und ihre biotechnologische Nutzung

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Exploiting the Concept of Multivalency with ⁶⁸Ga- and ⁸⁹Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Exploiting the Concept of Multivalency with ⁶⁸Ga- and ⁸⁹Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Dual Mode Fluorescent ¹⁸F-PET Tracers: Efficient Modular Synthesis of Rhodamine-[cRGD]₂-[¹⁸F]-Organotrifluoroborate, Rapid, and High Yielding One-Step ¹⁸F-Labeling at High Specific Activity, and Correlated in Vivo PET Imaging and ex Vivo Fluorescence