Angiogenesis has a pivotal role in tumor growth and the metastatic process. Molecular imaging was shown to be useful for imaging of tumor-induced angiogenesis. A great variety of radiolabeled peptides have been developed to target αvβ3 integrin, a target structure involved in the tumor-induced angiogenic process. The presented study aimed to synthesize deferoxamine (DFO)-based c(RGD) peptide conjugate for radiolabeling with gallium-68 and perform its basic preclinical characterization including testing of its tumor-imaging potential. DFO-c(RGDyK) was labeled with gallium-68 with high radiochemical purity. In vitro characterization including stability, partition coefficient, protein binding determination, tumor cell uptake assays, and ex vivo biodistribution as well as PET/CT imaging was performed. [68Ga]Ga-DFO-c(RGDyK) showed hydrophilic properties, high stability in PBS and human serum, and specific uptake in U-87 MG and M21 tumor cell lines in vitro and in vivo. We have shown here that [68Ga]Ga-DFO-c(RGDyK) can be used for αvβ3 integrin targeting, allowing imaging of tumor-induced angiogenesis by positron emission tomography.

• Klíčová slova
• PET imaging, RGD peptides, deferoxamine, integrins, radiodiagnostics,
• MeSH
• deferoxamin analogy a deriváty   chemická syntéza   chemie   MeSH
• glioblastom diagnostické zobrazování   MeSH
• integrin alfaVbeta3 metabolismus   MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• patologická angiogeneze diagnostické zobrazování   MeSH
• počítačová rentgenová tomografie metody   MeSH
• pozitronová emisní tomografie metody   MeSH
• radioizotopy galia chemie   MeSH
• tkáňová distribuce MeSH
• transplantace heterologní MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• deferoxamin MeSH
• Gallium-68 MeSH Prohlížeč
• integrin alfaVbeta3 MeSH
• radioizotopy galia MeSH

Aspergillus fumigatus (A. fumigatus) is a human pathogen causing severe invasive fungal infections, lacking sensitive and selective diagnostic tools. A. fumigatus secretes the siderophore desferri-triacetylfusarinine C (TAFC) to acquire iron from the human host. TAFC can be labelled with gallium-68 to perform positron emission tomography (PET/CT) scans. Here, we aimed to chemically modify TAFC with fluorescent dyes to combine PET/CT with optical imaging for hybrid imaging applications. Starting from ferric diacetylfusarinine C ([Fe]DAFC), different fluorescent dyes were conjugated (Cy5, SulfoCy5, SulfoCy7, IRDye 800CW, ATTO700) and labelled with gallium-68 for in vitro and in vivo characterisation. Uptake assays, growth assays and live-cell imaging as well as biodistribution, PET/CT and ex vivo optical imaging in an infection model was performed. Novel fluorophore conjugates were recognized by the fungal TAFC transporter MirB and could be utilized as iron source. Fluorescence microscopy showed partial accumulation into hyphae. µPET/CT scans of an invasive pulmonary aspergillosis (IPA) rat model revealed diverse biodistribution patterns for each fluorophore. [68Ga]Ga-DAFC-Cy5/SufloCy7 and -IRDye 800CW lead to a visualization of the infected region of the lung. Optical imaging of ex vivo lungs corresponded to PET images with high contrast of infection versus non-infected areas. Although fluorophores had a decisive influence on targeting and pharmacokinetics, these siderophores have potential as a hybrid imaging compounds combining PET/CT with optical imaging applications.

• Klíčová slova
• PET, fluorescence microscopy, gallium-68, invasive pulmonary aspergillosis, near infrared, siderophores,
• MeSH
• Aspergillus fumigatus MeSH
• fluorescenční barviva MeSH
• fluorescenční mikroskopie MeSH
• invazivní plicní aspergilóza diagnostické zobrazování   mikrobiologie   MeSH
• kompetitivní vazba MeSH
• koncentrace vodíkových iontů MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• PET/CT MeSH
• potkani inbrední LEW MeSH
• radioizotopy galia chemie   MeSH
• siderofory metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluorescenční barviva MeSH
• Gallium-68 MeSH Prohlížeč
• radioizotopy galia MeSH
• siderofory MeSH

Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting.

• MeSH
• chelátory chemie   farmakokinetika   MeSH
• heterografty MeSH
• integrin alfaVbeta3 metabolismus   MeSH
• kyseliny hydroxamové farmakokinetika   MeSH
• lidé MeSH
• molekulární sondy chemie   farmakokinetika   MeSH
• multimodální zobrazování metody   MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory diagnostické zobrazování   metabolismus   MeSH
• PET/CT MeSH
• radioizotopy galia farmakokinetika   MeSH
• receptor cholecystokininu B metabolismus   MeSH
• železité sloučeniny farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• fusigen MeSH Prohlížeč
• integrin alfaVbeta3 MeSH
• kyseliny hydroxamové MeSH
• molekulární sondy MeSH
• radioizotopy galia MeSH
• receptor cholecystokininu B MeSH
• železité sloučeniny MeSH