Bifunctional HPPH-N2S2-99mTc conjugates as tumor imaging agents: synthesis and biodistribution studies

2003 ◽  
Vol 07 (07) ◽  
pp. 500-507 ◽  
Author(s):  
Bing Ma ◽  
Guolin Li ◽  
Peter Kanter ◽  
Dominick Lamonica ◽  
Zachary Grossman ◽  
...  
Keyword(s):  
Half Life ◽  
Tumor Imaging ◽  
Post Injection ◽  
Tumor Uptake ◽  
In Vivo Biodistribution ◽  
Structure Activity ◽  
Biodistribution Studies ◽  
Activity Screening ◽  
Pyropheophorbide A

Pyropheophorbide-a and the corresponding 3-(1'-hexyloxyethyl)-3-devinyl derivative ( HPPH ), the tumor-avid photosensitizers were conjugated with mono- or di-bisaminoethanethiols ( N 2 S 2 ligand). The in vivo biodistribution study of the related 99m Tc complexes was performed in F-344 rats bearing Ward colon tumors at 4 h and 24 h post injection. These data show that the complexes are stable and among four tracers, HPPH di-99 m Tc N 2 S 2 conjugate reaches the highest tumor uptake (%ID/g). The larger tumors reach higher concentrations of the tracer. However, the short 6 h half life of 99 m Tc is incompatible with the 24 h imaging time, suggesting that the use of a longer-lived isotope such as 111 In could still provide a useful scanning agent, or that further structure-activity screening could yield an HPPH analog with more appropriate pharmacokinetics for tumor imaging with 99 m Tc .

scholarly journals CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer

2019 ◽  
Author(s):  
Sarah Erdmann ◽  
Lars Niederstadt ◽  
Eva Jolanthe Koziolek ◽  
Juan Daniel Castillo Gómez ◽  
Sonal Prasad ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mr Imaging ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Organ Distribution ◽  
Post Injection ◽  
Tumor Uptake ◽  
Biodistribution Studies ◽  
Targeting Peptide

AbstractMolecular targeting remains to be a promising approach in cancer medicine. Knowledge about molecular properties such as overexpression of G protein-coupled receptors (GPCRs) is thereby offering a powerful tool for tumor-selective imaging and treatment of cancer cells. We utilized chemerin-based peptides for CMKLR1 receptor targeting in a breast cancer xenograft model. By conjugation with radiolabeled chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of highly specific and affine tracers for hybridin vivoimaging with positron emission tomography (PET)/ magnetic resonance (MR) and concomitant biodistribution studies.MethodsWe developed five highly specific and affine peptide tracers targeting CMKLR1 by linker-based conjugation of chemerin peptide analogs (CG34 and CG36) with radiolabeled (68Ga) chelator DOTA. Our established xenograft model with target-positive DU4475 and negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imagingin vivo. Therefore, we acquired small animal PET/MR images, assessed biodistribution byex vivomeasurements and investigated the tracer specificity by blocking experiments.ResultsThe family of five CMKLR1-targeting peptide tracers demonstrated high biological activity and affinityin vitrowith EC50and IC50values being below 2 nM. Our target-positive (DU4475) and target-negative (A549) xenograft model could be confirmed byex vivoanalysis of CMKLR1 expression and binding. After preliminary PET imaging, the three most promising tracers68Ga-DOTA-AHX-CG34,68Ga-DOTA-KCap-CG34 and68Ga-DOTA-ADX-CG34 with apparent DU4475 tumor uptake were further analyzed. Hybrid PET/MR imaging along with concomitant biodistribution studies revealed distinct CMKLR1-specific uptake (5.1% IA/g, 4.5% IA/g and 6.2% IA/g 1 h post-injection) of our targeted tracers in DU4475 tumor tissue. More strikingly, the tumor uptake could be blocked by excess of unlabeled peptide (6.4-fold, 7.2-fold and 3.4-fold 1 h post-injection) and further confirmed the CMKLR1 specificity. As our five tracers, each with particular degree of hydrophobicity, showed different results regarding tumor uptake and organ distribution, we identified these three tracers with moderate, balanced properties to be the most potent in receptor-mediated tumor targeting.ConclusionWith the breast cancer cell line DU4475, we established a model endogenously expressing our target CMKLR1 to evaluate our chemerin-based peptide tracers as highly affine and specific targeting agents. Eventually, we demonstrated the applicability of our68Ga-labeled tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR imaging and thus developed promising theranostics for tumor treatment.

In vitro binding and in vivo biodistribution studies of the neuroprotective peptide humanin using [125I]humanin derivatives

Peptides ◽  
2009 ◽  
Vol 30 (12) ◽  
pp. 2409-2417 ◽  
Author(s):  
Alexandra Evangelou ◽  
Christos Zikos ◽  
Dimitra Benaki ◽  
Maria Pelecanou ◽  
Penelope Bouziotis ◽  
...  
Keyword(s):  
In Vitro Binding ◽  
In Vivo Biodistribution ◽  
Biodistribution Studies ◽  
Vitro Binding

scholarly journals Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 164 ◽  
Author(s):  
Mohamed Altai ◽  
Charles Leitao ◽  
Sara Rinne ◽  
Anzhelika Vorobyeva ◽  
Christina Atterby ◽  
...  
Keyword(s):  
Half Life ◽  
Molecular Design ◽  
Growth Factor Receptor ◽  
Fusion Construct ◽  
Affibody Molecules ◽  
Binding Domains ◽  
Biodistribution Studies ◽  
C Terminus ◽  
Type 3

Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.

scholarly journals Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 528
Author(s):  
Panagiotis Kanellopoulos ◽  
Aikaterini Kaloudi ◽  
Marion de Jong ◽  
Eric P. Krenning ◽  
Berthold A. Nock ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Ace Inhibitor ◽  
Tumor Imaging ◽  
Colon Adenocarcinoma ◽  
Ace Inhibition ◽  
Tumor Uptake ◽  
Protease Inhibition ◽  
Structural Modifications

Neurotensin subtype 1 receptors (NTS1R) represent attractive molecular targets for directing radiolabeled neurotensin (NT) analogs to tumor lesions for diagnostic and therapeutic purposes. This approach has been largely undermined by the rapid in vivo degradation of linear NT-based radioligands. Herein, we aim to increase the tumor targeting of three 99mTc-labeled NT analogs by the in-situ inhibition of two key proteases involved in their catabolism. DT1 ([N4-Gly7]NT(7-13)), DT5 ([N4-βAla7,Dab9]NT(7-13)), and DT6 ([N4-βAla7,Dab9,Tle12]]NT(7-13)) were labeled with 99mTc. Their profiles were investigated in NTS1R-positive colon adenocarcinoma WiDr cells and mice treated or not with the neprilysin (NEP)-inhibitor phosphoramidon (PA) and/or the angiotensin converting enzyme (ACE)-inhibitor lisinopril (Lis). Structural modifications led to the partial stabilization of 99mTc-DT6 in peripheral mice blood (55.1 ± 3.9% intact), whereas 99mTc-DT1 and 99mTc-DT5 were totally degraded within 5 min. Coinjection of PA and/or Lis significantly stabilized all three analogs, leading to a remarkable enhancement of tumor uptake for 99mTc-DT1 and 99mTc-DT5, but was less effective in the case of poorly internalizing 99mTc-DT6. In conclusion, NEP and/or ACE inhibition represents a powerful tool to improve tumor targeting and the overall pharmacokinetics of NT-based radioligands, and warrants further validation in the field of NTS1R-targeted tumor imaging and therapy.

scholarly journals Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor bearing Balb/C mice

Nukleonika ◽  
2015 ◽  
Vol 60 (3) ◽  
pp. 497-502 ◽  
Author(s):  
Javad Razjouyan ◽  
Hamidreza Zolata ◽  
Omid Khayat ◽  
Fereidoun Nowshiravan ◽  
Nami Shadanpour ◽  
...  
Keyword(s):  
Folic Acid ◽  
Folate Receptor ◽  
Superparamagnetic Iron Oxide ◽  
Fibroblast Cell ◽  
Mouse Fibroblast ◽  
Tumor Uptake ◽  
Mri Imaging ◽  
Tumor Bearing ◽  
Biodistribution Studies

Abstract To design a potent agent for positron emission tomography/magnetic resonance imaging (PET/MRI) imaging and targeted magnetic hyperthermia-radioisotope cancer therapy radiolabeled surface modified superparamagnetic iron oxide nanoparticles (SPIONs) were used as nanocarriers. Folic acid was conjugated for increasing selective cellular binding and internalization through receptor-mediated endocytosis. SPIONs were synthesized by the thermal decomposition of tris (acetylacetonato) iron (III) to achieve narrow and uniform nanoparticles. To increase the biocompatibility of SPIONs, they were coated with (3-aminopropyl) triethoxysilane (APTES), and then conjugated with synthesized folic acid-polyethylene glycol (FA-PEG) through amine group of (3-aminopropyl) triethoxysilane. Finally, the particles were labeled with 64Cu (t1/2 = 12.7 h) using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxy succinimide ester) DOTA-NHS chelator. After the characterization of SPIONs, their cellular internalization was evaluated in folate receptor (FR) overexpressing KB (established from a HeLa cell contamination) and mouse fibroblast cell (MFB) lines. Eventually, active and passive targeting effects of complex were assessed in KB tumor-bearing Balb/C mice through biodistribution studies. Synthesized bare SPIONs had low toxicity effect on healthy cells, but surface modification increased their biocompatibility. Moreover, KB cells viability was reduced when using folate conjugated SPIONs due to FR-mediated endocytosis, while having little effect on healthy cells (MFB). Moreover, this radiotracer had tolerable in vivo characteristics and tumor uptake. In the receptor blocked case, tumor uptake was decreased, indicating FR-specific uptake in tumor tissue while enhanced permeability and retention effect was major mechanism for tumor uptake.

scholarly journals In vivo biodistribution studies and ex vivo lymph node imaging using heavy metal-free quantum dots

Biomaterials ◽  
2016 ◽  
Vol 104 ◽  
pp. 182-191 ◽  
Author(s):  
Elnaz Yaghini ◽  
Helen D. Turner ◽  
Alix M. Le Marois ◽  
Klaus Suhling ◽  
Imad Naasani ◽  
...  
Keyword(s):  
Heavy Metal ◽  
Quantum Dots ◽  
Lymph Node ◽  
Ex Vivo ◽  
Metal Free ◽  
Lymph Node Imaging ◽  
In Vivo Biodistribution ◽  
Biodistribution Studies

scholarly journals 124I-Radiolabeling of a Au(III)-NHC Complex for in Vivo Biodistribution Studies

2020 ◽  
Author(s):  
Federica Guarra ◽  
Alessio Terenzi ◽  
Christine Pirker ◽  
Rossana Passannante ◽  
Dina Baier ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Direct Evidence ◽  
Heterocyclic Carbenes ◽  
Emission Tomography ◽  
Direct Oxidation ◽  
In Vivo Biodistribution ◽  
Biodistribution Studies ◽  
Positron Emission

Au(III) complexes with N-Heterocyclic Carbenes (NHCs) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Herein we report on the synthesis of new Au(III)-NHC complexes via direct oxidation with radioactive [124I]I2 as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET) and, in combination with in vitro analyses, to provide direct evidence of the importance of Au(III)-to-Au(I) reduction for achieving full anticancer activity.

scholarly journals 124 I Radiolabeling of a Au III ‐NHC Complex for In Vivo Biodistribution Studies

2020 ◽  
Vol 59 (39) ◽  
pp. 17130-17136 ◽  
Author(s):  
Federica Guarra ◽  
Alessio Terenzi ◽  
Christine Pirker ◽  
Rossana Passannante ◽  
Dina Baier ◽  
...  
Keyword(s):  
In Vivo Biodistribution ◽  
Biodistribution Studies

Characterization of 89Zr-trastuzumab for clinical HER2 immunoPET imaging

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3508-3508 ◽  
Author(s):  
E. Dijkers ◽  
M. N. Lub-de Hooge ◽  
J. G. Kosterink ◽  
P. L. Jager ◽  
A. H. Brouwers ◽  
...  
Keyword(s):  
Negative Control ◽  
Tracer Uptake ◽  
Post Injection ◽  
Clinical Use ◽  
Breast Cancers ◽  
Tumor Uptake ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Liver Uptake

3508 Background: SPECT imaging with 111In-DTPA-trastuzumab has recently identified new tumor lesions, undetected with conventional staging, in 13/15 patients with HER2++ breast cancers (Perik et al., J Clin Oncol 2006). The aim of this study was to develop an immunoPET label, suitable for clinical use, which would allow excellent detection of HER2 positive tumor lesions and quantification of HER2 expression levels in vivo. Methods: Trastuzumab has essentially been radiolabeled as described by Verel et al. (J Nucl Med 2003). Radiochemical purity (rcp) and stability were determined by SEC-HPLC, immunoreactivity with a Lindmo assay. Biodistribution was performed in nude mice bearing HER2 positive (SKOV3) or HER2 negative (GLC4) xenografts. Five animals per group were co-injected with 111In-ITC-DTPA-trastuzumab and 89Zr-trastuzumab, imaged on a microPET (Focus 220) and sacrificed 144 hours post injection. Results: The immunoreactive fraction of 89Zr-trastuzumab was 0.96, labeling efficiency > 90% and rcp > 95%. 89Zr-trastuzumab was stable for 7 days in buffer at 4 °C and in human serum at 37 °C. MicroPET imaging showed excellent tumor uptake and could easily detect metastases with a size approximating the spatial resolution of the microPET scanner. 89Zr- and 111In-ITC-DTPA-trastuzumab showed similar biodistribution. Highest uptake was found in HER2 positive tumors at 144 hours post injection (40% ID/g tissue for 89Zr-trastuzumab and 47% ID/g for 111In-ITC-DTPA-trastuzumab) compared to 8% ID/g tissue in HER2 negative control tumors. Liver uptake was low (8–12% ID/g tissue). Preliminary results in HER2 positive breast cancer patients show excellent tumor tracer uptake and a resolution unapproachable by 111In-DTPA-trastuzumab. Conclusions: 89Zr-trastuzumab is stable, shows excellent and specific tumor uptake and is suitable for clinical use. Minimal aspecific tracer uptake in the liver allows detection of abdominal metastases. No significant financial relationships to disclose.

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