scholarly journals A Novel Radioimmune 99mTc-Labeled Tracer for Imaging Sphingosine 1-Phosphate Receptor 1 in Tumor Xenografts: An In Vitro and In Vivo Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Ye ◽  
Yongkang Gai ◽  
Hao Ji ◽  
Yaqun Jiang ◽  
Pengxin Qiao ◽  
...  
Keyword(s):  
Biological Activities ◽  
Photon Emission ◽  
Cell Uptake ◽  
Emission Computed Tomography ◽  
Tumor Bearing ◽  
Study Results ◽  
Sphingosine 1 Phosphate ◽  
Mcf 7

Sphingosine-1-phosphate (S1P) is a phospholipid that regulates pleiotropic biological activities and exerts extracellular functions by binding to five specific G-protein-coupled receptors, S1P receptors (S1PR) 1–5. When activated by S1P, S1PR promote the proliferation and invasion of tumor cells by inducing the formation of new blood vessels. We developed and assessed a new monoclonal antibody imaging probe 99mTc-HYNIC-S1PR1mAb, to explore the feasibility of targeting the S1PR1 in vitro and in vivo. S1PR1mAb was prepared and followed by technetium-99m labeling with succinimidyl 6-hydraziniumnicotinate hydrochloride. Cell uptake and blocking studies were performed to investigate the binding specificity of 99mTc-HYNIC-S1PR1mAb in vitro. 99mTc-HYNIC-S1P1mAb was also tested in vivo in mice xenografted with SK-HEP-1 (high-expression of S1PR1) and MCF-7 (low-expression of S1PR1) using single-photon emission-computed tomography (SPECT). Ex vivo gamma counting of tissues from tumor-bearing mice was used to evaluate 99mTc-HYNIC-S1PR1mAb biodistribution. The biodistribution study results showed significantly higher uptake in SK-HEP-1 tumors than in MCF-7 tumors (P < 0.001). Reduced uptake of 99mTc-HYNIC-S1PR1mAb in SK-HEP-1 was observed in tumor-bearing nude mice pretreated with fingolimod, which binds competitively to the receptors, especially S1PR1. 99mTc-HYNIC-S1PR1mAb can be synthesized and specifically targeted to S1PR1 in vitro and in vivo, allowing S1PR1 expression assessment with SPECT imaging.

scholarly journals Application and Evaluation of [99mTc]-Labeled Peptide Nucleic Acid Targeting MicroRNA-155 in Breast Cancer Imaging

2020 ◽  
Vol 19 ◽  
pp. 153601212091612
Author(s):  
Yaqun Jiang ◽  
Yongkang Gai ◽  
Yu Long ◽  
Qingyao Liu ◽  
Chunbao Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nucleic Acid ◽  
Peptide Nucleic Acid ◽  
Single Photon ◽  
Specific Binding ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Study Results ◽  
Mcf 7

It has been reported that dysregulation of microRNA-155 expression and function is associated with tumorigenesis, growth, tumor subtypes, invasion, and poor survival rates. Peptide nucleic acid (PNA), an artificially synthesized nucleic acid mimic, has been applied for molecular diagnosis. In this study, a PNA sequence that undergoes complementary binding to miR-155 was labeled with 99mTc to evaluate whether the tracer could visualize the expression of miR-155 in breast cancer. Both antisense PNA (anti-PNA, fully complementary bound to human mature miR-155, referred to as “anti-PNA-155”) and mismatched PNA (referred to as “mis-PNA”) single strands containing 23-mer were synthesized. The relative expression of miR-155 in MCF-7 cells and tumors was higher than that in MDA-MB-231 cells and tumors. Single-photon emission computed tomography (SPECT) scan showed that radioactivity mainly accumulated in kidney. MCF-7 tumors, but not MDA-MB-231 tumors, were clearly visualized after [99mTc]anti-PNA-155 injection. MCF-7 tumors were less visible when coinjected with 100-fold excess of anti-PNA-155 or injected with [99mTc]mis-PNA, which suggested specific binding. Biodistribution study results were consistent with SPECT imaging. We successfully demonstrated that [99mTc]anti-PNA-155 could visualize miR-155 expression in vivo, suggesting it may be a promising probe applied in breast cancer.

Correlation between in vitro and in vivo Data of Radiolabeled Peptide for Tumor Targeting

2019 ◽  
Vol 19 (12) ◽  
pp. 950-960
Author(s):  
Soghra Farzipour ◽  
Seyed Jalal Hosseinimehr
Keyword(s):  
Tumor Targeting ◽  
Single Photon ◽  
Specific Binding ◽  
Specific Interaction ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Mixed Effect ◽  
Radiolabeled Peptides

Tumor-targeting peptides have been generally developed for the overexpression of tumor specific receptors in cancer cells. The use of specific radiolabeled peptide allows tumor visualization by single photon emission computed tomography (SPECT) and positron emission tomography (PET) tools. The high affinity and specific binding of radiolabeled peptide are focusing on tumoral receptors. The character of the peptide itself, in particular, its complex molecular structure and behaviors influence on its specific interaction with receptors which are overexpressed in tumor. This review summarizes various strategies which are applied for the expansion of radiolabeled peptides for tumor targeting based on in vitro and in vivo specific tumor data and then their data were compared to find any correlation between these experiments. With a careful look at previous studies, it can be found that in vitro unblock-block ratio was unable to correlate the tumor to muscle ratio and the success of radiolabeled peptide for in vivo tumor targeting. The introduction of modifiers’ approaches, nature of peptides, and type of chelators and co-ligands have mixed effect on the in vitro and in vivo specificity of radiolabeled peptides.

scholarly journals In vitro/ In vivo Electrochemical Detection of Pt(II) Species

2021 ◽  
Author(s):  
Alexander Vaneev ◽  
Petr Gorelkin ◽  
Olga Krasnovskaya ◽  
Roman Akasov ◽  
Daniil Spector ◽  
...  
Keyword(s):  
Electrochemical Detection ◽  
Single Cells ◽  
Electrochemical Technique ◽  
Breast Adenocarcinoma ◽  
Tumor Spheroids ◽  
Tumor Bearing ◽  
Advanced Tumor ◽  
Mcf 7

The biodistribution of chemotherapy compounds within tumor tissue is one of the main challenges in the development of antineoplastic drugs, and novel techniques for simple, non-expensive, sensitive, and selective detection of various analytes in tumors are of great importance. In this paper we propose the use of platinized carbon nanoelectrodes (PtNE) for electrochemical detection of platinum-based drugs in various biological models, including single cells and tumor spheroids in vitro, and inside solid tumors in vivo. We have demonstrated quantitative direct detection of Pt(II) in breast adenocarcinoma MCF-7 cells treated with cisplatin and cisplatin-based DNP prodrug. To realize the potential of this technique in advanced tumor models, we measured Pt(II) in 3D tumor spheroids in vitro and tumor-bearing mice in vivo. The concentration gradient of Pt (II) species correlated with the distance from the sample surface in MCF-7 tumor spheroids. We then performed detection of Pt(II) species in tumor-bearing mice treated intravenously with cisplatin and DNP. We found that there was deeper penetration of DNP in comparison to cisplatin. This research demonstrates a novel minimally invasive, real-time electrochemical technique for the study of platinum-based drugs.

scholarly journals Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 182
Author(s):  
Ayman Abouzayed ◽  
Sara S. Rinne ◽  
Hamideh Sabahnoo ◽  
Jens Sörensen ◽  
Vladimir Chernov ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Computed Tomography ◽  
Single Photon ◽  
Specific Binding ◽  
Photon Emission ◽  
Absorbed Dose ◽  
Single Step ◽  
Emission Computed Tomography

Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced 99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers. Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG2-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG2-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) were radiolabeled with 99mTc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice. SPECT/CT imaging and dosimetry calculations were performed for [99mTc]Tc-maSSS-PEG2-RM26. Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [99mTc]Tc-maSSS-PEG2-RM26 outperformed [99mTc]Tc-maSES-PEG2-RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [99mTc]Tc-maSSS-PEG2-RM26 had tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios of 97 ± 56, 188 ± 32, and 177 ± 79, respectively. SPECT/CT images of [99mTc]Tc-maSSS-PEG2-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [99mTc]Tc-maSSS-PEG2-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10−3 mGy/MBq), and the effective dose is 3.49 × 10−3 mSv/MBq. Conclusion: The GRPR antagonist maSSS-PEG2-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced 99mTc and used for imaging of GRPR-expressing prostate cancer.

scholarly journals Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 358 ◽  
Author(s):  
Ayman Abouzayed ◽  
Cheng-Bin Yim ◽  
Bogdan Mitran ◽  
Sara S. Rinne ◽  
Vladimir Tolmachev ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Computed Tomography ◽  
Solid Phase ◽  
Single Photon ◽  
Solid Phase Peptide Synthesis ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Radiochemical Yields

Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)8 (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [125I]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [125I]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [125I]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%–35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [125I]I-BO530 is a promising agent for theranostics application in prostate cancer.

scholarly journals Imaging Hydrogen Sulfide in Hypoxic Tissue with [99mTc]Tc-Gluconate

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 96
Author(s):  
Yongkyoung Kweon ◽  
Ji-Yong Park ◽  
Young-Joo Kim ◽  
Yun-Sang Lee ◽  
Jae-Min Jeong
Keyword(s):  
Computed Tomography ◽  
Hydrogen Sulfide ◽  
Single Photon ◽  
Ischemia Reperfusion ◽  
Photon Emission ◽  
Standard Uptake Value ◽  
Emission Computed Tomography ◽  
Ischemic Limb

Hydrogen sulfide (H2S) is the third gasotransmitter and is generated endogenously in hypoxic or inflammatory tissues and various cancers. We have recently demonstrated that endogenous H2S can be imaged with [99mTc]Tc-gluconate. In the present study, we detected H2S generated in hypoxic tissue, both in vitro and in vivo, using [99mTc]Tc-gluconate. In vitro uptake of [99mTc]Tc-gluconate was measured under hypoxic and normoxic conditions, using the colon carcinoma cell line CT26, and was higher in hypoxic cells than that in normoxic cells. An acute hindlimb ischemia-reperfusion model was established in BALB/c mice by exposing the animals to 3 h of ischemia and 3 h of reperfusion prior to in vivo imaging. [99mTc]Tc-gluconate (12.5 MBq) was intravenously injected through the tail vein, and uptake in the lower limb was analyzed by single-photon emission computed tomography/computed tomography (SPECT/CT). SPECT/CT images showed five times higher uptake in the ischemic limb than that in the normal limb. The standard uptake value (SUVmean) of the ischemic limb was 0.39 ± 0.03, while that of the normal limb was 0.07 ± 0.01. [99mTc]Tc-gluconate is a novel imaging agent that can be used both in vitro and in vivo for the detection of endogenous H2S generated in hypoxic tissue.

High non-specific binding of the β1-selective radioligand 2-125I-ICI-H

2003 ◽  
Vol 42 (04) ◽  
pp. 173-180 ◽  
Author(s):  
M. P. Law ◽  
K. Kopka ◽  
St. Wagner ◽  
S. Luthra ◽  
V. W. Pike ◽  
...  
Keyword(s):  
Specific Activity ◽  
Single Photon ◽  
Specific Binding ◽  
Photon Emission ◽  
Radiochemical Yield ◽  
Emission Computed Tomography ◽  
Biodistribution Studies ◽  
Positron Emission

Summary: Aim: As results of cardiac biopsies suggest, myocardial β1-adrenoceptor density is reduced in patients with chronic heart failure. However, changes in cardiac β2-adrenoceptors vary. With suitable radiopharmaceuticals single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer the opportunity to assess β-adrenoceptors non-invasively. Among the novel racemic analogues of the established β1-selective adrenoceptor antagonist ICI 89.406 the iodinated 2-I-ICI-H showed high affinity and selectivity to β1-adrenoceptors in murine ventricular membranes. The aim of this study was its evaluation as a putative sub-type selective β1-adrenergic radioligand in cardiac imaging. Methods: Competition studies in vitro and in vivo were used to investigate the kinetics of 2-I-ICI-H binding to cardiac β-adrenoceptors in mice and rats. In addition, the radiosynthesis of 2-125I-ICI-H from the silylated precursor 2-SiMe3-ICI-H was established. The specific activity was 80 GBq/µmol, the radiochemical yield ranged from 70 to 80%. Results: The unlabelled compound 2-I-ICI-H showed high β1-selectivity and -affinity in the in vitro competition studies. In vivo biodistribution studies apparently showed low affinity to cardiac β-adrenoceptors. The radiolabelled counterpart 2-125I-ICI-H showed a high degree of non-specific binding in vitro and no specific binding to cardiac β1-adrenoceptors in vivo. Conclusion: Because of its high non-specific binding 2-125I-ICI-H is no suitable radiotracer for imaging in vivo.

scholarly journals Sorbitol as a Polar Pharmacological Modifier to Enhance the Hydrophilicity of 99mTc-Tricarbonyl-Based Radiopharmaceuticals

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2680
Author(s):  
Carolina Giammei ◽  
Theresa Balber ◽  
Katarina Benčurová ◽  
Jens Cardinale ◽  
Neydher Berroterán-Infante ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
General Applicability ◽  
Cell Internalization ◽  
Significant Difference ◽  
Pharmacokinetic Properties

The organometallic technetium-99m tricarbonyl core, [99mTc][Tc(CO)3(H2O)3]+, is a versatile precursor for the development of radiotracers for single photon emission computed tomography (SPECT). A drawback of the 99mTc-tricarbonyl core is its lipophilicity, which can influence the pharmacokinetic properties of the SPECT imaging probe. Addition of polar pharmacological modifiers to 99mTc-tricarbonyl conjugates holds the promise to counteract this effect and provide tumor-targeting radiopharmaceuticals with improved hydrophilicities, e.g., resulting in a favorable fast renal excretion in vivo. We applied the “Click-to-Chelate” strategy for the assembly of a novel 99mTc-tricarbonyl labeled conjugate made of the tumor-targeting, modified bombesin binding sequence [Nle14]BBN(7–14) and the carbohydrate sorbitol as a polar modifier. The 99mTc-radiopeptide was evaluated in vitro with PC-3 cells and in Fox-1nu mice bearing PC-3 xenografts including a direct comparison with a reference conjugate lacking the sorbitol moiety. The glycated 99mTc-tricarbonyl peptide conjugate exhibited an increased hydrophilicity as well as a retained affinity toward the Gastrin releasing peptide receptor and cell internalization properties. However, there was no significant difference in vivo in terms of pharmacokinetic properties. In particular, the rate and route of excretion was unaltered in comparison to the more lipophilic reference compound. This could be attributed to the intrinsic properties of the peptide and/or its metabolites. We report a novel glycated (sorbitol-containing) alkyne substrate for the “Click-to-Chelate” methodology, which is potentially of general applicability for the development of 99mTc-tricarbonyl based radiotracers displaying an enhanced hydrophilicity.

scholarly journals In Vivo Evaluation of Indium-111–Labeled 800CW as a Necrosis-Avid Contrast Agent

2020 ◽  
Vol 22 (5) ◽  
pp. 1333-1341
Author(s):  
Marcus C. M. Stroet ◽  
Erik de Blois ◽  
Debra C. Stuurman ◽  
Corrina M. A. de Ridder ◽  
Joost Haeck ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Fluorescent Dyes ◽  
Photon Emission ◽  
Tunel Staining ◽  
Emission Computed Tomography ◽  
Treatment Efficiency ◽  
Psychological Burden ◽  
Indium 111

Abstract Purpose Current clinical measurements for tumor treatment efficiency rely often on changes in tumor volume measured as shrinkage by CT or MRI, which become apparent after multiple lines of treatment and pose a physical and psychological burden on the patient. Detection of therapy-induced cell death in the tumor can be a fast measure for treatment efficiency. However, there are no reliable clinical tools for detection of tumor necrosis. Previously, we studied the necrosis avidity of cyanine-based fluorescent dyes, which suffered long circulation times before tumor necrosis could be imaged due to low hydrophilicity. We now present the application of radiolabeled 800CW, a commercially available cyanine with high hydrophilicity, to image tumor necrosis in a mouse model. Procedures We conjugated 800CW to DOTA via a PEG linker, for labeling with single-photon emission-computed tomography isotope indium-111, yielding [111In]In-DOTA-PEG4-800CW. We then investigated specific [111In]In-DOTA-PEG4-800CW uptake by dead cells in vitro, using both fluorescence and radioactivity as detection modalities. Finally, we investigated [111In]In-DOTA-PEG4-800CW uptake into necrotic tumor regions of a 4T1 breast tumor model in mice. Results We successfully prepared a precursor and developed a reliable procedure for labeling 800CW with indium-111. We detected specific [111In]In-DOTA-PEG4-800CW uptake by dead cells, using both fluorescence and radioactivity. Albeit with a tumor uptake of only 0.37%ID/g at 6 h post injection, we were able to image tumor necrosis with a tumor to background ratio of 7:4. Fluorescence and radioactivity in cryosections from the dissected tumors were colocalized with tumor necrosis, confirmed by TUNEL staining. Conclusions [111In]In-DOTA-PEG4-800CW can be used to image tumor necrosis in vitro and in vivo. Further research will elucidate the application of [111In]In-DOTA-PEG4-800CW or other radiolabeled hydrophilic cyanines for the detection of necrosis caused by chemotherapy or other anti-cancer therapies. This can provide valuable prognostic information in treatment of solid tumors.

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