68Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with 68Ga-NODAGA-AE105

2019 ◽  
Vol 18 (9) ◽  
pp. 1289-1294 ◽  
Author(s):  
Kusum Vats ◽  
Rohit Sharma ◽  
Haladhar D. Sarma ◽  
Drishty Satpati ◽  
Ashutosh Dash
Keyword(s):  
Solid Phase ◽  
Evaluation Studies ◽  
Radiochemical Yield ◽  
In Vivo Evaluation ◽  
Peptide Conjugates ◽  
Biodistribution Studies ◽  
Target Organs ◽  
U87mg Tumor

Aims: The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes. Method: The peptide conjugates, HBED-CC-AE105-NH2 and NODAGA-AE105-NH2 were manually synthesized by standard Fmoc solid phase strategy and subsequently radiolabeled with 68Ga eluted from a commercial 68Ge/68Ga generator. In vitro cell studies for the two radiotracers were performed with uPAR positive U87MG cells. Biodistribution studies were carried out in mouse xenografts with the subcutaneously induced U87MG tumor. Results: The two radiotracers, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 that were prepared in >95% radiochemical yield and >96% radiochemical purity, exhibited excellent in vitro stability. In vivo evaluation studies revealed higher uptake of 68Ga-HBED-CC-AE105 in U87MG tumor as compared to 68Ga-NODAGAAE105; however, increased lipophilicity of 68Ga-HBED-CC-AE105 resulted in slower clearance from blood and other non-target organs. The uPAR specificity of the two radiotracers was ascertained by significant (p<0.05) reduction in the tumor uptake with a co-injected blocking dose of unlabeled AE-105 peptide. Conclusion: Amongst the two radiotracers studied, the neutral 68Ga-NODAGA-AE105 with more hydrophilic chelator exhibited faster clearance from non-target organs. The conjugation of HBED-CC chelator (less hydrophilic) resulted in negatively charged 68Ga-HBED-CC-AE105 which was observed to have high retention in blood that decreased target to non-target ratios.

scholarly journals Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

2021 ◽  
Author(s):  
Thu Hang Lai ◽  
Magali Toussaint ◽  
Rodrigo Teodoro ◽  
Sladjana Dukić-Stefanović ◽  
Daniel Gündel ◽  
...  
Keyword(s):  
Specific Binding ◽  
Radiochemical Yield ◽  
Toxicity Study ◽  
In Vivo Evaluation ◽  
One Pot ◽  
Specific Binding Ratio ◽  
Mri Studies ◽  
The Brain

Abstract Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [18F]FLUDA towards striatal A2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application.

scholarly journals Microemulsion-based hydrogels for enhancing epidermal/dermal deposition of topically administered 20(S)-protopanaxadiol: in vitro and in vivo evaluation studies

2018 ◽  
Vol 42 (4) ◽  
pp. 512-523 ◽  
Author(s):  
Ki-Taek Kim ◽  
Min-Hwan Kim ◽  
Ju-Hwan Park ◽  
Jae-Young Lee ◽  
Hyun-Jong Cho ◽  
...  
Keyword(s):  
Evaluation Studies ◽  
In Vivo Evaluation

Nanocarriers with Gentamicin to Treat Intracellular Pathogens

2006 ◽  
Vol 6 (9) ◽  
pp. 3296-3302 ◽  
Author(s):  
C. Lecaroz ◽  
C. Gamazo ◽  
M. J. Blanco-Prieto
Keyword(s):  
Macrophage Activation ◽  
Polymeric Nanoparticles ◽  
Current Treatment ◽  
Delivery Systems ◽  
Oxygen Intermediates ◽  
Water Solvent ◽  
Biodistribution Studies ◽  
Target Organs

Brucellosis is a worldwide zoonosis caused by different species of the genus Brucella. The intracellular localisation of this pathogen, particularly in macrophages, renders treatment difficult since most antibiotics known to be efficient in vitro do not actively pass through cellular membranes. As alternative to current treatment, polymeric drug delivery systems containing gentamicin have been developed. These particulate carriers target the drug into the mononuclear-phagocytic system, where the pathogen resides that will allow intracellular accumulation of the antibiotic after particle degradation. Besides, particle uptake may induce macrophage activation, increasing the production of reactive oxygen intermediates, involved in host defense against the intracellular pathogen. The aim of the present work was to study the suitability of polymeric nanoparticles for gentamicin entrapment in view to treat brucellosis. Different poly(lactide-co-glycolide) PLGA polymers were used to formulate the nanoparticles containing gentamicin by a water-oil-water solvent evaporation method. Furthermore, in vitro macrophage activation upon nanoparticles phagocytosis and in vivo distribution of the nanocarriers in the target organs for Brucella (liver and spleen) were also studied. The nanoparticle sizes were below 350 nm, the gentamicin encapsulation efficiency depended on the polymer type used for their preparation and the in vitro release of the antibiotic exhibited a continuos pattern (PLGA 502H). PLGA 502H nanoparticles were the most suitable due to the highest entrapment and the most sustained release. The nanoparticles were successfully phagocyted by a J774 murine monocytes cell line and biodistribution studies in mice after intravenous administration of the delivery systems revealed that the particles reached the target organs of Brucella (liver and spleen). All together, these results indicate that the nanocarriers described in this work may be suitable as gentamicin delivery system to control brucellosis.

scholarly journals Evaluation of Radioiodinated Fluoronicotinamide/Fluoropicolinamide-Benzamide Derivatives as Theranostic Agents for Melanoma

2020 ◽  
Vol 21 (18) ◽  
pp. 6597
Author(s):  
Chao-Cheng Chen ◽  
Yang-Yi Chen ◽  
Yi-Hsuan Lo ◽  
Ming-Hsien Lin ◽  
Chih-Hsien Chang ◽  
...  
Keyword(s):  
Absorbed Dose ◽  
Radiochemical Yield ◽  
Amelanotic Melanoma ◽  
In Vivo Studies ◽  
Log P ◽  
Theranostic Agent ◽  
Biodistribution Studies ◽  
Theranostic Agents

Malignant melanoma is the most harmful type of skin cancer and its incidence has increased in this past decade. Early diagnosis and treatment are urgently desired. In this study, we conjugated picolinamide/nicotinamide with the pharmacophore of 131I-MIP-1145 to develop 131I-iodofluoropicolinamide benzamide (131I-IFPABZA) and 131I-iodofluoronicotiamide benzamide (131I-IFNABZA) with acceptable radiochemical yield (40 ± 5%) and high radiochemical purity (>98%). We also presented their biological characteristics in melanoma-bearing mouse models. 131I-IFPABZA (Log P = 2.01) was more lipophilic than 131I-IFNABZA (Log P = 1.49). B16F10-bearing mice injected with 131I-IFNABZA exhibited higher tumor-to-muscle ratio (T/M) than those administered with 131I-IFPABZA in planar γ-imaging and biodistribution studies. However, the imaging of 131I-IFNABZA- and 131I-IFPABZA-injected mice only showed marginal tumor uptake in A375 amelanotic melanoma-bearing mice throughout the experiment period, indicating the high binding affinity of these two radiotracers to melanin. Comparing the radiation-absorbed dose of 131I-IFNABZA with the melanin-targeted agents reported in the literature, 131I-IFNABZA exerts lower doses to normal tissues on the basis of similar tumor dose. Based on the in vitro and in vivo studies, we clearly demonstrated the potential of using 131I-IFNABZA as a theranostic agent against melanoma.

scholarly journals Radiosynthesis and Evaluation of Talazoparib and its Derivatives as PARP-1-Targeting Agents

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 565
Author(s):  
Dong Zhou ◽  
Huaping Chen ◽  
Cedric Mpoy ◽  
Sadia Afrin ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Tumor Model ◽  
Repair Process ◽  
In Vivo Evaluation ◽  
Competitive Binding Assay ◽  
Targeted Radiotherapy ◽  
Molar Activity ◽  
Biodistribution Studies ◽  
Parp 1

Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of [18F]talazoparib and its in vitro and in vivo evaluation. Talazoparib (3a”) and its bromo- or iodo-derivatives were synthesized as racemic mixtures (3a, 3b and 3c), and these compounds exhibit high affinity to PARP-1 (Ki for talazoparib (3a”): 0.65 ± 0.07 nM; 3a: 2.37 ± 0.56 nM; 3b: 1.92 ± 0.41 nM; 3c: 1.73 ± 0.43 nM; known PARP-1 inhibitor Olaparib: 1.87 ± 0.10 nM; non-PARP-1 compound Raclopride: >20,000 nM) in a competitive binding assay using a tritium-labeled PARP-1 radioligand [3H]WC-DZ for screening. [18F]Talazoparib (3a”) was radiosynthesized via a multiple-step procedure with good radiochemical and chiral purities (98%) and high molar activity (28 GBq/μmol). The preliminary biodistribution studies in the murine PC-3 tumor model showed that [18F]talazoparib had a good level of tumor uptake that persisted for over 8 h (3.78 ± 0.55 %ID/gram at 4 h and 4.52 ± 0.32 %ID/gram at 8 h). These studies show the potential for the bromo- and iodo- derivatives for PARP-1 targeted radiotherapy studies using therapeutic radionuclides.

Radioiodination and biological evaluation of Cimetidine as a new highly selective radiotracer for peptic ulcer disorder detection

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Mahmoud H. Sanad ◽  
Safaa B. Challan ◽  
Fawzy A. Marzook ◽  
Sayed M. Abd-Elhaliem ◽  
Ebtisam A. Marzook
Keyword(s):  
Peptic Ulcer ◽  
Nuclear Imaging ◽  
Radiochemical Yield ◽  
Biological Evaluation ◽  
Stomach Ulcer ◽  
Control Group ◽  
Factors Affecting ◽  
Biodistribution Studies

AbstractOne of the most famous techniques for stomach ulcer imaging is the nuclear imaging technique. We aim to focus on the synthesis of 125I-cimetidine (125I-cim) as an agent for peptic ulcer imaging. Cimetidine was labeled with Iodine-125 using a different oxidizing agent (Ch-T, NBS). All factors affecting the labeling yield were optimized. The radiochemical yield of 125I-cim was 98 ± 0.22% at optimum conditions. In vitro stability, in vivo biodistribution of 125I-cimetidine was studied in three groups: control group, pretreated group, and ulcer bearing group. In vivo biodistribution studies of 125I-cim revealed high uptake in the stomach ulcer, reaching about 75.4 ± 1.2% ID/g at 15 min post-injection, than pretreated groups compared to the control. The results showed the suitability of using 125I-cimetidine for stomach ulcer imaging.

Formulation and In Vivo Evaluation of Ticagrelor Self- Nanoemulsifying Drug Delivery Systems.

2020 ◽  
Vol 08 ◽  
Author(s):  
Adella Aparna ◽  
Yamsani Shravan Kumar ◽  
D.V.R.N. Bhikshapathi
Keyword(s):  
Drug Release ◽  
Oral Bioavailability ◽  
Ternary Phase Diagram ◽  
Evaluation Studies ◽  
Antiplatelet Agent ◽  
In Vivo Evaluation ◽  
Release Analysis ◽  
Pure Drug

Background: Ticagrelor (TGR) being antiplatelet agent belongs to BCS class IV drug with low solubility and permeability that undergoes first-pass metabolism leads to reduced bioavailability of 36%. Objective: The main goal of the present study was to develop TGR SNEDDS for improving solubility and oral bioavailability. Methods: An oil, surfactant and co-surfactant (miglyol 810, brij 35 and lauro glycol FCC) were chosen based on the maximum solubility of TGR. The chosen vehicles were mixed in varying ratios and agitated mildly and transmittance values more than 80 were noted and used for constructing pseudo ternary phase diagram. Formulations that passed stability testing were evaluated for % transmission, drug content and in vitro drug release analysis. In-vivo bioavailability studies of optimized SNEDDS were performed in wistar rats. Results: From evaluation studies of TGR, formulation F13 with maximum drug release of 98.99% in 60 minutes that is higher than 31.99 % of pure drug is considered the optimised formulation. The particle size, Z average and zeta potential of the optimized TGR formulation F13 was 289.6 nm, 185.1 nm and -18.3 mV respectively. The FTIR and SEM studies do not indicate any drug excipient interaction and confirm nanosize and stable for 3 months. From in vivo bioavailability studies in rats, the Cmax of optimized TGR SNEDDS (302.43±4.78ng/ml) was higher than pure TGR suspension (47.32±2.75ng/ml) and optimized SNEDDS exhibited 5 folds increased oral bioavailability than pure drug. Conclusion: Hence, the results revealed that application of SNEDDS formulation technique for TGR increased solubility and oral bioavailability.

scholarly journals Preclinical Evaluation of Radiolabeled Peptides for PET Imaging of Glioblastoma Multiforme

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2496 ◽  
Author(s):  
Zbynek Novy ◽  
Jana Stepankova ◽  
Michaela Hola ◽  
Dominika Flasarova ◽  
Miroslav Popper ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Tumor Imaging ◽  
Ex Vivo ◽  
Tumor Model ◽  
Rgd Peptides ◽  
Radiolabeled Peptides ◽  
Biodistribution Studies ◽  
Target Organs

In this study, we have compared four 68Ga-labeled peptides (three Arg-Gly-Asp (RGD) peptides and substance-P) with two 18F-tracers clinically approved for tumor imaging. We have studied in vitro and in vivo characteristics of selected radiolabeled tracers in a glioblastoma multiforme tumor model. The in vitro part of the study was mainly focused on the evaluation of radiotracers stability under various conditions. We have also determined in vivo stability of studied 68Ga-radiotracers by analysis of murine urine collected at various time points after injection. The in vivo behavior of tested 68Ga-peptides was evaluated through ex vivo biodistribution studies and PET/CT imaging. The obtained data were compared with clinically used 18F-tracers. 68Ga-RGD peptides showed better imaging properties compared to 18F-tracers, i.e., higher tumor/background ratios and no accumulation in non-target organs except for excretory organs.

In vitro and in vivo Evaluation of the Radiochemical Compound Based on 99mTechnetium Labelled DARPin 9_29 for Molecular Visualization of Malignancies Overexpressing Her2/neu

2020 ◽  
Vol 65 (1) ◽  
pp. 37-41
Author(s):  
O. Bragina ◽  
A. Vorobyeva ◽  
V. Tolmachev ◽  
A. Orlova ◽  
V. Chernov ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Radiochemical Yield ◽  
Blood Stream ◽  
The Body ◽  
Diagnostic Methods ◽  
In Vivo Studies ◽  
In Vivo Evaluation ◽  
High Accumulation

Purpose: Evaluation of a radiopharmaceutical based on 99mTc-labeled targeted molecules DARPin9_29 for radionuclide diagnostics of malignancies with Her2/neu overexpression. Material and methods: The DARPin9_29 sequence was amplified from the plasmid pET-DARP-6HIS for the DARPin9_29-His6 gene expression in E. coli cells. The eluent of 99mTcO4– (400–500 μl, 4 GBq) was added to the kit and incubated at a temperature of 100 °C for 20 minutes. After incubation, 40 μl of tricarbonyl technetium was added to 168 μg of DARPin9_29 in 100 μl of PBS (sodium phosphate buffer), followed by incubation at 40 °C for 60 minutes. The radiochemical yield and purity were determined by thin layer radiochromatography, the purification was performed using NAP-5 cleansing columns (GE Healthcare). Cell lines with different levels of Her2/neu expression were used: SKOV-3> BT474 >> DU-145 for the determination of the radiopharmaceutical specificity. Her2/neu expressing cell line SKOV-3 was used for in vitro study. The study was conducted 6 hours after the administration of the drug. Results: The radiochemical yield was 72 ± 8 %, the radiochemical purity after purification was 98.7 ± 1.0 %. The stability in PBS (phosphate buffered saline) solution after 1 hour was 99.8 ± 0.2; after 3 hours – 98.2 ± 0.1. In vitro studies showed that the accumulation of explored compound was directly proportional to the level of Her2/neu expression in cells, while blocking the receptors with an excess of unlabeled protein showed a significant reduction in binding in the group of cells. Data on biodistribution and SPECT/CT in the body of the animal BALB/c nu/nu demonstrated rapid removal of the compound from the blood stream and high accumulation in the liver, kidney and bladder 6 hours after the introduction of the radiopharmaceutical. Conclusion: The studies demonstrated high radiochemical yields and purity, as well as stability of the studied compound. The results of in vitro and in vivo analysis showed the specificity and affinity of the radiopharmaceutical to the Her2/neu receptor on the surface of tumor cells. The high accumulation of the drug in the liver and kidneys, detected in in vivo studies, is probably due to the lipophilicity of the 99mTc(CO)3-histidine tag and indicates the limitation of its further clinical use in assessing the condition of the above organs, which will require additional diagnostic methods, as well as possible modification chemical structure.

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.

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