Synthesis and biological evaluation of a 99mTc-labelled cyclic RGD peptide for imaging the αvβ3 expression

2004 ◽  
Vol 43 (01) ◽  
pp. 26-32 ◽  
Author(s):  
F. Bruchertseifer ◽  
M. Bock ◽  
H. Kessler ◽  
M. Schwaiger ◽  
H.-J. Wester ◽  
...  
Keyword(s):  
Background Level ◽  
Radiochemical Yield ◽  
Biological Evaluation ◽  
Negative Control ◽  
Human Melanoma ◽  
Water Soluble ◽  
Αvβ3 Integrin ◽  
In Vivo Evaluation ◽  
Tumour Metastasis

Summary Aim: The αvβ3 integrin is involved in tumour induced angiogenesis and tumour metastasis. We describe the synthesis and evaluation of a 99mTc-labelled RGD analogue for the visualisation of αvβ3 integrin expression. Methods: The linear peptides were assembled on a solid support. Cyclisation was performed under high dilution conditions. For conjugation with the chelator peptide, a water soluble carbodiimide was used. Radiolabelling was carried out due to standard procedures with high radiochemical yield and radiochemical purity. For in vivo evaluation, nude mice bearing αvβ3-positive human melanoma M21 and αv-negative human melanoma M21-L or Balb/c mice bearing αv-positive murine osteosarcoma were used. Results: Activity accumulation of 99mTc-DKCK-RGD 240 min p. i. was 1.1% ID/g in the αvβ3-positive melanoma and 0.3% ID/g in the negative control tumour. In the osteosarcoma model 2.2% ID/g was found 240 min p. i. Planar gamma camera images allowed contrasting visualisation of αvβ3-positive tumours 240 min p. i. Blocking of the tumour using the αvβ3-selective pentapeptide cyclo(-ArgGly-Asp-D-Phe-Val-) reduces activity accumulation in the tumour to background level. However, 240 min p. i. highest activity concentration was found in kidneys resulting in low tumour/kidney ratios. Metabolite analysis 240 min p. i. showed approximately 60% intact tracer in kidneys and 80% in the tumour. Only 24% intact tracer was found in blood 30 min p. i. Conclusion: 99mTc-DKCK-RGD allows imaging of αvβ3-positive tumours in mice. However, pharmacokinetics as well as metabolic stability of the tracer have to be improved for potential clinical application.

Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

2020 ◽  
Vol 13 (5) ◽  
pp. 5102-5109
Author(s):  
Venu Madhav K ◽  
Somnath De ◽  
Chandra Shekar Bonagiri ◽  
Sridhar Babu Gummadi
Keyword(s):  
Oral Bioavailability ◽  
Oral Delivery ◽  
Solid Dispersions ◽  
In Vitro Release ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Scanning Calorimetry ◽  
In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension.  From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

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 In vivo evaluation of modified gum karaya as a carrier for improving the oral bioavailability of a poorly water-soluble drug, nimodipine

2002 ◽  
Vol 3 (2) ◽  
pp. 55-63 ◽  
Author(s):  
Gedela V. Murali Mohan Babu ◽  
Namballa R. Kumar ◽  
Kasina H. Sankar ◽  
Battu J. Ram ◽  
Namburu K. Kumar ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Water Soluble ◽  
In Vivo Evaluation ◽  
Gum Karaya ◽  
Water Soluble Drug ◽  
Poorly Water Soluble ◽  
Poorly Water Soluble Drug

Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule

2006 ◽  
Vol 290 (4) ◽  
pp. F789-F794 ◽  
Author(s):  
Yasin Tayem ◽  
Tony R. Johnson ◽  
Brian E. Mann ◽  
Colin J. Green ◽  
Roberto Motterlini
Keyword(s):  
Carbon Monoxide ◽  
Caspase 3 ◽  
Morphological Changes ◽  
Antineoplastic Agent ◽  
Negative Control ◽  
Water Soluble ◽  
Plasma Urea ◽  
Therapeutic Benefits ◽  
Corticomedullary Junction

Nephrotoxicity is one of the main side effects caused by cisplatin (CP), a widely used antineoplastic agent. Here, we examined the effect of a novel water-soluble carbon monoxide-releasing molecule (CORM-3) on CP-mediated cytotoxicity in renal epithelial cells and explored the potential therapeutic benefits of carbon monoxide in CP-induced nephrotoxicity in vivo. Exposure of LLC-PK1 cells to CP (50 μM) caused significant apoptosis as evidenced by caspase-3 activation and an increased number of floating cells. Treatment with CORM-3 (1–50 μM) resulted in a remarkable and concentration-dependent decrease in CP-induced caspase-3 activity and cell detachment. This effect involved activation of the cGMP pathway as 1H-oxadiazole [4, 3-a] quinoxaline-1-ore (ODQ), a guanylate cyclase inhibitor, completely abolished the protection elicited by CORM-3. Using a rat model of CP-induced renal failure, we found that treatment with CP (7.5 mg/kg) caused a significant elevation in plasma urea (6.6-fold) and creatinine (3.1-fold) levels, which was accompanied by severe morphological changes and marked apoptosis in tubules at the corticomedullary junction. A daily administration of CORM-3 (10 mg/kg ip), starting 1 day before CP treatment and continuing for 3 days thereafter, resulted in amelioration of renal function as shown by reduction of urea and creatinine levels to basal values, a decreased number of apoptotic tubular cells, and an improved histological profile. A negative control (iCORM-3) that is incapable of liberating CO failed to prevent renal dysfunction mediated by CP, indicating that CO is directly involved in renoprotection. Our data demonstrate that CORM-3 can be used as an effective therapeutic adjuvant in the treatment of CP-induced nephrotoxicity.

Cytotoxic and antitumoral activity of N-(9H-purin-6-yl) benzamide derivatives and related water-soluble prodrugs

2021 ◽  
Vol 14 ◽  
Author(s):  
Emeline Cros-Perrial ◽  
Steve Saulnier ◽  
Muhammad Zawwad Raza ◽  
Rémi Charmelot ◽  
David Egron ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Biological Evaluation ◽  
Water Soluble ◽  
Antitumoral Activity ◽  
Cell Cycle Distribution ◽  
Synergistic Activity ◽  
Benzamide Derivatives

Background: The development of small molecules as cancer treatments is still of both interest and importance. Objective: Having synthesized and identified the initial cytotoxic activity of a series of chemically related N-(9H-purin-6-yl) benzamide derivatives, we continued their evaluation on cancer cell models. We also synthesized water-soluble prodrugs of the main compound and performed in vivo experiments. Method: We used organic chemistry to obtain compounds of interest and prodrugs. The biological evaluation included MTT assays, synergy experiments, proliferation assays by CFSE, cell cycle distribution and in vivo antitumoral activity. Results: Our results show activities on cancer cell lines ranging from 3-39 µM for the best compounds, with both induction of apoptosis and decrease in cell proliferation. Two compounds evaluated in vivo showed weak antitumoral activity. In addition, the lead compound and its prodrug had a synergistic activity with the nucleoside analogue fludarabine in vitro and in vivo. Conclusion: Our work allowed us to gain better knowledge on the activity of N-(9H-purin-6-yl) benzamide derivatives and showed new examples of water-soluble prodrugs. More research is warranted to decipher the molecular mechanisms of the molecules.

scholarly journals In Vivo Evaluation of the Genotoxic Effects of Poly (Butylene adipate-co-terephthalate)/Polypyrrole with Nanohydroxyapatite Scaffolds for Bone Regeneration

Materials ◽  
2019 ◽  
Vol 12 (8) ◽  
pp. 1330 ◽  
Author(s):  
Conceição de Maria Vaz Elias ◽  
Antônio Luiz Martins Maia Filho ◽  
Laryssa Roque da Silva ◽  
Fabrício Pires de Moura do Amaral ◽  
Thomas J. Webster ◽  
...  
Keyword(s):  
Micronucleus Test ◽  
Infusion Pump ◽  
Tail Length ◽  
Positive Control ◽  
Negative Control ◽  
Electrospinning Process ◽  
Genotoxic Effects ◽  
In Vivo Evaluation ◽  
In Vivo Assays

Here, butylene adipate-co-terephthalate/polypyrrole with nanohydroxyapatite (PBAT/PPy/nHAp) scaffolds were fabricated and characterized. The electrospinning process was carried out using 12 kV, a needle of 23 G, an infusion pump set at 0.3 mL/h, and 10 cm of distance. Afterwards, nHAp was directly electrodeposited onto PBAT/PPy scaffolds using a classical three-electrode apparatus. For in vivo assays (comet assay, acute and chronic micronucleus), 60 male albino Wistar rats with 4 groups were used in each test (n = 5): PBAT/PPy; PBAT/PPy/nHAp; positive control (cyclophosphamide); and the negative control (distilled water). Peripheral blood samples were collected from the animals to perform the comet test after 4 h (for damage) and 24 h (for repair). In the comet test, it was shown that the scaffolds did not induce damage to the % DNA tail and neither for tail length. After the end of 48 h (for acute micronucleus) and 72 h (for chronic micronucleus), bone marrow was collected from each rat to perform the micronucleus test. All of the produced scaffolds did not present genotoxic effects, providing strong evidence for the biological application of PBAT/PPy/nHAp scaffolds.

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