170 research outputs found
Supramolecular aggregates containing lipophilic Gd(III) complexes as contrast agents in MRI
Magnetic resonance imaging (MRI) contrast agents based on paramagnetic gadolinium complexes
are widely used in biomedical research and diagnosis. Their application is intended to improve efficacy
of MRI providing physiological information along with the impressive anatomical detail already
obtained by images without contrast. The classical gadolinium complexes currently used for MRI contrast
enhancement are all lowmolecularweightcompounds that rapidly equilibrate between the intra and
extravascular spaces after intravenous administration. In order to obtain gadolinium-based agents with
different pharmacokinetic properties, supramolecular aggregates such as micelles and liposomes have
been recently proposed. Micelles and liposomes, obtained by the aggregation of lipophilic gadolinium
complexes are here described, with the aim to correlate their structural and relaxometric properties.We
report on the state of the art in the development of supramolecular aggregates obtained by self-assembly
of lipophilic gadolinium complexes and aggregates in which lipophilic gadolinium complexes are assembled
with surfactants. Moreover aggregates derivatized with bioactive molecules, such as peptides and
antibodies, acting as target selective MRI contrast agents are described
In vitro and in vivo evaluation of In-111-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging
Regulatory peptides and their analogs are being extensively investigated as radiopharmaceuticals for cancer imaging and
therapy. Receptors of the cholecystokinin family have been shown to be overexpressed in different types of neuroendocrine
tumors. The purposes of this study were to evaluate the cholecystokinin octapeptide amide (CCK8) peptide tagged with a
diethylenetriaminepentaacetic acid derivative (DTPAGlu) and to test whether a 111In-labeled conjugate (111In-DTPAGlu-G-CCK8,
a derivative containing the chelating agent DTPAGlu bound through a glycine linker at the N-terminal end of the bioactive
peptide CCK8) is suitable for cholecystokinin-B receptor (CCKBR) imaging. Methods: CCK8 was synthesized by solidphase
techniques and covalently coupled to DTPAGlu through a glycine linker at its amino terminus. The compound was labeled
with 111In. The radiochemical purity and stability of the compound were assessed by chromatographic methods. NIH-3T3
and A431 cells overexpressing CCKBR were used to characterize the in vitro properties of the compound. Nude mice bearing
control and CCKBR-overexpressing A431 xenografts were used as an in vivo model. Results: DTPAGlu-G-CCK8 showed
rapid and efficient labeling with 111In. The radiolabeled conjugate showed specific binding to both cell lines overexpressing
CCKBR. Binding was saturable, with a dissociation constant of 20 nmol/L in both cell systems. Both cell lines showed internalization
of the ligand after interaction with the receptor. Biodistribution studies showed rapid localization of 111In-DTPAGlu-
G-CCK8 on CCKBR-overexpressing A431 xenografts that was severalfold higher than that on control tumors at all time points
tested. Unbound activity showed rapid clearance of over 80% through the kidneys by 30 min after injection. The labeled peptide
conjugate was very stable in serum but showed a rapid breakdown after injection. Incubation with kidney homogenates
suggested that most breakdown occurred in the kidneys, favoring the clearance of unbound activity. Conclusion: Our findings
indicate that the in vitro and in vivo characteristics of 111In-DTPAGlu-G-CCK8 are favorable for CCKBR imaging, as thepeptide shows high-affinity binding to the receptor, is internalized in CCKBR-expressing cells, and shows avid uptake in CCKBR-overexpressing xenografts, with rapid clearance of unbound radioactivity through the kidneys. Furthermore, the ease of synthesis, high labeling efficiency, and chemical stability of DTPAGlu make this chelating moiety an ideal candidate for widespread use in peptide radiolabeling for nuclear medicine
applications
Biophysical and biochemical characterization of a liposarcoma-derived recombinant MnSOD protein acting as an anticancer agent
A recombinant MnSOD (rMnSOD) synthesized by specific cDNA clones derived from a liposarcoma cell line was shown to have the same sequence as the wild-type MnSOD expressed in the human myeloid leukaemia cell line U937, except for the presence of the leader peptide at the N-terminus. These results were fully confirmed by the molecular mass of rMnSOD as evaluated by ES/MS analysis (26662.7 Da) and the nucleotide sequence of the MnSOD cDNA. The role of the leader peptide in rMnSOD was investigated using a fluorescent and/or 68Gallium-labelled synthetic peptide. The labelled peptide permeated MCF-7 cells and uptake could be inhibited in the presence of an excess of oestrogen. In vivo it was taken up by the tumour, suggesting that the molecule can be used for both therapy and diagnosis. The in vitro and in vivo pharmacology tests confirmed that rMnSOD is only oncotoxic for tumour cells expressing oestrogen receptors. Pharmacokinetic studies in animals performed with 125I- and 131I-labelled proteins confirmed that, when administered systemically, rMnSOD selectively reached the tumour, where its presence was unambiguously demonstrated by scintigraphic and PET scans. PCR analysis revealed that Bax gene expression was increased and the Bcl2 gene was down regulated in MCF7 cells treated with rMnSOD, which suggests that the protein induces a pro-apoptotic mechanism
Recommended from our members
In vivo cell tracking using pet: Opportunities and challenges for clinical translation in oncology
Data Availability Statement: Not applicable.Cell therapy is a rapidly evolving field involving a wide spectrum of therapeutic cells for personalised medicine in cancer. In vivo imaging and tracking of cells can provide useful information for improving the accuracy, efficacy, and safety of cell therapies. This review focuses on radiopharmaceuticals for the non-invasive detection and tracking of therapeutic cells using positron emission tomography (PET). A range of approaches for imaging therapeutic cells is discussed: Direct ex vivo labelling of cells, in vivo indirect labelling of cells by utilising gene reporters, and detection of specific antigens expressed on the target cells using antibody-based radiopharmaceuticals (immuno-PET). This review examines the evaluation of PET imaging methods for therapeutic cell tracking in preclinical cancer models, their role in the translation into patients, first-in-human studies, as well as the translational challenges involved and how they can be overcome.L.M.L. and F.A.G. have research grants from CRUK (C19212/A16628, C19212/A911376) and GlaxoSmithKline (RQAG/092)
Effect of n-acetylcysteine administration on 30-day mortality in critically ill patients with septic shock caused by carbapenem-resistant klebsiella pneumoniae and acinetobacter baumannii. A retrospective case-control study
Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Acinetobacter baumannii (CR-Ab) represent important cause of severe infections in intensive care unit (ICU) patients. N-Acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties, showing also in-vitro antibacterial activity. Aim was to evaluate the effect on 30-day mortality of the addition of intravenous NAC to antibiotics in ICU patients with CR-Kp or CR-Ab septic shock. A retrospective, observational case:control study (1:2) in patients with septic shock caused by CR-Kp or CR-Ab hospitalized in two different ICUs was conducted. Cases included patients receiving NAC plus antimicrobials, controls included patients not receiving NAC. Cases and controls were matched for age, SAPS II, causative agent and source of infection. No differences in age, sex, SAPS II score or time to initiate definitive therapy were observed between cases and controls. Pneumonia and bacteremia were the leading infections. Overall, mortality was 48.9% (33.3% vs. 56.7% in cases and controls, p = 0.05). Independent risk factors for mortality were not receiving NAC (p = 0.002) and CR-Ab (p = 0.034) whereas therapy with two in-vitro active antibiotics (p = 0.014) and time to initial definite therapy (p = 0.026) were protective. NAC plus antibiotics might reduce the 30-day mortality rate in ICU patients with CR-Kp and CR-Ab septic shock
Recommended from our members
The emerging role of cell surface receptor and protein binding radiopharmaceuticals in cancer diagnostics and therapy
Targeting specific cell membrane markers for both diagnostic imaging and radionuclide therapy is a rapidly evolving field in cancer research. Some of these applications have now found a role in routine clinical practice and have been shown to have a significant impact on patient management. Several molecular targets are being investigated in ongoing clinical trials and show promise for future implementation. Advancements in molecular biology have facilitated the identification of new cancer-specific targets for radiopharmaceutical development.This work was supported by Cancer Research UK, the CRUK Cambridge Centre, the CRUK & Engineering and Physical Science Research Council (EPSRC) Cancer Imaging Centre in Cambridge and Manchester, the Mark Foundation for Cancer Research, Addenbrooke's Charitable Trust, the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, CRUK National Cancer Imaging Translational Accelerator (NCITA)
Pericoronary and periaortic adipose tissue density are associated with inflammatory disease activity in Takayasu arteritis and atherosclerosis.
AimsTo examine pericoronary adipose tissue (PCAT) and periaortic adipose tissue (PAAT) density on coronary computed tomography angiography for assessing arterial inflammation in Takayasu arteritis (TAK) and atherosclerosis.Methods and resultsPCAT and PAAT density was measured in coronary (n = 1016) and aortic (n = 108) segments from 108 subjects [TAK + coronary artery disease (CAD), n = 36; TAK, n = 18; atherosclerotic CAD, n = 32; matched controls, n = 22]. Median PCAT and PAAT densities varied between groups (mPCAT: P P = 0.0002). PCAT density was 7.01 ± standard error of the mean (SEM) 1.78 Hounsfield Unit (HU) higher in coronary segments from TAK + CAD patients than stable CAD patients (P = 0.0002), and 8.20 ± SEM 2.04 HU higher in TAK patients without CAD than controls (P = 0.0001). mPCAT density was correlated with Indian Takayasu Clinical Activity Score (r = 0.43, P = 0.001) and C-reactive protein (r = 0.41, P P = 0.002). mPCAT density above -74 HU had 100% sensitivity and 95% specificity for differentiating active TAK from controls [area under the curve = 0.99 (95% confidence interval 0.97-1)]. The association of PCAT density and coronary arterial inflammation measured by 68Ga-DOTATATE positron emission tomography (PET) equated to an increase of 2.44 ± SEM 0.77 HU in PCAT density for each unit increase in 68Ga-DOTATATE maximum tissue-to-blood ratio (P = 0.002). These findings remained in multivariable sensitivity analyses adjusted for potential confounders.ConclusionsPCAT and PAAT density are higher in TAK than atherosclerotic CAD or controls and are associated with clinical, biochemical, and PET markers of inflammation. Owing to excellent diagnostic accuracy, PCAT density could be useful as a clinical adjunct for assessing disease activity in TAK
- …