1,721,234 research outputs found
PSMA - Targeted Clinical Molecular Imaging of Atherosclerosis:Correlation with Cardiovascular Risk Factors
No full textAim The early diagnosis of atherosclerotic changes to prevent ischemic events represents a clinical challenge. Prostate-specific membrane antigen (PSMA) as an established diagnostic in the field of prostate cancer also appears to detect neovascularization and inflammation in other diseases. We hypothesized that it might be also suited for detection of inflammation in atherosclerosis. Methods We analyzed data of 78 prostate cancer patients who received a PSMA ligand PET/CT for re-staging. The cardiovascular risk factors (CVRF) of each patient were documented. Target-to-background-ratios (TBR) were calculated from the individual uptake values for three different sections of thoracic aorta [ascending (AA) and descending aorta (AD), aortic arch (AoAC)]. Statistical analyses included a linear regression analysis with the PSMA ligand uptake values of the different arterial segments versus different CVRF as independent variables. Results The meanTBRmax was measured highest in the AoAC (1.66 +/- 0.33) compared to both other vessel sections (AA: 1.46 +/- 0.21, p=0.001; AD: 1.59 +/- 0.41, p=0.371). There was a correlation between the PSMA ligand uptake in all measured segments of the aorta and BMI, but only a significant correlation in the ascending aorta (r=0.347, p=0.001). This was confirmed in a subgroup analysis, which showed significantly higher uptake values in preadiposity (BMI >25) and obesity (BMI >30) patients in the ascending aorta (p=0.048). Conclusion PSMA ligand uptake in the ascending aorta was linked to BMI. PET detection of vascular PSMA ligand uptake may be indicative of vessel wall inflammation to some extent. However, PSMA ligands appear to be less suitable than other tracers for this purpose, given their absent correlation with most established CVRFs
Epigenetic-Like Stimulation of Receptor Expression in SSTR2 Transfected HEK293 Cells as a New Therapeutic Strategy
Full text linkSIMPLE SUMMARY: Neuroendocrine tumors (NETs) expressing the somatostatin receptor subtype 2 (SSTR2) are promising targets for peptide receptor radionuclide therapy (PRRT) using the somatostatin analogue Lu-177-DOTATATE. Patients expressing low levels of SSTR2 do not benefit from PRRT. Therefore, an approach to increase the efficacy of PRRT utilizing the effects of 5-aza-2′-deoxycytidine (5-aza-dC) and valproic acid (VPA) on the SSTR2 expression levels is investigated. The cell lines HEKsst(2) and PC3 are incubated with 5-aza-dC and VPA in different combinations. The drug pretreatment of HEKsst(2) cells leads to increased Lu-177-DOTATATE uptake values (factor 28) and lower cell survival (factor 4) in comparison to unstimulated cells; in PC3 cells, the effects are negligible. Further, for the stimulated cell types, the maintenance of the intrinsic radiosensitivity in each cell type is confirmed by X-ray irradiation. The increased SSTR2 expression induced by VPA and 5-aza-dC stimulation in HEKsst(2) cells might improve treatment strategies for patients with NETs. ABSTRACT: The aim of the study was to increase the uptake of the SSTR2-targeted radioligand Lu-177-DOTATATE using the DNA methyltransferase inhibitor (DNMTi) 5-aza-2′-deoxycytidine (5-aza-dC) and the histone deacetylase inhibitor (HDACi) valproic acid (VPA). The HEKsst(2) and PC3 cells were incubated with variable concentrations of 5-aza-dC and VPA to investigate the uptake of Lu-177-DOTATATE. Cell survival, subsequent to external X-rays (0.6 or 1.2 Gy) and a 24 h incubation with 57.5 or 136 kBq/mL Lu-177-DOTATATE, was investigated via colony formation assay to examine the effect of the epidrugs. In the case of stimulated HEKsst(2) cells, the uptake of Lu-177-DOTATATE increased by a factor of 28 in comparison to the unstimulated cells. Further, stimulated HEKsst(2) cells demonstrated lower survival fractions (factor 4). The survival fractions of the PC3 cells remained almost unchanged. VPA and 5-aza-dC did not induce changes to the intrinsic radiosensitivity of the cells after X-ray irradiation. Clear stimulatory effects on HEKsst(2) cells were demonstrated by increased cell uptake of the radioligand and enhanced SST2 receptor quantity. In conclusion, the investigated approach is suitable to stimulate the somatostatin receptor expression and thus the uptake of Lu-177-DOTATATE, enabling a more efficient treatment for patients with poor response to peptide radionuclide therapy (PRRT)
Evaluierung des Potenzials von neuralen Stammzellen als tumoradressierende Vehikel für Nanopartikel
No full textThe therapy of glioblastoma still poses a major challenge for medicine today. Many innovative approaches are being investigated to enable targeted and effective therapy and thus achieve a better prognosis for affected patients. Neural stem cells and their tumour-migrating properties can be used as a powerful tool in this regard. This work shows that neural stem cells of the ReNcell CX cell line can be effectively loaded with different PEG-based nanogels while maintaining their ability to migrate. The nucleoside analogue EdC was efficiently taken up and incorporated into DNA by glioblastoma cells but poorly by physiological astrocytes and NSC. EdC bound to nanogels via a redox-sensitive linker can be cleaved and incorporated into DNA by glioblastoma cells. The proposed therapeutic approach using NSCs as a transport medium seems very promising. Following further investigations, the use of the radiolabelled nucleoside analogue 125/123ITdU instead of EdC can then be examined in vitro and in vivo
Synthesis of 18F-Labelled β-Lactams by Using the Kinugasa Reaction
No full text© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Locking and loading the bullet against micro-calcification
Full text linkAims Despite recent medical advances, cardiovascular disease remains the leading cause of death worldwide. As (micro)-calcification is a hallmark of atherosclerosis, this review will elaborately discuss advantages of sodium fluoride positron emission tomography (PET) as a reliable cardiovascular imaging technique for identifying the early onset of vascular calcification (i.e. locking onto the target). We assess state-of-the-art meta-analysis and clinical studies of possible treatment options and evaluate the concept of vitamin K supplementation to preserve vascular health (i.e. loading the bullet). Methods and results After a structured PubMed search, we identified F-18-sodium fluoride (F-18-NaF) PET as the most suitable technique for detecting micro-calcification. Presenting the pros and cons of available treatments, vitamin K supplementation should be considered as a possible safe and cost-effective option to inhibit vascular (micro)-calcification. Conclusion This review demonstrates need for more extensive research in the concept of vitamin K supplementation (i.e. loading the bullet) and recommends monitoring the effects on vascular calcification using F-18-NaF PET (i.e. locking onto the target)
Evaluation of radiolabeled stimuli-sensitive nanogels for application in nuclear medicine
No full textEndogenous radiotherapy allows the direct delivery of radiation to a tumor by means of radiolabeled antibodies or minibodies as well as peptides, proteins or isotopes of halogens (like radioiodine therapy of thyroid cancer). However, still only few of these endogenous radiotherapy approaches are implemented in standard patient treatment. So far and irrespective of the strong research interest in nanomedicine, the efficacy of aqueous nanogels carrying radionuclides for endogenous radiotherapy has not been evaluated systematically and there are only few reports on the diagnostic potential of radiolabeled nanogels. Among the different types of nanocarriers (e.g. liposomes, polymeric micelles) which have been proposed as drug delivery vehicles, nanogels are rather unique due to their predominantly hydrophilic character. Nanogels can be “squeezed” and the fluctuations impede adsorption of proteins for entropic reasons. Hence, their aqueous consistence ensures minimized interaction with cells and proteins in the blood, which results in an extended circulation. The shape compliance can be tailored by the degree of crosslinking and very soft nanogels can squeeze through holes, which are much smaller than their hydrodynamic radius. This is important regarding excretion pathways as well as the passive accumulation of the nanogels into the tumor tissue by the enhanced permeability and retention (EPR) effect. The open structure is, however, in contradiction with a high loading capacity. Different from cytotoxic drugs, the dose-effect relation in diagnostic as well as therapeutic application of radionuclides is not only controlled by the concentration but also by the decay characteristics of the chosen radioisotope. While an auger electron emitter can promote cell death on a single cell level, an -emitter kills the cells only in decay proximity (radiation range 40-80 µm) and a --emitter can efficiently radiate the tumor tissue within a depths of 10-100 cells (long-range penetration with 0.1-10 mm). With respect to e.g. larger solid tumor manifestations and the intratumoral turgor effect, which limits the accessibility of the drugs to the deep tumor layers, the crossfire effect of - emitters can be a major advantage. Overall, their effective concentrations are significantly lower than those of a molecular drug and the radioisotope complexes established for medical application are mostly highly hydrophilic and can thus be incorporated in a hydrophilic nanogel without altering its stealth character. Thus, we designed stimuli-sensitive hydrophilic nanogels as carriers of radiolabeled chelators and tested their suitability in different preclinical settings. The nanogel-radionuclides were diagnostically evaluated by means of positron emitting radionuclides (68Ga and 64Cu), suitable for positron emission tomography (PET). In a general biodistribution study in healthy rodents, the radiolabeled nanoformulations showed a size dependent renal elimination and independent of the size only marginal accumulation in organs associated with the mononuclear phagocyte system (MPS). However, gel electrophoresis and size exclusion experiments indicated premature degradation in the circulation of the redox-sensitive nanogels within the first 5 h post injection (p.i.). This early degradation could be reduced by pre-treatment of the animals with buthionine sulfoximine (BSO) which significantly reduced glutathione (GSH; an antioxidant) levels in vivo (especially in liver/ spleen). This GSH reduction resulted in reduced renal excretion, however, with a slight increase in liver accumulation. The non-targeted nanogels rely on the passive accumulation into the tumor tissue by the EPR effect and upon degradation in the tumor microenvironment; an improved penetration of the released low molecular weight prepolymers was expected to yield a homogenous distribution of radioactivity throughout the tumor. However, the EPR effect has its own limitations, i.e., the tremendous heterogeneity in tumor vessel leakiness over space, time, and different types of tumors. Very crucial are variations in the blood flow to the tumor, i.e., density of vascular structures and permeability of the vasculature, as well as structural barriers imposed by the perivascular tumor cells and the extracellular matrix. Furthermore, increased interstitial fluid pressure limits the transport through the dense collagen matrix surrounding the tumor. Those limitations like the high interstitial fluid pressure in combination with drug efflux pumps resulted in a low retention of the proposed polymeric structures. To tackle this limitation receptor/transporter targeting ligands were introduced to yield radiolabeled degradation products that are suitable to actively target tumor cells. This concept was evaluated in somatostatin receptor positive pancreatic carcinoma xenografted mice and PET images indicated a significant higher retention compared to solely passively targeted nanogels as well as a deep penetration that was additionally confirmed by immunohistochemistry via staining of the radiolabeled targeting moiety. In another proof of concept study, nanogels were equipped with a cross reactive material (CRM-197) to promote receptor mediated transcytosis across the Blood Brain Barrier (BBB). Herein, an auger electron emitting radionuclide-labeled nucleoside analogue was covalently attached via enzyme cleavable substrates. The nucleoside analogue alone is not able to cross the BBB, while the nanogel can promote its delivery. The auger electron emitter reduces the crossfire effect and thus reduces damage to healthy tissue. Evaluation of the delivery of (nano)irradiation was performed in an in vitro model of the BBB in a co-culture of human cerebral endothelial cell line (hCMEC/D3), pericytes and astrocytes and/or different glioblastoma cell lines. Receptor mediated transport was confirmed via competition experiments. Upon cleavage, the nucleoside was still able to target cells and induce cell death. In summary, using different isotopes or radionuclides and different targeting moieties, the same construct of nanogels can be used for a variety of diseases and be tailored according to the scientific question
Endogenous nanoirradiation via dual addressing of thymidine synthesis pathway : an effective target in malignant melanoma treatment?
No full textProspektive Beobachtungsstudie zur Validierung von Mortalitätsfaktoren bei ischämischen und hämorrhagischen Schlaganfällen
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