Purpose To evaluate the speciation of gadolinium-containing species after multiple administrations of the gadolinium-based contrast agents (GBCAs) gadodiamide and gadoteridol and to quantify the ...amount of intact gadolinium complexes and insoluble gadolinium-containing species. Materials and Methods A total dose of 13.2 mmol per kilogram of body weight of each GBCA was administered in healthy Wistar rats over a period of 8 weeks. Three days after the final administration, rats were sacrificed, and the brains were excised and divided into three portions. Each portion of brain homogenate was divided into two parts, one for determination of the total gadolinium concentration with inductively coupled plasma mass spectrometry and one for determination of the amount of intact GBCA and gadolinium-containing insoluble species. Relaxometric measurements of gadodiamide and gadolinium trichloride in the presence of polysialic acid were also performed. Results The mean total gadolinium concentrations for gadodiamide and gadoteridol, respectively, were 0.317 μg/g ± 0.060 (standard deviation) and 0.048 μg/g ± 0.004 in the cortex, 0.418 μg/g ± 0.078 and 0.051 μg/g ± 0.009 in the subcortical brain, and 0.781 μg/g ± 0.079 and 0.061 μg/g ± 0.012 in the cerebellum. Gadoteridol comprised 100% of the gadolinium species found in rats treated with gadoteridol. In rats treated with gadodiamide, the largest part of gadolinium retained in brain tissue was insoluble species. In the cerebellum, the amount of intact gadodiamide accounts for 18.2% ± 10.6 of the total gadolinium found therein. The mass balance found for gadolinium implies the occurrence of other soluble gadolinium-containing species (approximately 30%). The relaxivity of the gadolinium polysialic acid species formed in vitro was 97.8 mM/sec at 1.5 T and 298 K. Conclusion Gadoteridol was far less retained, and the entire detected gadolinium was intact soluble GBCA, while gadodiamide yielded both soluble and insoluble gadolinium-containing species, with insoluble species dominating.
RSNA, 2017 Online supplemental material is available for this article.
Contrast in magnetic resonance imaging (MRI) arises from changes in the intensity of the proton signal of water between voxels (essentially, the 3D counterpart of pixels). Differences in intervoxel ...intensity can be significantly enhanced with chemicals that alter the nuclear magnetic resonance (NMR) intensity of the imaged spins; this alteration can occur by various mechanisms. Paramagnetic lanthanide(III) complexes are used in two major classes of MRI contrast agent: the well-established class of Gd-based agents and the emerging class of chemical exchange saturation transfer (CEST) agents. A Gd-based complex increases water signal by enhancing the longitudinal relaxation rate of water protons, whereas CEST agents decrease water signal as a consequence of the transfer of saturated magnetization from the exchangeable protons of the agent. In this Account, we survey recent progress in both areas, focusing on how MRI is becoming a more competitive choice among the various molecular imaging methods. Compared with other imaging modalities, MRI is set apart by its superb anatomical resolution; however, its success in molecular imaging suffers because of its intrinsic insensitivity. A relatively high concentration of molecular agents (0.01−0.1 mM) is necessary to produce a local alteration in the water signal intensity. Unfortunately, the most desirable molecules for visualization in molecular imaging are present at much lower concentrations, in the nano- or picomolar range. Therefore, augmenting the sensitivity of MRI agents is key to the development of MR-based molecular imaging applications. In principle, this task can be tackled either by increasing the sensitivity of the reporting units, through the optimization of their structural and dynamic properties, or by setting up proper amplification strategies that allow the accumulation of a huge number of imaging reporters at the site of interest. For Gd-based agents, high sensitivities can be attained by exploiting a range of nanosized carriers (micelles, liposomes, microemulsions, and the like, as well as biological structures such as apoferritin and lipoproteins) properly loaded with Gd-based chelates. Furthermore, the sensitivity of Gd-based agents can be markedly affected either by their interactions with biological structures or by their cellular localization. For CEST agents, a huge sensitivity enhancement has been obtained by using the water molecules contained in the inner cavity of liposomes as the exchangeable source of protons for magnetization transfer. Several “tricks” (for example, the use of multimeric lanthanide(III) shift reagents, changes in the shape of the liposome container, and so forth) have been devised to improve the chemical shift separation between the intraliposomal water and the “bulk” water resonances. Overall, excellent sensitivity enhancements have been obtained for both classes of agents, enabling their use in MR molecular imaging applications.
Poly-aromatic peptide sequences are able to self-assemble into a variety of supramolecular aggregates such as fibers, hydrogels, and tree-like multi-branched nanostructures. Due to their ...biocompatible nature, these peptide nanostructures have been proposed for several applications in biology and nanomedicine (tissue engineering, drug delivery, bioimaging, and fabrication of biosensors). Here we report the synthesis, the structural characterization and the relaxometric behavior of two novel supramolecular diagnostic agents for magnetic resonance imaging (MRI) technique. These diagnostic agents are obtained for self-assembly of DTPA(Gd)-PEG8-(FY)3 or DOTA(Gd)-PEG8-(FY)3 peptide conjugates, in which the Gd-complexes are linked at the N-terminus of the PEG8-(FY)3 polymer peptide. This latter was previously found able to form self-supporting and stable soft hydrogels at a concentration of 1.0% wt. Analogously, also DTPA(Gd)-PEG8-(FY)3 and DOTA(Gd)-PEG8-(FY)3 exhibit the trend to gelificate at the same range of concentration. Moreover, the structural characterization points out that peptide (FY)3 moiety keeps its capability to arrange into β-sheet structures with an antiparallel orientation of the β-strands. The high relaxivity value of these nanostructures (~12 mM
·s
at 20 MHz) and the very low in vitro cytotoxicity suggest their potential application as supramolecular diagnostic agents for MRI.
Breast Cancer is the most diffuse cancer among women and the treatment outcome is largely determined by its early detection. MRI at fixed magnetic field is already widely used for cancer detection. ...Herein it is shown that the acquisition of proton T
at different magnetic fields adds further advantages. In fact, Fast Field Cycling Nuclear Magnetic Resonance Dispersion (FFC-NMRD) profiles have been shown to act as a high -sensitivity tool for cancer detection and staging in ex vivo murine breast tissues collected from Balb/NeuT mice. From NMRD profiles it was possible to extract two new cancer biomarkers, namely: (i) the appearance of
N-quadrupolar peaks (QPs) reporting on tumor onset and (ii) the slope of the NMRD profile reporting on the progression of the tumor. By this approach it was possible to detect the presence of tumor in transgenic NeuT mice at a very early stage (5-7 weeks), when the disease is not yet detectable by using conventional high field (7 T) MRI and only minimal abnormalities are present in histological assays. These results show that, NMRD profiles may represent a useful tool for early breast cancer detection and for getting more insight into an accurate tumor phenotyping, highlighting changes in composition of the mammary gland tissue (lipids/proteins/water) occurring during the development of the neoplasia.
Procedures To preliminary assess the relationship between Manganese Enhanced Magnetic Resonance Imaging (MEMRI) and the expression of calcium receptors in human prostate and breast cancer animal ...models. Methods NOD/SCID mice were inoculated with MDA-MB-231 breast cancer cells and prostate PC3 cancer cells to develop orthotopic or pseudometastatic cancer animal models. Mice were studied on a clinical 3T scanner by using a prototype birdcage coil before and after intravenous injection of MnCl.sub.2 . Assessment of receptor's status was carried out after the MR images acquisition by immunohistochemistry on excised tumours. Results Manganese contrast enhancement in breast or prostate cancer animal models well correlated with CaSR expression (p<0.01), whereas TRPV6 expression levels appeared not relevant to the Mn uptake. Conclusion Our preliminary results suggest that MEMRI appears an efficient tool to characterize human breast and prostate cancer animal models in the presence of different expression level of calcium receptors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Two new cyclic hexapeptoids incorporating N-carboxyethylglycine and N-methoxyethylglycine residues are able to efficiently bind Gd(3+). Their thermodynamic stabilities and relaxivities have been ...assessed by (1)H-relaxometric investigations.
Very recently we proposed novel di- and tetra-phenylalanine peptides derivatized with gadolinium complexes as potentials supramolecular diagnostic agents for applications in MRI (Magnetic Resonance ...Imaging). It was observed that in very short FF dipeptide building blocks, the propensity to aggregate decreases significantly after modification with bulky moiety such as Gd-complexes, thus limiting their potential as CAs. We hypothesized that the replacement of the Phe side chain with more extended aromatic groups could improve the self-assembling. Here we describe the synthesis, structural and relaxometric behavior of a novel water soluble self-assembled peptide CA based on 2-naphthylalanine (2Nal). The peptide conjugate Gd-DOTA-L
-(2Nal)
is able to self-assemble in long fibrillary nanostructures in water solution (up to 1.0 mg/mL). CD and FTIR spectroscopies indicate a β sheet secondary structure with an antiparallel orientation of single strands. All data are in good agreement with WAXS and SAXS characterizations that show the typical "cross-β pattern" for fibrils at the solid state. Molecular modeling indicates the three-dimensional structure of the peptide spine of aggregates is essentially constituted by extended β-sheet motifs stabilized by hydrogen bonds and hydrophobic interactions. The high relaxivity of nanoaggregates (12.3 mM
s
at 20 MHz) and their capability to encapsulate doxorubicin suggest their potential application as supramolecular theranostic agents.
MRI Paramagnetic Probes for Cellular Labeling Gianolio, Eliana; Stefania, Rachele; Di Gregorio, Enza ...
European journal of inorganic chemistry,
April 2012, Letnik:
2012, Številka:
12
Journal Article
Recenzirano
This review discusses the main procedures that have been developed for pursuing the task of an efficient cellular labelling with paramagnetic metal complexes for MRI detection. Although most of the ...work deals with GdIII‐based relaxation enhancers it is shown that the emerging class of paraCEST agents can allow the visualization of more cell types in the same MR image. To improve the detection of labelled cells, it is often necessary to deal with the use of nano‐sized carriers able to deliver a large number of paramagnetic metal complexes. Finally, selected examples are reported to show how proper design of the paramagnetic complex can offer the way to acquire key information on underlying processes in the labelled cells.
The main procedures which allow an efficient cellular labelling with paramagnetic metal complexes for MRI detection are discussed. Systems which use GdIII and MnII‐based relaxation enhancers as labeling probes have been considered, as well as the emerging class of paraCEST agents which allows the visualization of more cell types in the same MR image.
Generated by a hierarchical and multiscale self-assembling phenomenon, peptide-based hydrogels (HGs) are soft materials useful for a variety of applications. Short and ultra-short peptides are ...intriguing building blocks for hydrogel fabrication. These matrices can also be obtained by mixing low-molecular-weight peptides with other chemical entities (e.g., polymers, other peptides). The combination of two or more constituents opens the door to the development of hybrid systems with tunable mechanical properties and unexpected biofunctionalities or morphologies. For this scope, the formulation, the multiscale analysis, and the supramolecular characterization of novel hybrid peptide-polymer hydrogels are herein described. The proposed matrices contain the Fmoc-FF (N
-fluorenylmethyloxycarbonyl diphenylalanine) hydrogelator at a concentration of 0.5 wt% (5.0 mg/mL) and a diacrylate α-/ω-substituted polyethylene-glycol derivative (PEGDA). Two PEGDA derivatives, PEGDA 1 and PEGDA2 (mean molecular weights of 575 and 250 Da, respectively), are mixed with Fmoc-FF at different ratios (Fmoc-FF/PEGDA at 1/1, 1/2, 1/5, 1/10 mol/mol). All the multicomponent hybrid peptide-polymer hydrogels are scrutinized with a large panel of analytical techniques (including proton relaxometry, FTIR, WAXS, rheometry, and scanning electronic microscopy). The matrices were found to be able to generate mechanical responses in the 2-8 kPa range, producing a panel of tunable materials with the same chemical composition. The release of a model drug (Naphthol Yellow S) is reported too. The tunable features, the different topologies, and the versatility of the proposed materials open the door to the development of tools for different applicative areas, including diagnostics, liquid biopsies and responsive materials. The incorporation of a diacrylate function also suggests the possible development of interpenetrating networks upon cross-linking reactions. All the collected data allow a mutual comparison between the different matrices, thus confirming the significance of the hybrid peptide/polymer-based methodology as a strategy for the design of innovative materials.
Four novel MRI Gd(III)-based probes have been synthesized and evaluated for their labeling properties on cultured cell lines K562, C6, and B16. The labeling strategy relies upon the fact that cells ...display a large number of reactive exofacial protein thiols (EPTs) that can be exploited as anchorage points for suitably activated MRI probes. The probes are composed of a Gd(III) chelate (based on either DO3A or DTPA) connected through a flexible linker to the 2-pyridyldithio chemical function for binding to EPTs. GdDO3A-based chelates could efficiently label cells (up to a level of 1.2 × 1010 Gd(III) atoms/cell), whereas GdDTPA-based chelates showed poor or no cell labeling ability at all. Among the GdDO3A based compounds, that having the longest spacer (compound GdL1A) showed the best labeling efficacy. The mechanism of EPT mediated cell labeling by GdL1A involves probe internalization without sequestration of the Gd(III) chelate within subcellular structures such as endosomes.
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