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1.
ACS Appl Mater Interfaces ; 10(45): 38819-38832, 2018 Nov 14.
Article in English | MEDLINE | ID: mdl-30351897

ABSTRACT

In the last years, extensive attention has been paid on designing and developing functional imaging contrast agents for providing accurate noninvasive evaluation of pathology in vivo. However, the issue of false-positives or ambiguous imaging and the lack of a robust strategy for simultaneous dual-mode imaging remain to be fully addressed. One effective strategy for improving it is to rationally design magnetic resonance imaging (MRI) contrast agents (CAs) with intrinsic T1/ T2 dual-mode imaging features. In this work, the development and characterization of one-pot synthesized nanostructured coordination polymers (NCPs) which exhibit dual mode T1/ T2 MRI contrast behavior is described. The resulting material comprises the combination of different paramagnetic ions (Fe3+, Gd3+, Mn2+) with selected organic ligands able to induce the polymerization process and nanostructure stabilization. Among them, the Fe-based NCPs showed the best features in terms of colloidal stability, low toxicity, and dual T1/ T2 MRI contrast performance overcoming the main drawbacks of reported CAs. The dual-mode CA capability was evaluated by different means: in vitro phantoms, ex vivo and in vivo MRI, using a preclinical model of murine glioblastoma. Interestingly, the in vivo MRI of Fe-NCPs show T1 and T2 high contrast potential, allowing simultaneous recording of positive and negative contrast images in a very short period of time while being safer for the mouse. Moreover, the biodistribution assays reveals the persistence of the nanoparticles in the tumor and subsequent gradual clearance denoting their biodegradability. After a comparative study with commercial CAs, the results suggest these nanoplatforms as promising candidates for the development of dual-mode MRI CAs with clear advantages.


Subject(s)
Brain Neoplasms/diagnostic imaging , Contrast Media/chemistry , Glioblastoma/diagnostic imaging , Metal Nanoparticles/chemistry , Animals , Brain Neoplasms/metabolism , Contrast Media/pharmacokinetics , Female , Ferric Compounds/chemistry , Gadolinium/chemistry , Glioblastoma/metabolism , HeLa Cells , Humans , Magnetic Resonance Imaging/instrumentation , Magnetic Resonance Imaging/methods , Manganese/chemistry , Mice, Inbred C57BL , Tissue Distribution
2.
NMR Biomed ; 29(6): 732-43, 2016 06.
Article in English | MEDLINE | ID: mdl-27061401

ABSTRACT

Characterization of glioblastoma (GB) response to treatment is a key factor for improving patients' survival and prognosis. MRI and magnetic resonance spectroscopic imaging (MRSI) provide morphologic and metabolic profiles of GB but usually fail to produce unequivocal biomarkers of response. The purpose of this work is to provide proof of concept of the ability of a semi-supervised signal source extraction methodology to produce images with robust recognition of response to temozolomide (TMZ) in a preclinical GB model. A total of 38 female C57BL/6 mice were used in this study. The semi-supervised methodology extracted the required sources from a training set consisting of MRSI grids from eight GL261 GBs treated with TMZ, and six control untreated GBs. Three different sources (normal brain parenchyma, actively proliferating GB and GB responding to treatment) were extracted and used for calculating nosologic maps representing the spatial response to treatment. These results were validated with an independent test set (7 control and 17 treated cases) and correlated with histopathology. Major differences between the responder and non-responder sources were mainly related to the resonances of mobile lipids (MLs) and polyunsaturated fatty acids in MLs (0.9, 1.3 and 2.8 ppm). Responding tumors showed significantly lower mitotic (3.3 ± 2.9 versus 14.1 ± 4.2 mitoses/field) and proliferation rates (29.8 ± 10.3 versus 57.8 ± 5.4%) than control untreated cases. The methodology described in this work is able to produce nosological images of response to TMZ in GL261 preclinical GBs and suitably correlates with the histopathological analysis of tumors. A similar strategy could be devised for monitoring response to treatment in patients. Copyright © 2016 John Wiley & Sons, Ltd.


Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/diagnosis , Brain Neoplasms/drug therapy , Glioblastoma/diagnosis , Glioblastoma/drug therapy , Magnetic Resonance Spectroscopy/methods , Molecular Imaging/methods , Animals , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/metabolism , Cell Line, Tumor , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Female , Glioblastoma/metabolism , Magnetic Resonance Imaging/methods , Mice , Mice, Inbred C57BL , Reproducibility of Results , Sensitivity and Specificity , Temozolomide , Treatment Outcome
3.
Br J Cancer ; 106(11): 1816-25, 2012 May 22.
Article in English | MEDLINE | ID: mdl-22568967

ABSTRACT

BACKGROUND: In the preceding decade, various studies on glioblastoma (Gb) demonstrated that signatures obtained from gene expression microarrays correlate better with survival than with histopathological classification. However, there is not a universal consensus formula to predict patient survival. METHODS: We developed a gene signature using the expression profile of 47 Gbs through an unsupervised procedure and two groups were obtained. Subsequent to a training procedure through leave-one-out cross-validation, we fitted a discriminant (linear discriminant analysis (LDA)) equation using the four most discriminant probesets. This was repeated for two other published signatures and the performance of LDA equations was evaluated on an independent test set, which contained status of IDH1 mutation, EGFR amplification, MGMT methylation and gene VEGF expression, among other clinical and molecular information. RESULTS: The unsupervised local signature was composed of 69 probesets and clearly defined two Gb groups, which would agree with primary and secondary Gbs. This hypothesis was confirmed by predicting cases from the independent data set using the equations developed by us. The high survival group predicted by equations based on our local and one of the published signatures contained a significantly higher percentage of cases displaying IDH1 mutation and non-amplification of EGFR. In contrast, only the equation based on the published signature showed in the poor survival group a significant high percentage of cases displaying a hypothesised methylation of MGMT gene promoter and overexpression of gene VEGF. CONCLUSION: We have produced a robust equation to confidently discriminate Gb subtypes based in the normalised expression level of only four genes.


Subject(s)
Brain Neoplasms/genetics , Gene Expression Profiling/methods , Glioblastoma/genetics , Algorithms , Biopsy , Brain Neoplasms/classification , Brain Neoplasms/mortality , DNA Methylation , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Discriminant Analysis , Gene Amplification , Genes, erbB-1 , Glioblastoma/classification , Glioblastoma/mortality , Humans , Isocitrate Dehydrogenase/genetics , Kaplan-Meier Estimate , Mutation , Oligonucleotide Array Sequence Analysis , Proportional Hazards Models , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins/genetics , Vascular Endothelial Growth Factor A/biosynthesis
4.
JBR-BTR ; 94(6): 319-29, 2011.
Article in English | MEDLINE | ID: mdl-22338386

ABSTRACT

MRI and MRS are established methodologies for evaluating intracranial lesions. One MR spectral feature suggested for in vivo grading of astrocytic tumours is the apparent myo-lnositol (ml) intensity (ca 3.55 ppm) at short echo times, although glycine (gly) may also contribute in vivo to this resonance. The purpose of this study was to quantitatively evaluate the ml + gly contribution to the recorded spectral pattern in vivo and correlate it with in vitro data obtained from perchloric acid extraction of tumour biopsies. Patient spectra (n = 95) at 1.5T at short (20-31 ms) and long (135-136 ms) echo times were obtained from the INTERPRET MRS database (http://gabrmn.uab.eslinterpretvalidateddbl). Phantom spectra were acquired with a comparable protocol. Spectra were automatically processed and the ratios of the (ml + gly) to Cr peak heights ((ml + gly)/Cr) calculated. Perchloric acid extracts of brain tumour biopsies were analysed by high-resolution NMR at 9.4T. The ratio (ml + gly)/Cr decreased significantly with astrocytic grade in vivo between low-grade astrocytoma (A2) and glioblastoma multiforme (GBM). In vitro results displayed a somewhat different tendency, with anaplastic astrocytomas having significantly higher (ml + gly)/Cr than A2 and GBM. The discrepancy between in vivo and in vitro data suggests that the NMR visibility of glycine in glial brain tumours is restricted in vivo.


Subject(s)
Astrocytoma/metabolism , Astrocytoma/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Glycine/metabolism , Inositol/metabolism , Magnetic Resonance Spectroscopy/methods , Analysis of Variance , Biopsy , Choline/metabolism , Contrast Media , Creatine/metabolism , Humans , Neoplasm Grading , Perchlorates , Phantoms, Imaging , Statistics, Nonparametric
5.
NMR Biomed ; 19(2): 223-30, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16485320

ABSTRACT

The aim of this work was to identify spectral markers of cell proliferation that could be of use in clinical MRS. Cultured C6 ATCC rat glioma cells were used as models for this purpose and metabolites were extracted with perchloric acid at three different growth curve stages: log, confluence and post-confluence. 1D and 2D in vitro(1)H NMR spectra were recorded at 9.4 T. Statistically significant changes in myo-inositol and glutamine concentrations between log phase and post-confluence were found when normalized to the creatine ratio. The myo-inositol/creatine ratio was 2.76 +/- 0.82 at log phase increasing to 7.43 +/- 1.34 at post-confluence, while the glutamine/creatine ratio decreased from 0.22 +/- 0.03 to 0.10 +/- 0.02. No significant differences were recorded for other metabolites investigated. The fact that both myo-inositol and glutamine are detectable by in vivo MRS at clinical fields makes their changes relevant as potential astrocytic tumour proliferation rate markers in clinical MRS.


Subject(s)
Biomarkers, Tumor/metabolism , Glioma/physiopathology , Magnetic Resonance Spectroscopy/methods , Perchlorates/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Glioma/pathology , Metabolic Clearance Rate , Protons , Rats , Tissue Extracts/metabolism
6.
MAGMA ; 17(1): 36-46, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15340855

ABSTRACT

MRI and MRS are established techniques for the evaluation of intracranial mass lesions and cysts. The 2.03 ppm signal recorded in their (1)H-MRS spectra is often assigned to NAA from outer volume contamination, although it has also been detected in non-infiltrating tumours and large cysts. We have investigated the molecular origin of this resonance in ten samples of cystic fluids from human brain tumours. The NMR detected content of the 2.03 ppm resonance in 136 ms echo time spectra, assuming an N- CH(3) origin, was 3.19 +/- 1.01 mM. Only one third (34 +/- 12%) of the N-acetyl containing compound (NAC) signal could be extracted by perchloric acid (PCA) indicating that most of it originated in a macromolecular PCA-insoluble component. Chemical analysis of the cyst fluids showed that sialic acid bound to macromolecules would account for 64.3% and hexuronic containing compounds for 29.2% of the NMR-detectable ex vivo signal, 93.4% of the signal at TE 136 ms. Lactate content measured by NMR (6.4 +/- 4.4 mM) and the predominance of NAC originating in sialic acid point to a major origin from tumour rather than from plasma for this 2.03 ppm resonance.


Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/metabolism , Magnetic Resonance Spectroscopy/methods , Brain/pathology , Brain Abscess/metabolism , Cysts/metabolism , Humans , Macromolecular Substances/metabolism , Magnetic Resonance Imaging/methods , N-Acetylneuraminic Acid/chemistry , N-Acetylneuraminic Acid/metabolism , Perchlorates/pharmacology , Time Factors
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