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ABSTRACT: Apoferritin has been exploited to deliver simultaneously therapeutic and imaging agents (loaded into its internal cavity) to hepatocytes as this protein is efficiently taken up from blood by hepatocyte scavenger receptor class A type 5 via the ferritin transporting route. To this purpose the protein has been loaded with the MRI contrast agent GdHPDO3A and Curcumin, a polyphenolic substance endowed with multiple pharmacological actions namely: antioxidant, anti-inflammatory, antineoplastic. Curcumin and GdHPDO3A loaded apoferritin has been used with the aim to attenuate the thioacetamide-induced hepatitis together with the evaluation by MRI of drug delivery efficiency. Mice pre-treated by intraperitoneal administration showed significantly attenuated hepatic injury as assessed by measuring alanine aminotransferase (ALT) activity in plasma and by histology assessment. The encapsulation of curcumin inside the apoferritin cavity significantly increases its stability and bioavailability while maintaining its therapeutic anti-inflammatory properties.
Molecular Pharmaceutics 04/2013; · 4.78 Impact Factor
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ABSTRACT: Parametric MRI: A paramagnetic gadolinium-loaded liposome for the MRI assessment of the activity of matrix metalloproteinase-2 (MMP-2) is described. The assessment relies on a procedure that involves the ratio R2p /R1p between the transverse and longitudinal paramagnetic contributions to the water proton relaxation rate. This method is independent of the total gadolinium concentration.
Angewandte Chemie International Edition 02/2013; · 13.45 Impact Factor
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ABSTRACT: Introduction: The use of hyperpolarized molecules allows one to obtain information about metabolism in both cells and animals; such a task represents a tremendous advancement with respect to the results achieved so far with in vivo NMR techniques. Pyruvate appears an excellent tumor biomarker as it allows the attainment of early diagnosis, stadiation and monitoring of response to therapy. Areas covered: As pyruvate conversion to lactate in the glycolytic pathway is highly enhanced in tumor cells, the 1-13C-lactate levels after administration of hyperpolarized 1-13C-pyruvate are markedly higher in tumor tissues and depend on the type and grade of the tumor. This review covers the most recent research results (both in vitro and in vivo) about the use of hyperpolarized 1-13C-pyruvate for tumor localization, stadiation and for monitoring the response to therapy. The technique may find application in clinics, especially when other imaging modalities are of difficult applicability. Expert opinion: While 13C-pyruvate has been shown to be the candidate of choice for metabolic imaging, high expectations are present in the scientific community to see if other hyperpolarized substrates could provide more specific and sensitive biomarkers. The use of hyperpolarized molecules will have a tremendous impact in the armory of diagnostic tools.
Expert Opinion on Medical Diagnostics 07/2012; 6(4):335-345.
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Dario Livio Longo, Walter Dastrù,
Giuseppe Digilio,
Jochen Keupp,
Sander Langereis,
Stefania Lanzardo,
Simone Prestigio,
Oliver Steinbach,
Enzo Terreno,
Fulvio Uggeri,
Silvio Aime
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ABSTRACT: Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH-dependent. Thus, a ratiometric method for pH assessment has been set-up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5-7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH-changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition.
Magnetic Resonance in Medicine 01/2011; 65(1):202-11. · 2.96 Impact Factor
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ABSTRACT: The application of hyperpolarization techniques for MRI purposes is gathering increasing attention, especially for nuclei such as (13)C or (129)Xe. Among the different proposed methods, ParaHydrogen Induced Polarization requires relatively cheap equipment. The setup of an MRI experiment by means of parahydrogen requires the application of skills and methodologies that derive from different fields of knowledge. The basic theory and a practical insight of this method are presented here. Parahydrogenation of alkynes, having a labelled (13)CO group adjacent to the triple bond, catalyzed by Rh(I) complexes containing a chelating phosphine, represents the best choice for producing and maintaining high heteronuclear polarization effect. In order to transform anti-phase into in-phase (net) (13)C polarization for MRI application it is necessary to set up the described magnetic field cycle procedure. In vitro and in vivo images have been acquired using fast imaging sequences (RARE and trueFISP). Copyright © 2010 John Wiley & Sons, Ltd.
Contrast Media & Molecular Imaging 12/2010; · 3.33 Impact Factor
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ABSTRACT: This work aims at developing a MRI method that allows to get more insight into the understanding of the in vivo fate of liposomes and their payload. The method relies on the temporal assessment of the contrast changes induced by the presence of a classical relaxation agent versus the effect induced by a CEST (chemical exchange saturation transfer) agent. Liposomes were loaded with the paramagnetic complexes, Gd-HPDO3A and [Tm-DOTMA](-) [Na](+), in order to endow the nanovesicles with the characteristic properties of T(1)/T(2) and CEST/T(2) MRI agents, respectively. The paramagnetically loaded liposomes were injected directly into the tumor (B16 melanoma xenograft in mice) where they generate T(1), T(2), and CEST MR contrasts that were quantitatively monitored over time (0-48h). The kinetic of each contrast enhancement reports about peculiar properties relative to the fate of the liposomes in the tumor environment. A kinetic model has been set-up to fit the experimental multicontrast data in order to extract the relevant information about the cellular uptake of the liposomes and the release of their payload. Upon comparing conventional stealth liposomes with pH-sensitive ones, it has been shown that the latter ones differ essentially in the step associated with the release of the drug that is likely occurring in the endosomal acidic vesicles.
Journal of Controlled Release 03/2010; 144(3):271-9. · 5.73 Impact Factor
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ABSTRACT: Two hybrid materials based on mesoporous silicas SBA-15 and MCM-41 functionalized with stable and electrically neutral Gd(iii) macrocyclic complexes were prepared, and their (1)H NMR relaxometric properties investigated as a function of temperature and magnetic field strength.
Chemical Communications 04/2009; · 6.17 Impact Factor
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ABSTRACT: Two hybrid materials based on NH2-functionalized mesoporous silicas with different pore size and grafted by DOTA monoamide Gd-complexes show a four-fold difference in their proton relaxivity arising from a selective localization of the paramagnetic probes on the inner and outer silica surfaces.
Chemical Communications 01/2009; · 6.17 Impact Factor
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ABSTRACT: Two alkyne derivatives, which contain one and two oligooxyethylenic chains respectively, showed to be good substrates for para-hydrogenation reactions, yielding the corresponding hyperpolarized alkenes in good yields. A suitable theory has been developed to account for the observed results, fully explaining the different para-H 2 induced effects observed upon the para-hydrogenation of symmetrically and asymmetrically substituted alkynes in ALTADENA and PASADENA modes. The oligooxyethylenic substituent provides good water solubility to the para-hydrogenated symmetrical derivative. (13)C-MR in vitro images of the latter derivative were obtained both in acetone and in water solutions (130 mM), using the ALTADENA procedure and after application of the field cycling procedure which allows acquisition of an in-phase (13)C carbonyl resonance. The finding that the hydrogenated product is water-soluble in contrast to the parent alkyne which is not allows for the pursuit of a fast phase-transfer separation from the organic solvent, the unreacted substrate, and the catalyst to obtain a "ready-to-use" water solution suitable for further in vivo MRI applications.
Journal of the American Chemical Society 11/2008; 130(45):15047-53. · 9.91 Impact Factor
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ABSTRACT: This article illustrates some innovative applications of liposomes loaded with paramagnetic lanthanide-based complexes in MR molecular imaging field. When a relatively high amount of a Gd(III) chelate is encapsulated in the vesicle, the nanosystem can simultaneously affect both the longitudinal (R(1)) and the transverse (R(2)) relaxation rate of the bulk H2O H-atoms, and this finding can be exploited to design improved thermosensitive liposomes whose MRI response is not longer dependent on the concentration of the probe. The observation that the liposome compartmentalization of a paramagnetic Ln(III) complex induce a significant R(2) enhancement, primarily caused by magnetic susceptibility effects, prompted us to test the potential of such agents in cell-targeting MR experiments. The results obtained indicated that these nanoprobes may have a great potential for the MR visualization of cellular targets (like the glutamine membrane transporters) overexpressing in tumor cells. Liposomes loaded with paramagnetic complexes acting as NMR shift reagents have been recently proposed as highly sensitive CEST MRI agents. The main peculiarity of CEST probes is to allow the MR visualization of different agents present in the same region of interest, and this article provides an illustrative example of the in vivo potential of liposome-based CEST agents.
Chemistry & Biodiversity 11/2008; 5(10):1901-12. · 1.80 Impact Factor
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Berichte der deutschen chemischen Gesellschaft 08/2008; 2008(28):4348 - 4351. · 2.94 Impact Factor
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Paolo Accornero,
Giuseppe Lattanzio,
Tony Mangano,
Roberto Chiarle,
Riccardo Taulli,
Francesca Bersani,
Paolo E Forni,
Silvia Miretti,
Claudio Scuoppo, Walter Dastrù,
James G Christensen,
Tiziana Crepaldi,
Carola Ponzetto
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ABSTRACT: Met, the tyrosine kinase receptor for hepatocyte growth factor, is frequently deregulated in human cancer. Recent evidence indicates that Met amplification may confer resistance to treatments directed toward other receptor tyrosine kinases. Thus, there is a need to develop Met inhibitors into therapeutic tools, to be used alone or in combination with other molecularly targeted drugs. Preclinical validation of Met inhibitors has thus far been done in nude mice bearing cancer cells xenografts. A far superior model would be a transgenic line developing spontaneous Met-driven tumors with high penetrance and short latency.
To this end, we introduced into the mouse genome TPR-MET, the oncogenic form of MET. The Tpr-Met protein ensures deregulation of Met signaling because dimerization motifs in the Tpr moiety cause ligand-independent activation of the Met kinase.
Here, we describe a TPR-MET transgenic line that develops thymic T-cell lymphoma with full penetrance and very short latency. In the tumors, Tpr-Met and its effectors were phosphorylated. Treatment of tumor-derived T lymphocytes with the selective Met inhibitor PHA-665752 at nanomolar concentrations abolished phosphorylation of Met and downstream effectors and led to caspase-mediated apoptosis. I.v. administration of PHA-665752 to transgenic mice bearing lymphomas in exponential growth phase led to a significant decrease in tumor growth and, in some cases, to tumor regression.
Our transgenic line, which within 2 months reliably develops Tpr-Met-driven T-cell lymphoma, represents a valuable tool to explore the efficacy and therapeutic potential of Met kinase inhibitors as anticancer drugs.
Clinical Cancer Research 05/2008; 14(7):2220-6. · 7.74 Impact Factor
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ABSTRACT: The intrinsic low sensitivity of the NMR phenomenon can be overcome thanks to hyperpolarization procedures that break the limits of the Boltzmann equilibrium and may increase the NMR signal by a factor of 10(5). Hyperpolarization procedures have been applied to enhance the signal from noble gases, such as 3He and 129Xe, and small 13C-containing molecules. For the latter class, attention has been focused on the use of methods based on dynamic nuclear polarization (DNP) and para-hydrogen induced polarization (PHIP). After discussion of the basics of the methods, an overview of the main applications with 13C-containing molecules is presented. This includes pre-clinical MR investigations of vascular imaging, perfusion and catheter tracking as well as molecular imaging protocols that allow the development of highly innovative studies in the field of metabolic imaging.
Handbook of experimental pharmacology 02/2008;
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Elisa Ciraolo,
Manuela Iezzi,
Romina Marone,
Stefano Marengo,
Claudia Curcio,
Carlotta Costa,
Ornella Azzolino,
Cristiano Gonella,
Cristina Rubinetto,
Haiyan Wu, [......],
Fiorella Altruda,
Emilia Turco,
Letizia Lanzetti,
Piero Musiani,
Thomas Rückle,
Christian Rommel,
Jonathan M Backer,
Guido Forni,
Matthias P Wymann,
Emilio Hirsch
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ABSTRACT: The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110beta (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB(K805R) mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110beta function revealed that p110beta catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors as well as to sustain long-term insulin signaling. In addition, PIK3CB(K805R) mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110beta catalytic activity in diabetes and cancer, opening potential avenues for therapeutic intervention.
Science Signaling 02/2008; 1(36):ra3. · 7.50 Impact Factor
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Paolo E Forni,
Claudio Scuoppo,
Itaru Imayoshi,
Riccardo Taulli, Walter Dastrù,
Valentina Sala,
Ulrich A K Betz,
Patrizia Muzzi,
Daniela Martinuzzi,
Alessandro E Vercelli,
Ryoichiro Kageyama,
Carola Ponzetto
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ABSTRACT: Hydrocephalus is a common and variegated pathology often emerging in newborn children after genotoxic insults during pregnancy (Hicks and D'Amato, 1980). Cre recombinase is known to have possible toxic effects that can compromise normal cell cycle and survival. Here we show, by using three independent nestin Cre transgenic lines, that high levels of Cre recombinase expression into the nucleus of neuronal progenitors can compromise normal brain development. The transgenics analyzed are the nestin Cre Balancer (Bal1) line, expressing the Cre recombinase with a nuclear localization signal, and two nestin CreER(T2) (Cre recombinase fused with a truncated estrogen receptor) mice lines with different levels of expression of a hybrid CreER(T2) recombinase that translocates into the nucleus after tamoxifen treatment. All homozygous Bal1 nestin Cre embryos displayed reduced neuronal proliferation, increased aneuploidy and cell death, as well as defects in ependymal lining and lamination of the cortex, leading to microencephaly and to a form of communicating hydrocephalus. An essentially overlapping phenotype was observed in the two nestin CreER(T2) transgenic lines after tamoxifen mediated-CreER(T2) translocation into the nucleus. Neither tamoxifen-treated wild-type nor nestin CreER(T2) oil-treated control mice displayed these defects. These results indicate that some forms of hydrocephalus may derive from a defect in neuronal precursors proliferation. Furthermore, they underscore the potential risks for developmental studies of high levels of nuclear Cre in neurogenic cells.
Journal of Neuroscience 10/2006; 26(37):9593-602. · 7.11 Impact Factor
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ABSTRACT: This communication reports the dramatic relaxation enhancements that can be obtained upon the interaction of substrates like lactate, trifluorolactate and inorganic phosphate with the paramagnetic GdDO3A agent. This occurs thanks to the formation of kinetically labile ternary complexes in which the substrate nuclei are in close proximity to the paramagnetic center. It is demonstrated that heteronuclear (13)C, (19)F and (31)P-MR images can be obtained from phantoms containing the substrate in the millimolar concentration range.
Contrast Media & Molecular Imaging 06/2006; 1(3):101-5. · 3.33 Impact Factor
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ABSTRACT: Four alkyne-functionalized poly(lysine) derivatives have been synthesized and characterized by 1H and 13C NMR spectroscopy. In the first poly(lysine) derivative, phenylpropiolate moieties are directly bound to the aminic arms, whereas in the other derivatives, propargylamine moieties are bound to the aminic poly(lysine) arms through glucaric acid and diethylene glycol (DG) chains, respectively. para-Hydrogenation of the alkyne-functionalized poly(lysine) compounds has been investigated and the results have been discussed in terms of spin lattice relaxation properties of the hydrogenated products. It is shown that the longer the mobile chain separating the unsaturation from the poly(lysine) backbone, the more intense the polarized signals when para-hydrogenation is carried out. This is due to (a) the maintenance of short reorientational times on the unsaturated ends, and therefore a sufficiently long T(1) of the protons added during hydrogenation, and (b) the minor effect of steric hindrance by the poly(lysine) backbone that decreases interaction of the unsaturation with the catalyst, allowing higher hydrogenation rates.
Organic & Biomolecular Chemistry 12/2005; 3(21):3948-54. · 3.70 Impact Factor
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ABSTRACT: Gd(III) complexes are under intense scrutiny as contrast agents for magnetic resonance imaging (MRI). They act by enhancing tissutal proton relaxation rates. Much has already been done in order to get an in-depth understanding of the relationships between structure, dynamics, and contrastographic ability of these paramagnetic complexes. Their potential in the assessment of flow, perfusion, and capillary permeability has already been established. The next challenges are in the field of molecular imaging applications, which would allow the attainment of early diagnosis based on the recognition of specific reporters of the onset of the pathological state. To this end, Gd(III) complexes have to be endowed with improved targeting capabilities by conjugating suitable recognition synthons on their surfaces. Small peptides are candidates of choice for the attainment of this goal. Moreover, the intrinsic low sensitivity of the NMR techniques implies the need to deliver large amounts of contrast agents to the target in order to get its visualization in the resulting images. Highly efficient delivery systems have been identified, which bring a great promise for the development of innovative diagnostic agents based on Gd(III) complexes.
Biopolymers 02/2002; 66(6):419-28. · 2.87 Impact Factor
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ABSTRACT: The hydrogenation of symmetric dienes with para-H2 catalyzed by Rhodium complexes leads to remarkable effects in the 1H NMR spectra of the corresponding alkene derivatives, namely, an emission peak (negative peak) in the aliphatic region ascribed to protons of the hydrogenated double bond and one or more enhanced absorption peaks. The strongest absorption peak is invariantly assigned to the two equivalent olefinic protons in the free alkene. The possibility that the observed behavior could be associated with a reversible exchange between para-H2 and the olefinic hydrogens has been ruled out on the basis of the lack of deuterium incorporation when the experiments are carried out with D2. Variable magnetic field experiments have indicated that the positive peaks arise from relaxation processes, i.e., from cross-relaxation transfers (generally denoted as NOE transfers; NOE = nuclear Overhauser effect) originating from the enhanced magnetization at the hydrogenation sites in the product or, more likely, at the hydride ligands in intermediate species.
06/2001;
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ABSTRACT: The title compound appears to be present in solution as one major (98%) and two minor (ca. 1% each) isomers. All three isomers contain one bridging and one terminal hydride ligand. However, they differ in the location of the terminal hydride. Proton T1 measurements at variable temperature have allowed the determination of HT−HB distances in each isomer. An estimation of the relative “hydridicity” of bridging and terminal hydrides has been gained by measuring the T1 of 2H(μ-2H)Os3(CO)11, while insights into the terminal/bridging hydride exchange have been gained from 1H variable-temperature NMR.
05/2000;
