In vivo imaging of inhibitory, GABAergic neurons by MRI.

The unambiguous detection of specific neuronal subtypes is up to now only possible with invasive techniques or optical imaging after genetic modification. High field magnetic resonance imaging (MRI) has the ability to visualize the brain structure and anatomy noninvasively, with high resolution--but missing the cell specific and functional information. Here we present a new tool for neuroimaging with MRI, enabling the selective detection of GABAergic neurons under in vivo conditions.

Paramagnetic self-assembled nanoparticles as supramolecular MRI contrast agents.

Nanometer-sized materials offer a wide range of applications in biomedical technologies, particularly imaging and diagnostics. Current scaffolds in the nanometer range predominantly make use of inorganic particles, organic polymers or natural peptide-based macromolecules. In contrast we hereby report a supramolecular approach for the preparation of self-assembled dendritic-like nanoparticles for applications as MRI contrast agents.

Mn-loaded apoferritin: a highly sensitive MRI imaging probe for the detection and characterization of hepatocarcinoma lesions in a transgenic mouse model.

Mn-Apo is a highly sensitive MRI contrast agent consisting of ca. 1000 manganese atoms entrapped in the inner cavity of apoferritin. Part of the metallic payload is in the form of Mn(2+) ions that endow the nano-sized system with a very high relaxivity that can be exploited to detect hepatocellular carcinoma in mice.

Novel Gd(III)-based probes for MR molecular imaging of matrix metalloproteinases.

Two novel Gd-based contrast agents (CAs) for the molecular imaging of matrix metalloproteinases (MMPs) were synthetized and characterized in vitro and in vivo. These probes were based on the PLG*LWAR peptide sequence, known to be hydrolyzed between Gly and Leu by a broad panel of MMPs. A Gd-DOTA chelate was conjugated to the N-terminal position through an amide bond, either directly to proline (compd Gd-K11) or through a hydrophilic spacer (compd Gd-K11N).

A vaccine targeting angiomotin induces an antibody response which alters tumor vessel permeability and hampers the growth of established tumors.

Angiomotin (Amot) is one of several identified angiostatin receptors expressed by the endothelia of angiogenic tissues. We have shown that a DNA vaccine targeting Amot overcome immune tolerance and induce an antibody response that hampers the progression of incipient tumors. Following our observation of increased Amot expression on tumor endothelia concomitant with the progression from pre-neoplastic lesions to full-fledged carcinoma, we evaluated the effect of anti-Amot vaccination on clinically evident tumors.

Mn loaded apoferritin as an MRI sensor of melanin formation in melanoma cells.

Mn(III)-loaded apoferritin is promptly reduced to Mn(II)-apoferritin by the oxidation of L-DOPA to melanin. The process is nicely witnessed by a marked relaxation enhancement of water proton relaxation rate that has been detected both in cultured melanoma cells and in tumor animal models.

Boronated compounds for imaging guided BNCT applications.

Boron neutron capture therapy (BNCT) is based on the capture of thermal neutrons by boron 10 ((10)B) nuclei that have been selectively delivered to tumor cells. The amount of 10-30 μg of boron for g of tumor mass is needed to attain an acceptable therapeutic advantage. Despite that the potentialities of BNCT have been demonstrated in several preclinical studies, this technique has not yet been fully accepted in the armory of tools for tumor treatment.

Structure-function relationships of iodinated contrast media and risk of nephrotoxicity.

Characteristics of CM have greatly changed over time. First-generation ionic CM have many-fold (5-7) greater osmolalities than plasma. Subsequently non ionic CM generations were looked for to reduce osmolality, and encompass nonionic monomers and nonionic dimers reaching osmolality as low as that of plasma (iso-osmolar CM) but paying however dear, as viscosity is considerably increased.

MRI of cells and mice at 1 and 7 Tesla with Gd-targeting agents: when the low field is better!

Tumor cells were targeted with Gd-loaded/LDL (low density lipoproteins) adducts consisting of ca 300 Gd(III) amphiphilic complexes incorporated in the lipophilic LDL particles. The long reorientational time of the Gd(III) complex in the supramolecular adduct yielded a relaxivity peak at ca 1 T, whereas its relaxivity at 7 T was 5 times less. The field-dependent relaxivity markedly affected the signal enhancement attainable at the two magnetic fields.

Synthesis and testing of a p-H2 hyperpolarized 13C probe based on the pyrazolo[1,5-a]pyrimidineacetamide DPA-713, an MRI vector to target the peripheral benzodiazepine receptors.

DPA-713 is the lead compound of a recently developed 2-phenylpyrazolo[1,5-a]pyrimidineacetamide series that has been shown to display a good targeting capability toward peripheral benzodiazepine receptors, recently renamed translocator protein (18 kDa) or in short TSPO. On the basis of this structure, a novel derivative bearing a [(13)C]butynoate moiety has been designed and synthesized (three steps-42% overall yield) providing, upon rapid and quantitative para-hydrogenation, the corresponding hyperpolarized [(13)C]alkene. Para-hydrogen-induced polarization effects have been detected in both (1)H and (13)C-NMR spectra.

β-Gal gene expression MRI reporter in melanoma tumor cells. Design, synthesis, and in vitro and in vivo testing of a Gd(III) containing probe forming a high relaxivity, melanin-like structure upon β-Gal enzymatic activation.

The aim of this work is to design and test an MRI probe (Gd-DOTAtyr-gal) able to report on the gene expression of β-galactosidase (β-Gal) in melanoma cells. The probe consists of a Gd-DOTA reporter bearing on its surface a tyrosine-galactose-pyranose functionality that, upon the release of the sugar moiety, readily transforms, in the presence of tyrosinase, into melanin oligomeric/polymeric mixture. The formation of Gd-DOTA-containing melanin oligomers and polymers is accompanied by a marked increase of the water proton relaxation rate.

Assessment of iron absorption in mice by ICP-MS measurements of (57)Fe levels.

Background: The study of iron metabolism is essential in nutritional sciences as iron deficiency is one of the most common nutritional deficiencies in humans and represents a serious health problem worldwide. The mouse is utilized as a unique and powerful model for the identification and characterization of genes involved in iron metabolism and for studying the pathogenesis of iron disorders. Thus, sophisticated and sensitive techniques have been developed to study iron metabolism in this animal model.

MRI evaluation of the antitumor activity of paramagnetic liposomes loaded with prednisolone phosphate.

The design of long circulating liposomes co-loaded with the glucocorticoid prednisolone phosphate (PLP) and the amphiphilic paramagnetic contrast agent Gd-DOTAMA(C(18))(2) allowed the MRI-guided in vivo visualization of the delivery and biodistribution of PLP, as well as the monitoring of drug efficacy. The performance of this theranostic probe was investigated in a mouse model bearing a melanoma B16 syngeneic tumor. The release kinetics of the drug were evaluated in vitro where it displayed a peculiar behavior characterized by a fast process (completed in few hours) involving only a small portion (<5%) of the drug.

Yeast cell wall particles: a promising class of nature-inspired microcarriers for multimodal imaging.

This communication demonstrates that yeast cell wall particles (YCWPs) are a promising class of nature-inspired biocompatible microcarriers for the delivery of amphipathic/lipophilic imaging reporters. When a paramagnetic MRI agent is loaded, the longitudinal relaxivity per particle at 0.5 T is the highest ever reported for Gd-based systems.

Properties, solution state behavior, and crystal structures of chelates of DOTMA.

The chemistry of polyamino carboxylates and their use as ligands for Ln(3+) ions is of considerable interest from the point of view of the development of new imaging agents. Of particular interest is the chemistry of the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives. Herein we report that the tetramethylated DOTA derivative, DOTMA, possess several properties that, from an imaging agent development point of view, are more advantageous than those of the parent DOTA.

In vivo labeling of B16 melanoma tumor xenograft with a thiol-reactive gadolinium based MRI contrast agent.

Murine melanoma B16 cells display on the extracellular side of the plasma membrane a large number of reactive protein thiols (exofacial protein thiols, EPTs). These EPTs can be chemically labeled with Gd-DO3A-PDP, a Gd(III)-based MRI contrast agent bearing a 2-pyridinedithio chemical function for the recognition of EPTs. Uptake of gadolinium up to 10(9) Gd atoms per cell can be achieved.

Contrast agents and mechanisms.

MRI contrast agents are routinely used in clinical settings. Important advances in their design have been attained in the past few years to overcome sensitivity issues and to make possible molecular imaging applications by means of this modality. Besides the sensitivity enhancement of paramagnetic relaxation probes, outstanding results have been obtained in the development of novel classes of frequency-encoding agents such as chemical exchange saturation transfer and hyperpolarized (13)C-enriched molecules.

MRI-guided neutron capture therapy by use of a dual gadolinium/boron agent targeted at tumour cells through upregulated low-density lipoprotein transporters.

The upregulation of low-density lipoprotein (LDL) transporters in tumour cells has been exploited to deliver a sufficient amount of gadolinium/boron/ligand (Gd/B/L) probes for neutron capture therapy, a binary chemio-radiotherapy for cancer treatment. The Gd/B/L probe consists of a carborane unit (ten B atoms) bearing an aliphatic chain on one side (to bind LDL particles), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other (for detection by magnetic resonance imaging (MRI)). Up to 190 Gd/B/L probes were loaded per LDL particle.

Development of a strain-specific real-time PCR assay for the detection and quantification of the biological control agent Fo47 in root tissues.

Being able to identify specifically a biological control agent at the strain level is not the only requirement set by regulations (EC)1107/2009, it is also necessary to study the interactions of the agent with the plant and the pathogen in the rhizosphere. Fo47 is a soil-borne strain of Fusarium oxysporum which has the capacity to protect several plant species against the pathogenic formae speciales of F. oxysporum inducing wilts.

Improved paramagnetic liposomes for MRI visualization of pH triggered release.

This work aims at assessing the in vitro potential of paramagnetic pH sensitive liposomes as imaging tools for visualizing drug-delivery and release processes by Magnetic Resonance Imaging (MRI). pH sensitive liposomes (pSLs) were formulated using the fusogenic phospholipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), the membrane stabilizer D-α-tocopherol-hemisuccinate (THS), and were loaded with several paramagnetic complexes including the clinically approved Gadoteridol (marketed as ProHance™). The proposed formulation allows the fast and full release of Gadoteridol at pH 5.

Theranostic nanomedicine.

Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically administered (chemo)therapeutic agents. Many different types of nanomedicines have been evaluated over the years, including for instance liposomes, polymers, micelles and antibodies, and a significant amount of evidence has been obtained showing that these submicrometer-sized carrier materials are able to improve the balance between the efficacy and the toxicity of therapeutic interventions. Besides for therapeutic purposes, nanomedicine formulations have in recent years also been increasingly employed for imaging applications.

How to design 13C para-hydrogen-induced polarization experiments for MRI applications.

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.

Dose estimation in B16 tumour bearing mice for future irradiation in the thermal column of the TRIGA reactor after B/Gd/LDL adduct infusion.

To test the efficacy of a new (10)B-vector compound, the B/Gd/LDL adduct synthesised at Torino University, in vivo irradiations of murine tumours are in progress at the TRIGA Mark II reactor of the Pavia University. A localised B16 melanoma tumour is generated in C57BL/6 mice and subsequently infused with the adduct. During the irradiation, the mouse will be put in a shield to protect the whole body except the tumour in the back-neck area.

Advances in bio-imaging: a survey from WWMR 2010.

The paper deals with a survey on major advances in the field of bio-imaging presented at the WWMR2010 Conference, held in Florence (Italy) from 4th to 9th July 2010. The selected contributions have been organized into the following headings: Hyperpolarization, Acquisition Methods and Molecular Imaging applications. Overall, the Conference has witnessed an outstanding progress in either methods and applications that further stresses the key-role of MRI in many fields of biomedicine.