Cyclotron production of manganese-52: a promising avenue for multimodal PET/MRI imaging.

BACKGROUND: The integration of positron emission tomography (PET) and magnetic resonance imaging (MRI) holds promise for advancing diagnostic imaging capabilities. The METRICS project aims to develop cyclotron-driven production of 52Mn for PET/MRI imaging. RESULTS: Using the 52Cr(p,n)52Mn reaction, we designed chromium metal targets via Spark Plasma Sintering and developed a separation procedure for isolating 52Mn. Labeling tests were conducted with traditional chelators (i.e. S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid) and the 1.4-dioxa-8-azaspiro[4.5]decane-8- carbodithioate ligand to produce radioactive complexes suitable for PET/MRI applications. Our methodology yielded high-quality 52Mn suitable for PET radiopharmaceuticals and PET/MRI imaging. Preliminary studies on phantom imaging using microPET and clinical MRI demonstrated the efficacy of our approach. CONCLUSIONS: The developed technology offers a promising avenue for producing 52Mn and enhancing PET/MRI imaging capabilities. Further in vivo investigations are warranted to evaluate the potential advantages of this hybrid imaging technique.

Manganese in Diagnostics: A Preformulatory Study.

This investigation aims to find lipid-based nanosystems to be used as tools to deliver manganese for diagnostic purposes in multimodal imaging techniques. In particular, the study describes the production and characterization of aqueous dispersions of anionic liposomes as delivery systems for two model manganese-based compounds, namely manganese chloride and manganese acetylacetonate. Negatively charged liposomes were obtained using four different anionic surfactants, namely sodium docusate (SD), N-lauroylsarcosine (NLS), Protelan AG8 (PAG) and sodium lauroyl lactylate (SLL). Liposomes were produced by the direct hydration method followed by extrusion and characterized in terms of size, polydispersity, surface charge and stability over time. After extrusion, liposomes are homogeneous and monodispersed with an average diameter not exceeding 200 nm and a negative surface charge as confirmed by ζ potential measurement. Moreover, as indicated by atomic absorption spectroscopy analyses, the loading of manganese-based compounds was almost quantitative. Liposomes containing NLS or SLL were the most stable over time and the presence of manganese-based compounds did not affect their size distribution. Liposomes containing PAG and SD were instable and therefore discarded. The in vitro cytotoxicity of the selected anionic liposomes was evaluated by MTT assay on human keratinocyte. The obtained results highlighted that the toxicity of the formulations is dose dependent.

Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma.

Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3-4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h).

Interdisciplinary Tasks in the Cyclotron Production of Radiometals for Medical Applications. The Case of 47Sc as Example.

The growing number of cyclotrons of different sizes installed in the territory has given a strong impulse to the production of conventional and emerging radionuclides for medical applications. In particular, the great advantage of using medical cyclotrons is the possibility to produce on-site, when needed (on-demand), with medical radionuclides of interest encouraging the personalized medicine approach. Radiometals satisfy the ideal characteristics that radionuclides should have for routine employment in nuclear medicine, especially since they have a robust chemistry suitable to synthetize stable in vivo radiopharmaceuticals with high radiochemical yields. In this letter several interdisciplinary aspects involved in the radiometals cyclotron production cycle are summarized focusing the attention on cyclotron production facilities, target material, and chemical processing available for medical applications. As an example, the current status and recent development in the production of the theranostic radionuclide scandium-47 have been reported.

Formation of Supramolecular Clusters at the Interface of Zeolite X Following the Adsorption of Rare-Earth Cations and Their Impact on the Macroscopic Properties of the Zeolite.

The adsorption behavior of neodymium (Nd3+ ) and yttrium (Y3+ ) cations on synthetic FAU zeolite X in its sodium form (NaX) has been investigated by means of macroscopic (adsorption isotherm determination and thermal analysis) and microscopic measurements (including solid-state NMR spectroscopy and X-ray powder diffraction). The multidisciplinary study reveals some unexpected features. Firstly, adsorption constants of cations are not correlated to their ionic radii or hydration enthalpy. The adsorption constant of Y3+ on NaX was indeed about twice that of Nd3+ , which is the opposite of what could be expected based on the size of the cations. In addition, adsorption was accompanied by partial dealumination of the zeolite framework. The extent of dealumination changed depending on the exchanged cations, with the extent being more significant on the Nd-exchanged zeolite than on the Y-exchanged one. The most interesting finding of this study, however, is the presence of supramolecular clusters composed of water, Nd3+ , residual sodium ions, and extra-framework aluminum at the interface of Nd-exchanged zeolite. The hypothesis that these host-guest complexes are responsible of the significantly different behavior exhibited by NaX towards the adsorption/desorption of Nd3+ and Y3+ has been formulated.

Integration of Inverse Supercritical Fluid Extraction and Miniaturized Asymmetrical Flow Field-Flow Fractionation for the Rapid Analysis of Nanoparticles in Sunscreens.

We report the use of inverse supercritical fluid extraction (SFE) and miniaturized asymmetrical flow field-flow fractionation (mAF4) for the preparation and subsequent analysis of titanium dioxide nanoparticles in model and commercial sunscreens. The approach allows for the fast and reliable fractionation and sizing of TiO2 nanoparticles and their quantitation in commercial products. This new method represents a powerful and efficient tool for the verification of nanoparticle content in a wide range of matrixes, as demanded by recently introduced regulatory requirements. Furthermore, the use of carbon dioxide as an environmentally friendly solvent is in line with the increasing need for ecologically compatible analytical techniques.

Urban PM2.5 oxidative potential: Importance of chemical species and comparison of two spectrophotometric cell-free assays.

Oxidative potential (OP) of particulate matter (PM) - defined as the capacity of PM to oxidize target molecules generating reactive oxygen species (ROS) - has been proposed as a more health relevant metric than PM mass. In this study two cell-free methods were used to assess the OP of PM filters collected at an urban site and to evaluate correlation with PM mass and PM composition. Among the different assays existing, two inexpensive and user-friendly methods were used both based on spectrophotometric measurements of depletion rate of target reagents oxidized by redox-active species present in PM. One assay measures the consumption of dithiothreitol (OPDTT) and the other the ascorbate (OPAA). Although both assays respond to the same redox-active species, i.e., quinones and transition metals, no correlations were found between OPDTT and OPAA responses to compounds standard solutions as well as to ambient samples. When expressed in relation to air volume, OPDTT m-3 strongly correlates with PM2.5 mass whereas no correlation was found for OPAA m-3 with PM2.5. When expressed on mass basis, both OPDTT µg-1 and OPAA µg-1 show a strong dependence on the sample composition, with higher OP for summer samples. OPDTT m-3 were highly correlated with the determined metals (Cu, Zn, Cr, Fe, Ni, Mn) whereas OPAA m-3 showed only moderate correlation with Cu and Mn. Thus, the two assays could potentially provide complementary information on oxidative potential characteristic of PM. Consequently, the combination of the two approaches can strengthen each other in giving insight into the contribution of chemical composition to oxidative properties of PM, which can subsequently be used to study health effects.

Lipid-based nanoparticles containing cationic derivatives of PTA (1,3,5-triaza-7-phosphaadamantane) as innovative vehicle for Pt complexes: Production, characterization and in vitro studies.

The aliphatic phosphine PTA (1,3,5-triaza-7-phosphaadamantane) is a promising ligand for metal complexes designed and developed as innovative inorganic drugs. In the present paper, an N-alkylated derivative of PTA, (PTAC16H33)X (X=I, C1, or X=PF6, C2) and its platinum coordination complex cis-[PtCl2(PTAC16H33)2](PF6)2, C3, were considered as components of cationic lipid nanoparticles (CLNs). Particularly, CLN1, CLN2 and CLN3 were obtained by adding derivatives C1, C2 or C3 during nanoparticles preparation, while CLN2-Pt were obtained by treating preformed CLN2 with Pt(II). It was demonstrated that CLN1, CLN2 and CLN3 can be produced with technological conventional methods. However, among the two here proposed protocols, the one based on the treatment of preformed nanoparticles appears more advantageous as compared to the other since it allows a quantitative association yield of Pt. As determined by ICP-OES, a content of P and Pt 2.2-fold and 2.5-fold higher in CLN2-Pt than in CLN3 was evidenced. For the first time was demonstrated that properly functionalized preformed nanoparticles can be efficiently used to obtain a post production Pt(II) complex while maintaining a cytotoxic activity toward cultured cells. In fact, the antiproliferative activity shown by CLN3, CLN2-Pt on the three model cancer cell lines was substantially similar and comparable to that of complex C3 in dmso solution. Thus N-alkylated-PTA derivatives in CLNs could be proposed as innovative biocompatible and water dispersible nanoparticles carrying lipophilic Pt complexes becoming an interesting and improved system with respect to dmso solution.

A new strategy for pressed powder eye shadow analysis: allergenic metal ion content and particle size distribution.

Nine cheap eye shadow products were analyzed through graphite furnace atomic absorption spectrometry (GF-AAS) to quantify their Cr, Co and Ni contents, all known to be skin sensitizers. In many cases, the concentrations were higher than 1 or 5 ppm (µg/g), i.e. the limits recommended in the scientific literature to minimize the risk of reaction in particularly sensitive subjects. In most cases, the concentration of Cr was higher than that of Ni and Co, up to a limit case of 150 mg/g. In this particular sample, the potential amount of Cr that could be released in ionic form was determined in sweat simulating solutions by GF-AAS and confirmed through a specific spectrofluorimetric method; the results indicated the presence of approximately 80-90 ppb (ng/g) of Cr(3+). The water dispersible particles were isolated from the eye shadow powders through a simple solvent extraction procedure. The aqueous suspensions were then sorted through sedimentation field flow fractionation (SdFFF) and the particles sizes were calculated from experimental fractograms using theory. For the most part, the computed sizes were in the micron range, as confirmed by some SEM photographs taken on fractions collected during the separations. The SdFFF coupled off-line with the GFAAS enabled elemental characterization of pigment particles as a function of size. This finding reduces the concern that the ingredients of such makeup formulations may contain nanoparticles.

Morpho-physiological and biochemical responses in the floating lamina of Trapa natans exposed to molybdenum.

The response to molybdenum (Mo) was studied in the metal-tolerant hydrophyte Trapa natans L. Previously, it was shown that the plant accumulates Mn in the floating lamina by means of phenolic compounds and responded with acclimation responses of the chloroplast. Since the involvement of phenolics has been proposed also in Mo resistance, we tested the response of T. natans to increasing doses (5, 50, 150, 600 microM) of Mo using the photosynthetic apparatus as an indicator of cellular stress. Only 5 microM Mo did not cause evident modifications with respect to controls. Conversely, 50 to 600 microM Mo induced progressively marked alterations of the lamina morphology. The chloroplast ultrastructure showed disorganisation of the thylakoid system, and correspondingly, the photosynthetic pigment pattern was altered with a fall-down in photosynthesis. Microspectrofluorimetry indicated alterations of photosystem II, with differences among the three cell layers (first and second palisade and spongy tissues). While the highest dose caused plant death, 50 and 150 microM Mo-treated plants underwent partial recovery, and the plant survived up to the end of the vegetative season. However, reproduction was unsuccessful. Mo treatment did not induce increase in total phenolics, but only in anthocyanin. In contrast to Mn, detoxification of Mo by chelation inside vacuoles, possibly by anthocyanins, is suggested to be an insufficient mechanism to reduce Mo toxicity, which probably includes an impairment of nitrogen metabolism. However, the metal was accumulated in the lamina. On the whole, T. natans showed limited capabilities to survive Mo excess as compared with Mn.

Synthesis, characterization of strontium-bile acid salts and their bioactivity vs. the anti-osteoporosis drug strontium ranelate.

The strontium salts Sr(cholate)2, (Compound 1), Sr(dehydrocholate)2, (Compound 2) and Sr3(3-dehydrocholanoyliden-L-tartrate)2, (Compound 3) have been prepared and characterized. The potential anti-osteoporotic activity of these compounds was tested on human primary osteoblasts (hOBs) and human primary osteoclasts (hOCs) in comparison with the bioactivity of strontium ranelate, previously registered as drug in the treatment of post-menopausal osteoporosis. Our results led to the hypothesis that the tested compounds, particularly Compound 2, may have requirements for modulating skeletal tissue regeneration or at least down regulating the loss of bone mass. In fact, all tested compounds have been shown to induce maturation in human primary osteoblasts (hOBs) and apoptosis of human primary osteoclasts (hOCs) at the same time.

Measurement of nickel, cobalt and chromium in toy make-up by atomic absorption spectroscopy.

Cosmetics should not contain more than 5 ppm of nickel, chromium or cobalt and, in order to minimize the risk of sensitization in very sensitive subjects, the target amount should be as low as 1 ppm. However, there are no published reports on the presence of these metals in toy make-up. This study analysed 52 toy make-ups using atomic absorption spectroscopy. More than 5 ppm of nickel was present in 14/52 (26.9%) samples. Chromium exceeded 5 ppm in 28/52 (53.8%) samples, with values over 1000 ppm in 3 eye shadows. Cobalt was present in amounts over 5 ppm in 5/52 (9.6%) samples. Powdery toy make-up (eye shadows) had the highest levels of metals, and "creamy" toy make-up (lip gloss and lipsticks) the lowest. Toy make-ups are potentially sensitizing items, especially for atopic children, who have a damaged skin barrier that may favour penetration of allergens.

TiO2 in commercial sunscreen lotion: flow field-flow fractionation and ICP-AES together for size analysis.

A new method for determining the size of titanium dioxide particles is proposed and assayed in a commercial sunscreen product. Today many sun protection cosmetics incorporate physical UV filters as active ingredients, and there are no official methods for determining these compounds in sunscreen cosmetics. Here flow field-flow fractionation (FlFFF) has been tested, first to sort two different types of TiO2 nano- and microstandard materials (AeroxideTiO2 Degussa P-25 and TiO2 rutile 0.1-0.2-microm size) and then to fractionate TiO2 particles, extracted from a commercial sunscreen lotion. All the TiO2 FlFFF separations were detected by UV but during elution fractions were collected and their Ti content measured by inductively coupled plasma-atomic emission spectrometer (ICP-AES); the Ti concentration profiles obtained by ICP-AES were well correlated with the UV signals. The TiO2 particle mass-size distribution were calculated from the UV profiles. This methodology is relatively simple and rapid, and the sample treatment is as a whole easy and low cost.

Cisplatin cytotoxicity in organ of Corti-derived immortalized cells.

Cisplatin is an anticancer drug currently used in the treatment of genital and head and neck tumors. Its use in these and other types of tumors is narrowed by onset of chemoresistance and severe undesired side effects, like as nephro- and ototoxicity, whose mechanisms of action are only partially understood. In the present study we investigated the effects of cisplatin (cis-dichlorodiaminoplatin, CDDP) on a cell line (OC-k3) developed from organs of Corti of transgenic mice. We observed at 48 h that cell death due to cisplatin was time and concentration-dependent. The cell death displayed some morphological hallmarks of apoptosis, including nuclear fragmentation into several large nuclear fragments, surrounded by a rearranged and thickened actin cytoskeleton. No DNA laddering was detected, suggesting absence of endonuclease activity, nor annexin V positivity, suggesting absence of phosphatidylserine externalization. Several molecules protected the cells against CDDP induced cytotoxicity, including methionine, suramin and PD98059. Methionine reduced CDDP-uptake, while suramin, a polycathionic compound a specifically binding external proteins, did not. This finding suggested that suramin could exert its protective effect by acting on an intracellular transduction pathway. We tested this hypothesis by studying the effect of suramin and PD98059, a MEK inhibitor, on the mitogen activated protein kinase (MAPK) cascade. After CDDP treatment, we found an increase of phosphorylation of extracellular regulated kinases (ERK)1/2, that could be inhibited by PD98059 and suramin. These data suggest that ERK pathways can play a role in mediating the cell death induction in presence of a CDDP challenge.