Search

Cancer is one of the most devastating diseases that the world is currently facing, accounting for 10 million deaths in 2020 (WHO). In the last two decades, advanced medical imaging has played an ever more important role in the early detection of the disease, as it increases the chances of survival and the potential for full recovery. To date, dynamic glucose-enhanced (DGE) MRI using glucose-based chemical exchange saturation transfer (glucoCEST) has demonstrated the sensitivity to detect both d-glucose and glucose analogs, such as 3-oxy-methyl-d-glucose (3OMG) uptake in tumors. As one of the recent international efforts aiming at pushing the boundaries of translation of the DGE MRI technique into clinical practice, a multidisciplinary team of eight partners came together to form the “glucoCEST Imaging of Neoplastic Tumors (GLINT)” consortium, funded by the Horizon 2020 European Commission. This paper summarizes the progress made to date both by these groups and others in increasing our knowledge of the underlying mechanisms related to this technique as well as translating it into clinical practice.

This survey reports on topics that were presented at the workshop on “Challenges with Rare Earth Elements. The Periodic Table at work for new Science & Technology” hold at the Academia dei Lincei in November 2019. The herein reported materials refer to presentations dealing with studies and applications of rare earth elements (REE) in several areas of Biology and Medicine. All together they show the tremendous impact REE have in relevant fields of living systems and highlight, on one hand, the still existing knowledge gap for an in-depth understanding of their function in natural systems as well as the very important role they already have in providing innovative scientific and technological solutions in a number of bio-medical areas and in fields related to the assessment of the origin of food and on their manufacturing processes. On the basis of the to-date achievements one expects that new initiatives will bring, in a not too far future, to a dramatic increase of our understanding of the REE involvement in living organisms as well as a ramp-up in the exploitation of the peculiar properties of REE for the design of novel applications in diagnostic procedures and in the set-up of powerful medical devices. This scenario calls the governmental authorities for new responsibilities to guarantee a continuous availability of REE to industry and research labs together with providing support to activities devoted to their recovery/recycling.

A magnetic resonance imaging contrast agent based on a tetrameric Gd-DTPA-like system linked to a fibrin-targeting peptide (Gd-F) has been designed for in vivo tumor characterization.Gd-F was synthesized following Fmoc-SPPS strategy. Binding was measured using soluble fibrin DD(E) fragment and a dried fibrin assay. Contrast efficiency was tested on human and mouse clots and in vivo on Neuro2A tumor model. An anti-thrombotic drug was used to evaluate Gd-F sensitivity for changes in fibrin availability at the tumor site.The high relaxivity of Gd-F (42 mM(-1) s(-1), per molecule) yielded a strong signal enhancement in human and murine clots. High contrast was also measured in vivo in Neuro2A tumors, with a persistent enhancement in tumor rim and stroma. Upon treatment with an anti-thrombotic drug, the contrast uptake was significantly reduced in the tumor area confirming the specificity of the probe.Gd-F resulted to be an efficient probe for tumor delineation and for monitoring fibrin deposits during tumor progression and anti-thrombotic therapy.

The development of nanomedicines in cancer therapy is constantly growing because of the advantages associated with the use of nanosized drug delivery systems. Among them, the possibility of accurate spatiotemporal control of the release of the chemotherapeutic from the carrier is one of the most interesting and clinically relevant. To further improve the therapy outcome, the clinical translation of imaging protocols for the in vivo visualization of the release step is of paramount importance. In this work, the combination of the great chemical versatility of liposomes and the outstanding potential of MRI chemical exchange saturation transfer agents has been successfully harnessed to image the selective release of the liposomal content stimulated by endogenous (variation of pH) and externally applied (nonfocused ultrasound) stimuli. The use of clinically safe components (both liposomes and MRI agents) and the good results obtained in vitro hold promise for a successful future in vivo translation.

The Gd(III) complexes currently used as MRI contrast agents are hydrophilic agents that distribute in the vascular and extracellular compartments. The visualization of atherosclerotic plaques requires systems endowed with lipophilic characteristics. Several Gd(III) complexes bearing lipophilic substituents have been reported. Among them Gd(III) complexes containing one or two aliphatic chains appear particularly useful for the intended application. These amphiphilic Gd(III) complexes have been incorporated into various types of supramolecular adducts that ensure enough sensibility for their detection in MR images of atherosclerotic plaques. Much attention has been devoted to the use of HDL and LDL Gd-loaded particles. The presence of long aliphatic chain(s) promotes the spontaneous aggregation of these complexes to form micelles that may associate as such to the surface of HDL particles. It has been shown that the transfer of single amphiphilic complexes into the lipidic core of the particles is possible by disassembling the micelles through the formation of “host-guest” adducts with β–cyclodextrin. Gd-loaded liposomes have also been successfully tested in plaque detection as well as perfluoronanoparticles loaded with CEST agents.

In situ tissue engineering within a stroke cavity is gradually emerging as a novel therapeutic paradigm. Considering the varied lesion topology within each subject, the placement and distribution of cells within the lesion cavity is challenging. The use of multiple cell types to reconstruct damaged tissue illustrates the complexity of the process, but also highlights the challenges to provide a non-invasive assessment. The distribution of implanted cells within the lesion cavity and crucially the contribution of neural stem cells and endothelial cells to morphogenesis could be visualized simultaneously using two paramagnetic chemical exchange saturation transfer (paraCEST) agents. The development of sophisticated imaging methods is essential to guide delivery of the building blocks for in situ tissue engineering, but will also be essential to understand the dynamics of cellular interactions leading to the formation of de novo tissue.

The advent of nuclear spins hyperpolarization techniques represents a breakthrough in the field of medical diagnoses by magnetic resonance imaging. Dynamic nuclear polarization (DNP) is the most widely used method, and hyperpolarized metabolites such as [1-(13)C]-pyruvate are shown to report on status of tumours. Parahydrogen-induced polarization (PHIP) is a chemistry-based technique, easier to handle and much less expensive in respect to DNP, with significantly shorter polarization times. Its main limitation is the availability of unsaturated precursors for the target substrates; for instance, acetate and pyruvate cannot be obtained by direct incorporation of the parahydrogen molecule. Herein we report a method that allows us to achieve hyperpolarization in this kind of molecule by means of a tailored precursor containing a hydrogenable functionality that, after polarization transfer to the target (13)C moiety, is cleaved to obtain the metabolite of interest. The reported procedure can be extended to a number of other biologically relevant substrates.

It is shown that the paramagnetic properties of lanthanides can be exploited to obtain information on specific parts of a protein surface. Owing to the high affinity of coordinatively unsaturated lanthanide complexes for oxygen donors, carboxylate groups can be used as preferential targets for the interaction. The DO3A ligand is particularly useful in these studies, as it coordinates lanthanides in a heptadentate fashion, leaving two sites available for exogenous donors. A solution of a (15)N-labeled sample protein, calbindin D(9k) (75 residues), was titrated with up to 200% of Gd(III)-DO3A complex, and an inversion recovery (15)N-(1)H HSQC experiment was used to measure the paramagnetic contributions to the longitudinal relaxation rates of the amide protons. Relaxation data were used as distance constraints to estimate the number of interacting complexes and the occupancies of their binding sites. Four preferential interaction sites on the protein surface are found. Inspection of the various carboxylate side chains on the surface of the protein indicates that Gd(III)-DO3A interacts preferentially with carboxylate-rich regions, rather than with isolated carboxylates, suggesting the possibility of chelation of one Gd(III)-DO3A molecule by two carboxylate groups. Gd(III)-DO3A is thus a valuable semi-selective probe for clusters of negative charges on the protein surface.

A novel heptacoordinating ligand consisting of a thirteen-membered tetraazamacrocycle containing the pyridine ring and bearing three methylenephosphonate groups (PCTP-[13]) has been synthesized. Its Gd(III) complex displays a remarkably high longitudinal water proton relaxivity (7.7 mM–1 s–1 at 25 °C, 20 MHz and pH 7.5) which has been accounted for in terms of contributions arising from (1) one water molecule bound to the metal ion, (2) hydrogen-bonded water molecules in the second coordination sphere, or (3) water molecules diffusing near the paramagnetic chelate. Variable-temperature 17O-NMR transverse relaxation data indicate that the residence lifetime of the metal-bound water molecule is very short (8.0 ns at 25 °C) with respect to the Gd(III) complexes currently considered as contrast agents for magnetic resonance imaging. Furthermore, GdPCTP-[13] interacts with human serum albumin (HSA), likely through electrostatic forces. By comparing water proton relaxivity data for the GdPCTP-[13]-HSA adduct, measured as a function of temperature and magnetic field strength, with those for the analogous adduct with GdDOTP (a twelve-membered tetraaza macrocyclic tetramethylenephosphonate complex lacking a metal-bound water molecule), it has been possible to propose a general picture accounting for the main determinants of the relaxation enhancement observed when a paramagnetic Gd(III) complex is bound to HSA. Basically, the relaxation enhancement in these systems arises from (1) water molecules in the hydration shell of the macromolecule and protein exchangeable protons which lie close to the interaction site of the paramagnetic complex and (2) the metal bound water molecule(s). As far as the latter contribution is concerned, the interaction with the protein causes an elongation of the residence lifetime of the metal-bound water molecule, which limits, to some extent, the potential relaxivity enhancement expected upon the binding of the paramagnetic complex to HSA.

The synthesis of three trinuclear platinum hydrides [Pt3(L-L)3(H)3]+ (L-L = 1,2-bis(diphenylphosphino)ethane, dppe, l; 1-diphenylphosphino-2-diphenylarsinoethane, dppae. 2; 1,2-bis(diphenylarsino)ethane, dpae, 3) is reported. The complexes were characterized by IR, FAB-MS, and NMR (1H,31P and195Pt) spectroscopic techniques. The fast exchange of the hydride ligands, observed at ambient temperature, is frozen out at low temperature. The low-temperature1H and31P NMR spectra are consistent with an open array of Pt atoms in the clusters, in keeping with a 16-electron configuration on each platinum atom. Two of the hydride ligands are terminally bonded to two metal centers, whereas the third one is µ3-coordinated, interacting more tightly with the unique platinum atom.

The solid state13C NMR spectra of four13CO enriched carbonyl clusters having a tri-iron metallic core have been analyzed to provide structural and dynamic information. In Fe3(CO)12 (1), the high temperature spectra suggest the occurrence of large amplitude motions of the CO groups around their position at the vertexes of the coordination polyhedron in addition to the motion involving the Fe3-triangle previously detected in the VT-13C MAS spectra.13C and31P NMR data of Fe3(CO)11PPh3 (2) indicates the presence of one molecule in the asymmetric unit in apparent disagreement with the previously reported X-ray data. Furthermore, we show that structural information can be obtained from the chemical shift tensor components readily available from the analysis of the spinning sideband manifold.

13C-n.m.r. spectra of (μ-SR)2Fe2(CO)6, (μ-SR)2Fe2(CO)5P(n-Bu)3 and (μ-X)2Fe2(CO)6 (X=S or Se) show that the solid state structure is maintained in solution. N.m.r. evidence indicates that two isomeric species, not separable by means of the usual physicochemical methods, are present for (μ-SPh)2Fe2(CO)6 with an overwhelming predominance of theanti form. The phosphine substitutes a COtrans to the iron-iron bond. For any of the iron chalcogen derivatives examined, variable temperature13C-n.m.r. spectra show that carbonyl exchange occur in one step. The energy barrier for the exchange of carbon monoxide in the phosphine derivative is lower than that in the unsubstituted complex.