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Mesocyclic chelating agents such as AAZTA and its derivatives have been recently reported to overcome the relatively low thermodynamic stability of metal complexes of acyclic chelating agents and the slow complexation kinetics of macrocyclic chelating agents. This work reports the preparation of a spirobicyclic hexadentate AAZTA-like chelating agent (TRASUTA) and the investigation of the thermodynamic, kinetic, and structural properties of the corresponding chelates with the PET-relevant Ga 3+ and selected metal ions. A combination of analytical techniques allowed identification of a coordination isomerization process, involving the coordinating side arms and the inversion of a nitrogen atom and leading to lower thermodynamic and kinetic inertness with respect to mononuclear mesocyclic analogues. The bicyclic system of TRASUTA retains significant dynamics despite the conformational constraint imposed by the spiro-fusion, resulting in a lower stability of the corresponding metal chelates.

Imaging in the shortwave infrared (SWIR, 1000-1700 nm) region is gaining traction for biomedical applications, leading to an in-depth search for fluorophores emitting at these wavelengths. The development of SWIR emitters, to be used in vivo in biological media, is mostly hampered by the considerable lipophilicity of the structures, resulting from the highly conjugated scaffold required to shift the emission to this region, that limit their aqueous solubility. In this work, we have modulated a known SWIR emitter, named Flav7, by adding hydrophilic moieties to the flavylium scaffold and we developed a new series of Flav7-derivatives, which proved to be indeed more polar than the parent compound, but still not freely water-soluble. Optical characterization of these derivatives allowed us to select FlavMorpho, a new compound with improved emission properties compared to Flav7. Encapsulation of the two compounds in micelles resulted in water-soluble SWIR emitters, with FlavMorpho micelles being twice as emissive as Flav7 micelles. The SWIR emission extent of FlavMorpho micelles proved also superior to the tail-emission of Indocyanine Green (ICG), the FDA-approved reference cyanine, in the same region, by exciting the probes at their respective absorption maxima in phosphate buffered saline (PBS) solution. The availability of optical imaging devices equipped with lasers able to excite these dyes at their maximum of absorption in the SWIR region, could pave the way for implemented SWIR imaging results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

[Gd(HP-DO3A)] (gadoteridol) as an active compound of ProHance ® is a widely employed contrast agent in clinical MRI scans in the last 30 years. Recent concerns about the long-term retention of gadolinium-based contrast agents (GBCAs) led to a deeper investigation of the structural features underlying the integrity of the paramagnetic metal complex. Several human and nonclinical studies have noted marked differences among the macrocyclic GBCAs, with the least retention of Gd traces and most rapid elimination consistently being reported for [Gd(HP-DO3A)]. It was deemed of interest to assess how minor structural/electronic changes associated to the ligand structure may affect basic properties of the metal complex with several [Gd(HP-DO3A)] analogues synthesized and characterized in the last years. We recently reported that the closest homolog of [Gd(HP-DO3A)], i. e.: [Gd(HB-DO3A)], in which a (±)-2-hydroxy-1-propyl pendant arm is replaced by a (±)-2-hydroxy-1-butyl moiety, showed a significantly different retention behaviour in the model interaction with collagen, despite the apparently very minor structural difference. In this paper we report a comprehensive study of the structural, thermodynamic, kinetic and relaxation properties of [Gd(HB-DO3A)], compared to the parent [Gd(HP-DO3A)] and to other closely related macrocyclic GBCAs to assess whether very minor structural changes can modulate the physico-chemical properties of Gd 3+ complexes., (© 2024 Wiley-VCH GmbH.)

Commercially available near-infrared (NIR) dyes, including indocyanine green (ICG), display an end-tail of the fluorescence emission spectrum detectable in the short-wave infrared (SWIR) window. Imaging methods based on the second NIR spectral region (1,000-1,700 nm) are gaining interest within the biomedical imaging community due to minimal autofluorescence and scattering, allowing higher spatial resolution and depth sensitivity. Using a SWIR fluorescence imaging device, the properties of ICG vs. heptamethine cyanine dyes with emission >800 nm were evaluated using tissue-simulating phantoms and animal experiments. In this study, we tested the hypothesis that an increased rigidity of the heptamethine chain may increase the SWIR imaging performance due to the bathochromic shift of the emission spectrum. Fluorescence SWIR imaging of capillary plastic tubes filled with dyes was followed by experiments on healthy animals in which a time series of fluorescence hindlimb images were analyzed. Our findings suggest that higher spatial resolution can be achieved even at greater depths (>5 mm) or longer wavelengths (>1,100 nm), in both tissue phantoms and animals, opening the possibility to translate the SWIR prototype toward clinical application., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Al(III) complexes have been recently investigated for their potential use in imaging with positron emission tomography (PET) by formation of ternary complexes with the radioisotope fluorine-18 ( 18 F). Although the derivatives of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) are the most applied chelators for [Al 18 F] 2+ labelling and (pre)clinical PET imaging, non-macrocyclic, semi-rigid pentadentate chelators having two N- and three O-donor atoms such as RESCA1 and AMPDA-HB have been proposed with the aim to allow room temperature labelling of temperature-sensitive biomolecules. The paucity of stability data on Al(III) complexes used for PET imaging instigated a complete thermodynamic and kinetic solution study on Al(III) complexes with aminomethylpiperidine (AMP) derivatives AMPTA and AMPDA-HB and the comparison with a RESCA1-like chelator CD3A-Bn ( trans -1,2-diaminocyclohexane- N -benzyl- N , N' , N' -triacetic acid). The stability constant of [Al(AMPDA-HB)] is about four orders of magnitude higher than that of [Al(AMPTA)] and [Al(CD3A-Bn)], highlighting the greater affinity of phenolates with respect to acetate O-donors. On the other hand, the kinetic inertness of the complexes, determined by following the Cu 2+ -mediated transmetallation reactions in the 7.5-10.5 pH range, resulted in a spontaneous and hydroxide-assisted dissociation slightly faster for [Al(AMPTA)] than for the other two complexes ( t 1/2 = 4.5 h for [Al(AMPTA)], 12.4 h for [Al(AMPDA-HB)], and 24.1 h for [Al(CD3A-Bn)] at pH 7.4 and 25 °C). Finally, the [AlF] 2+ ternary complexes were prepared and their stability in reconstituted human serum was determined by 19 F NMR experiments.

The introduction of a phenolate pendant arm in place of an acetate on AAZTA- and DATA-like ligands resulted in hepta- and hexadentate chelators able to form Ga(III) complexes with thermodynamic stability and kinetic inertness higher than that of other Ga(III) complexes based on the parent 6-amino-6-methylperhydro-1,4-diazepine scaffold. In particular, the heptadentate AAZ3A-endoHB with a phenolate arm on an endocyclic N-atom shows a logK GaL of 27.35 and a remarkable resistance to hydroxide coordination up to basic pH (pH>9). This behaviour allows to also improve the kinetic inertness of the complex showing a dissociation half-life (t 1/2 ) at pH 7.4 of 76 h. Although also the hexadentate AAZ2A-exoHB chelator forms a stable (logK GaL =24.69) and inert (t 1/2 =33 h at pH 7.4) Ga(III) complex, the 68 Ga labelling showed a better radiochemical yield with AAZ3A-endoHB, especially at room temperature. Thus, a bifunctional chelator of AAZ3A-endoHB was synthesized bearing an isothiocyanate group that was conjugated to the N-terminus of a c(RGD) peptide for integrin receptor targeting. Finally, the conjugate was successfully labelled with 68 Ga isotope, and the resulting radiotracer tested for its stability in human serum and then in vivo for targeting B16-F10 tumours with miniPET imaging., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

In this study, we report the synthesis and the equilibrium, kinetic, relaxation, and structural properties of two new Gd III complexes based on modified 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HPDO3A) designed to modulate the relaxivity at acidic and basic pH due to intra- and intermolecular proton exchange. The presence of a carboxylic or ester moieties in place of the methyl group of HPDO3A allowed differentiation of a protic and nonprotic functional group, highlighting the importance of the formation of an intramolecular hydrogen bond between the coordinated hydroxyl and the carboxylate groups for proton exchange ( k H M 11 M -1 s -1 , k M OH = 1.7 × 10 9 M -1 s -1 ). The determination of the thermodynamic stability and kinetic inertness of the Gd III complexes confirmed that the modification of peripheral groups does not significantly affect the coordination environment and thus the stability (log K hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity ( GdL = 19.26, t 1/2 = 2.14 × 10 7 hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity ( r 1 ) was measured as a function of pH to investigate the proton exchange kinetics, and as a function of the magnetic field strength to extrapolate the relaxometric parameters ( r 1 GdL1 = 4.7 mM -1 s -1 and r 1 GdL2 = 5.1 mM -1 s -1 at 20 MHz, 25 °C, and pH 7.4). Finally, the X-ray crystal structure of the complex crystallized at basic pH showed the formation of a tetranuclear dimer with alkoxide and hydroxide groups bridging the Gd III ions.

Eu(HP-DO3A) is present in solution as a mixture of two diastereoisomers whose alcoholic groups are the source of the mobile protons for the CEST effect. The exchange is base catalyzed. Two novel Eu III complexes of HP-DO3A-like ligands containing an amino or a carboxylate functionality in the proximity of the -OH groups showed the occurrence of intramolecular catalysis of the prototropic exchange. New insights into the role of the intramolecular proton exchange on the CEST properties have been gained.

A current challenge in medical diagnostics is how to obtain high MRI relaxation enhancement using Gd III -based contrast agents (CAs) containing the minimum concentration of Gd III ions. We report that in GdHPDO3A-like complexes a primary amide group located in close proximity to the coordinated hydroxyl group can provide a strong relaxivity enhancement at slightly acidic pH. A maximum relaxivity of r 1 = 9.8 mM -1 s -1 (20 MHz, 298 K) at acidic pH was achieved, which is more than double that of clinically approved MRI contrast agents under identical conditions. This effect was found to strongly depend on the number of amide protons, i.e. it decreases with a secondary amide group and almost completely vanishes with a tertiary amide. This relaxivity enhancement is attributed to an acid-catalyzed proton exchange process between the metal-coordinated OH group, the amide protons and second sphere water molecules. The mechanism and kinetics of the corresponding H + assisted exchange process are discussed in detail and a novel simultaneous double-site proton exchange mechanism is proposed. Furthermore, 1 H and 17 O NMR relaxometry, Chemical Exchange Saturation Transfer (CEST) on the corresponding Eu III complexes, and thermodynamic and kinetic studies are reported. These highlight the optimal physico-chemical properties required to achieve high relaxivity with this series of Gd III -complexes. Thus, proton exchange provides an important opportunity to enhance the relaxivity of contrast agents, providing that labile protons close to the paramagnetic center can contribute., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Gold nanoparticles carrying fluorinated ligands in their monolayer are, by themselves, contrast agents for 19 F magnetic resonance imaging displaying high sensitivity because of the high density of fluorine nuclei achievable by grafting suitable ligands on the gold core surface. Functionalization of these nanoparticles with Gd(III) chelates allows adding a further functional activity to these systems, developing materials also acting as contrast agents for proton magnetic resonance imaging. These dual mode contrast agents may allow capitalizing on the benefits of 1 H and 19 F magnetic resonance imaging in a single diagnostic session. In this work, we describe a proof of principle of this approach by studying these nanoparticles in a high field preclinical scanner. The Gd(III) centers within the nanoparticles monolayer shorten considerably the 19 F T1 of the ligands but, nevertheless, these systems display strong and sharp NMR signals which allow recording good quality 19 F MRI phantom images at nanoparticle concentration of 20 mg/mL after proper adjustment of the imaging sequence. The Gd(III) centers also influence the T1 relaxation time of the water protons and high quality 1 H MRI images could be obtained. Gold nanoparticles protected by hydrogenated ligands and decorated with Gd(III) chelates are reported for comparison as 1 H MRI contrast agents.

The kinetic analysis of the place exchange reaction on the neutral Au25(SCH2CH2Ph)18 cluster by using 4-fluorobenzylthiol and a series of substituted arylthiols allowed us to establish, for the first time, that the selectivity for the inner and outer positions of the dimeric staples of the cluster can be modulated by using incoming thiols with different structures.

Two structurally different water-soluble homoligand gold nanoparticle systems, one featuring a rigid fluorous monolayer in the proximity of the gold core and the other featuring a flexible fluorinated region in a distal position, were studied as putative hosting systems by determining their binding constants for a series of fluorinated and non-fluorinated radical probes by means of ESR spectroscopy. Comparison of the binding constants obtained with hydrogenated homoligand nanoparticles of similar structure used as the reference evidenced that the binding of both hydrogenated and fluorinated guests is favoured in the presence of fluorinated nanoparticles. In addition, a flexible fluorinated monolayer acts as a better hosting system than the more rigid counterpart. In the latter case decreasing the size of the nanoparticles causes a small decrease of the binding affinities for both hydrogenated and fluorinated guests. The same nanoparticle systems were analysed for their ability to retard the phase transfer of a fluorescent dye from an aqueous solution to a toluene layer. All of the nanoparticles studied produced a significant decrease of the phase transfer rate of the dye because of the efficient interaction with the monolayer. These data support the introduction of fluorinated moieties in the monolayer of gold nanoparticles as a novel design tool for the development of drug delivery systems.

The [Pd(dppp)(OTf)2] complex acts as an efficient transporter of halide anions, in particular the biologically relevant chloride anion, across a phospholipid bilayer.

Gold nanoparticles coated with fluorinated ligands (F-MPCs) present features suitable for (19)F MRI as observed from phantom experiments. Cellular uptake, by HeLa cells, and toxicity of fluorescent dye-decorated F-MPCs are presented together with their ability to bind hydrophobic molecules allowing for a potential combination of targeting, delivery and imaging features.

The reaction between 5-(4-pyridyl)dipyrrylmethane and aromatic aldehydes affords meso-arylsubstituted trans-A2B2 di(4-pyridyl)porphyrins which are key building blocks in the metal-mediated self-assembling of supramolecular structures. A careful optimization of the reaction conditions allowed us to obtain 5,15-diphenyl-10,20-di(4-pyridyl)porphyrin (P1), and two analogues bearing on the meso-phenyl substituents two dipropyl- (P4) or dihexyl-alkyl chains (P5), with yields ranging from 53 to 63%. Porphyrin P1 reacts with Re(CO5)Br to give the expected 4 + 4 Re(I)-porphyrin metallacycle which has been fully characterized by means of infrared, NMR and UV-Vis (absorption and emission) spectroscopies and by guest inclusion studies. Unexpectedly the addition of alkyl chains to the porphyrin fragment, which increase the solubility of the porphyrin in organic solvents, has the opposite effect on the adduct with Re(I). Indeed, the reaction between Re(CO5)Br and porphyrins P4,5 gives very insoluble materials, hampering their complete characterization.

A stable tetraporphyrin metallacycle with Re(I) corners (1) is capable of forming nanopores in a liposomial membrane, provided that the porphyrin units are properly functionalized with peripheral carboxylic acid residues that, by establishing an hydrogen bond network, allow the formation of dimers that span the depth of the membrane.

In this work, carbohydrate-based systems designed as artificial ion transporters have been surveyed. Despite the large structural diversity and ease of manipulations of carbohydrates, in principle endowed with a variety of desirable properties for ionophoric activity, only few examples of sugar-containing compounds have been reported in the literature for these purposes. The most remarkable example is the family of modified β-cyclodextrins, resulting in active cation and/or anion transporters when long, flexible n-alkyl or oligo-ethylene or butylene glycol chains are appended at the lower rim of the macrocycle. Interesting features have been also found in amphiphilic CyPLOS (Cyclic Phosphate-Linked Oligosaccharide) dimers, that is macrocycles with two phenyl-β-D-glucopyranoside residues, 4,6-linked through phosphodiester bonds, derivatized with tetraethylene glycol tentacles. A wider repertoire of available carbohydrate-based scaffolds is expected to largely stimulate the discovery of novel, efficient artificial ionophores, of great interest for both technological and biomedical applications., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A small library of sugar-modified guanosine derivatives has been prepared, starting from a common intermediate, fully protected on the nucleobase. Insertion of myristoyl chains and of diverse hydrophilic groups, such as an oligoethylene glycol, an amino acid or a disaccharide chain, connected through in vivo reversible ester linkages, or of a charged functional group provided different examples of amphiphilic guanosine analogues, named G1-G7 herein. All of the sugar-modified derivatives were positive in the potassium picrate test, showing an ability to form G-tetrads. CD spectra demonstrated that, as dilute solutions in CHCl(3), distinctive G-quadruplex systems may be formed, with spatial organisations dependent upon the structural modifications. Two compounds, G1 and G2, proved to be good low-molecular-weight organogelators in polar organic solvents, such as methanol, ethanol and acetonitrile. Ion transportation experiments through phospholipid bilayers were carried out to evaluate their ability to mediate H(+) transportation, with G5 showing the highest activity within the investigated series. Moreover, G3 and G5 exhibited a significant cytotoxic profile against human MCF-7 cancer cells in in vitro bioassays., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel fluorescently labelled synthetic ionophore, based on a cyclic phosphate-linked disaccharide (CyPLOS) backbone and decorated with four tetraethylene glycol tails carrying dansyl units, has been synthesised in 12 steps in 26% overall yield. The key intermediate in the synthetic strategy is a novel glucoside building block, serving through its 2- and 3-hydroxy groups as the anchor point for flexible tetraethylene glycol tentacles with reactive azido moieties at their ends. To test the versatility of this glucoside scaffold, it was preliminarily functionalised with a set of diverse probes--as fluorescent, redox-active or hydrophobic tags--either by reduction of the azides followed by condensation with activated carboxylic acid derivatives, or by a direct coupling with a terminal alkyne in a Cu(I)-promoted 1,3-dipolar cycloaddition. Tagging of the monomeric building block with dansyl residues allowed us to prepare a fluorescent, amphiphilic macrocycle, which was investigated for its propensity to self-aggregate in CDCl(3)--studied by means of concentration-dependent (31)P NMR spectroscopy experiments--and in aqueous solution, in which combined dynamic light scattering (DLS) and small-angle neutron scattering (SANS) measurements provided a detailed physico-chemical analysis of the self-assembled systems, mainly organised in the form of large vesicles. Its ion-transport properties through phospholipid bilayers, determined by HPTS fluorescence assays, showed this compound to be more active than the previously synthesised CyPLOS congeners. Solvent-dependent fluorescence changes for the labelled ionophore in liposome suspension established that the dansyl moieties are dispersed in environments with polarity intermediate between those of CH(2)Cl(2) and propan-2-ol, suggesting that the CyPLOS tentacles infiltrate the mid-polar region of the membranes.

Unlabelled: Brain metastases from Non-Small Cell Lung Cancer are usually associated with poor prognosis and up to now chemotherapy has shown a modest activity upon cerebral localizations. We investigated the role of Pemetrexed, a new, well tolerated multi-target antifolate, on brain metastases., Patients and Methods: We collected 39 patients with evidence of cerebral nervous system (CNS) localizations from Non-Small Cell Lung Cancer (NSCLC) before starting treatment with Pemetrexed as second-line or further-line therapy., Results: We confirmed the good tolerability of Pemetrexed even in that setting of patients and we reported a progressive disease (PD) in 12 patients (30.8%), a stable disease (SD) and partial response (PR) in 12 (30.8%) and 15 (38.4%) patients respectively, with an overall clinical benefit obtained in 69% of patients. The cerebral response to Pemetrexed was interesting with a cerebral radiological benefit obtained in 32 patients (82%), while 7 patients only showed brain progressive disease. Overall median survival was 10 months. All irradiation-naïve patients and those with clear radiological evidence of cerebral progression after brain radiotherapy and before Pemetrexed, overall 22 patients, were included in one group, in order to avoid overlapping effects between brain radiotherapy and Pemetrexed over CNS localizations. Within that setting, we demonstrated an overall clinical benefit (SD+PR) and cerebral benefit in 63% and 68%, of patients respectively. Distribution of patients by overall response to Pemetrexed and CNS response was highly suggestive of activity of Pemetrexed on brain metastases., Conclusion: We demonstrated the good tolerability of Pemetrexed even in patients with advanced NSCLC and brain metastases, and we found a very good overall response rate with evidence of activity on brain localizations., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Several drugs have been approved for the treatment of patients affected by advanced non-small cell lung cancer (NSCLC) in progression after first line chemotherapy: Docetaxel, Pemetrexed and Erlotinib. Poor gain of survival has been demonstrated in randomised trials and patient characteristics predicting activity are poorly known yet. We evaluated the activity and toxicity of Pemetrexed, in a post-registration phase, to assess whether clinical benefits justify its employment in a second-line setting in routine clinical practice., Patients and Methods: We collected data on patients with advanced NSCLC treated with Pemetrexed 500mg/m(2) every 21 days, after progression to prior chemotherapy., Results: One hundred and sixty patients from 4 different Italian Institutions, treated with Pemetrexed, mostly as second-line therapy, were analysed. There was a predominance of males versus females, adenocarcinoma versus other histologies; the median age was 63.6 years. The toxicity profile was extremely mild and the response rate (11.2% patients in complete or partial response) was similar to previous reports from the literature. The median overall survival, 12 months, was better than previously reported., Conclusion: Improved efficacy and mild toxicity observed in this clinically relevant patient population confirms Pemetrexed as an interesting choice in second-line treatment of NSCLC. Patient characteristics alone are not able to predict response to Pemetrexed.

Purpose: UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent., Patients and Methods: In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy., Results: UGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7 compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7 patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7 when compared with TA6/TA6 patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)x(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7 genotype and a higher response rate, indicating that the polymorphism is functionally relevant., Conclusion: The results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.