Theranostics Through the Synergistic Cooperation of Heterometallic Complexes

Heterometallic drugs are emerging as a great alternative to conventional metallodrugs. Careful selection of different metallic fragments makes possible to enhance not only the therapeutic potential by a synergistic effect, but also to incorpore key features like traceability. Drugs that integrate traceability and therapy in one system are known as theranostic agents. In cancer research, theranostic agents are becoming increasingly important. They deliver crucial information regarding their biological interplay that can ultimately be used for optimization. The well-established therapeutic potential of PtII-, RuII- and AuI-based drugs combined with the outstanding optical properties of d6 transition metal complexes grant the delivery of traceable metallodrugs. These species can be easily fine-tuned through modification of their respective ligands to provide a new generation of drugs

Luminescent Re(I)/Au(I) Species As Selective Anticancer Agents for HeLa Cells

A series of neutral and cationic heterotrimetallic complexes of the type fac-[Re(CO)3(bipy(CC)2-(AuL)2)X]n, where bipy(CC)2 is 4, 4'-alkynyl-2, 2'-bipyridine; L is either triphenylphosphine (PPh3), [1, 3-bis(2, 6-diisopropylphenyl)-imidazol-2-ylidene] (IPr), or tert-butyl isocyanide (CNtBu); and X is a chloride (n = 0) or acetonitrile (n = 1), were synthesized and characterized together with their Re(I) precursors, i.e., fac-[Re(CO)3(bipy(CC)2)X]n. X-ray diffraction of complexes 1, 3, and 6 corroborated the expected octahedral and linear distribution of the ligands along the Re(I) and Au(I) centers, respectively. Luminescent studies showed that all the complexes displayed a broad emission band centered between 565 and 680 nm, corresponding to a 3MLCT from the Re(I) to the diimine derivative. The presence of the gold fragment coordinated to the diimine ligand shifted in all cases the emission maxima toward higher energies. Such an emission difference could be potentially used for assessing the precise moment of interaction of the probe with the biological target if the gold fragment is implicated. Antiproliferative studies in cancer cells, A549 (lung cancer) and HeLa (cervix cancer), showed a generalized selectivity toward HeLa cells for those heterotrimetallic species incubated at longer times (72 vs 24 h). ICP-MS spectrometry revealed the greater cell internalization of cationic vs neutral species. Preliminary fluorescence microscopy experiments showed a different behavior of the complexes in HeLa and A549 cell lines. Whereas the complexes in A549 were randomly distributed in the outside of the cell, those incubated with HeLa cells were located close to the cellular membrane, suggesting some type of interaction, and possibly explaining their cellular selectivity when it comes to the antiproliferative activity displayed in the different cell lines

Luminescent gold-thallium derivatives with a pyridine-containing 12-membered aza-thioether macrocycle

The coordination modes of the ligand 2, 5, 8-trithia[9](2, 6)pyridinophane (L) to thallium(i), gold(iii) and gold(i) have been studied. Thallium(i) is coordinated by the macrocyclic ligand in [Tl(L)](PF6) (1) through all the sulfur and nitrogen atoms, in a distorted square-pyramidal geometry with the thallium(i) ion in the apical position and with the presence of an inert lone pair. Gold(iii) is bonded by the ligand only through the nitrogen of the pyridine group in [AuCl3(L)] (2), whereas two AuI-C6F5fragments coordinate the sulfur atoms next to the pyridine moiety of the ligand in [{Au(C6F5)}2(µ-L)] (3), which form a linear polymer through intermolecular aurophilic contacts. The heterometallic TlI/AuIcomplex {[Au(C6F5)2Tl]2(L)}n(4) features a polymeric structural nature with a metallic pseudo-rhombic Au2Tl2core, which repeats itself forming a zig-zag polymer. In each Au2Tl2unit only one thallium atom is bonded by the NS3donor set of the macrocyclic ligand and also forms two unsupported Au-Tl bonds with two [Au(C6F5)2]-units in an overall pseudo-octahedral geometry. The other thallium atom similarly bridges the same [Au(C6F5)2]-units and links a neighbouring Au2Tl2moiety, thus exhibiting a distorted trigonal planar geometry being bonded only to three gold atoms with unsupported Au-Tl interactions. This complex displays an interesting thermochromic behaviour showing emissions mainly resulting from MM'CT transitions at room temperature. At 77 K a dual emission appears, probably arising from the two different thallium environments. DFT calculations have been carried out in the attempt to investigate the origin of the emissions of complex4. © The Royal Society of Chemistry 2021

Multifunctional heterometallic Iriii-Aui probes as promising anticancer and antiangiogenic agents

A new class of emissive cyclometallated IrIII-AuI complexes with a bis(diphenylphosphino) methanide bridging ligand was successfully synthesised from the diphosphino complex [Ir(N^C)2(dppm)]+ (1). The different gold ancillary ligand, a triphenylphosphine (2), a chloride (3) or a thiocytosine (4) did not reveal any significant effect on the photophysical properties, which are mainly due to metal-to-ligand charge-transfer (3MLCT) transitions based on IrIII. However, the AuI fragment, along with the ancillary ligand, seemed crucial for the bioactivity in A549 lung carcinoma cells versus endothelial cells. Both cell types display variable sensitivities to the complexes (IC50=0.6–3.5 µM). The apoptotic pathway is activated in all cases, and paraptotic cell death seems to take place at initial stages in A549 cells. Species 2–4 showed at least dual lysosomal and mitochondrial biodistribution in A549 cells, with an initial lysosomal localisation and a possible trafficking process between both organelles with time. The bimetallic IrIII-AuI complexes disrupted the mitochondrial transmembrane potential in A549 cells and increased reactive oxygen species (ROS) generation and thioredoxin reductase (TrxR) inhibition in comparison with that displayed by the monometallic complex 1. Angiogenic activity assays performed in endothelial cells revealed the promising antimetastatic potential of 1, 2 and 4. © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH

Luminescent Bimetallic IrIII /AuI Peptide Bioconjugates as Potential Theranostic Agents

Diverse iridium peptide bioconjugates and the corresponding iridium/gold bimetallic complexes have been synthesized starting from a cyclometallated carboxylic acid substituted IrIII complex [Ir(ppy)2 (Phen-5-COO)] by solid phase peptide synthesis (SPPS). The selected peptide sequences were an enkephalin derivative Tyr-Gly-Gly-Phe-Leu together with the propargyl-substituted species Tyr-Gly-Pgl-Phe-Leu to allow gold coordination (Pgl: propyrgyl-glycine, HC=C-Gly), and a specific short peptide, Ala-Cys-Ala-Phen, containing a cysteine residue. Introduction of the gold center has been achieved via a click reaction with the alkynyl group leading to an organometallic Au-C(triazole) species, or by direct coordination to the sulfur atom of the cysteine. The photophysical properties of these species revealed predominantly an emission originating from the Ir complex, using mixed metal-to-ligand and ligand-to-ligand charge transfer excited states of triplet multiplicity. The formation of the peptide bioconjugates caused a systematic redshift of the emission profiles. Lysosomal accumulation was observed for all the complexes, in contrast to the expected mitochondrial accumulation triggered by the gold complexes. Only the cysteine-containing Ir/Au bioconjugate displayed cytotoxic activity. The absence of activity may be related to the lack of endosomal/lysosomal escape for the cationic peptide conjugates. Interestingly, the different coordination sphere of the gold atom may play a crucial role, as the Au-S(cysteine) bond may be more readily cleaved in a biological environment than the Au-C(triazole) bond, and thus the Au fragment could be released from or trapped in the lysosomes, respectively. This work represents a starting point in the development of bimetallic peptide bioconjugates as theranostics and in the knowledge of factors that contribute to anti-proliferative activity

Bioactive and luminescent indole and isatin based gold(i) derivatives

A series of luminescent monometallic [AuL(PPh 3 )] (1-3) and bimetallic [Au 2 (µ-dppe)L 2 ] (4, 6, 8) and [Au 2 (µ-dppp)L 2 ] (5, 7, 9) complexes, where L is either 4-cyano-indole, isatin, or 5, 7-dimethyl-isatin, and dppe and dppp are 1, 2-bis(diphenylphosphino)ethane and 1, 3-bis(diphenylphosphino)propane, respectively, have been synthesised. X-ray diffraction confirmed the tendency to establish aurophillic interations for those complexes containing dppe. Luminescence studies and theoretical calculations revealed a different origin for both families, i.e. indole and isatin species. Thus, indole derivatives presented a ligand-to-ligand-charge-transfer transition (LLCT) from the indole to the PPh 3 fragment, whereas for the isatin derivatives an intraligand-charge-transfer transition (ILCT) within the isatin fragment is proposed. In both cases, the gold centre was slightly implicated as a ligand-to-metal-charge transfer transition (LMCT) (from the indole/isatin to Au(i)). Cell antiproliferative assays in lung cancer cells (A549), leukemia Jurkat-pLVTHM and Jurkat-shBak cells (cisplatin sensitive and resistant, respectively) showed excellent cytotoxic values (10.11-0.28 µM), showing the leukemia cells to be the most sensitive and the bimetallic species to be the most active agents. Preliminary studies associated the cytotoxicity with a combination of different factors, the metallic fragment being mainly responsible. Remarkably, these complexes are able to inhibit the cellular growth of cisplatin resistant Jurkat-shBak cells highlighting their promising future as an alternative anticancer agent

Micro and nano smart composite films based on copper-iodine coordination polymer as thermochromic biocompatible sensors

Herein is presented the preparation and characterization of a composite material obtained by the combination of nanosheets of a coordination polymer (CP) based on the copper(I)-I double chain with response to temperature and pressure with polylactic acid (PLA) as biodegradable organic matrix. The new films of composite materials are generated using a simple and low-cost method and can be created with long lateral dimensions and thicknesses ranging from a few microns to a few nanometers. Studies show that the new material maintains the optical response versus the temperature, while the elasticity and flexibility of the PLA totally quenches the response to pressure previously observed for the CP. This new material can act as a reversible sensor at low temperatures, thanks to the flexibility of the copper(I)-iodine chain that conforms the CP. The addition of CP to the PLA matrix reduces the elastic modulus and ultimate elongation of the organic matrix, although it does not reduce its tensile strength

Nitrogen fixation in the upwelling region off NW Iberia

Comunicación oralPicoplankton are the most abundant organisms in the ocean, often dominate planktonic biomass and primary production, and they could represent a substantial contribution to the global export of carbon. Nowadays, we have a limited understanding about the factors that control the picoplankton community structure. A recent analysis indicates that light and temperature are the main factors explaining Prochlorococcus and Synechococcus distributions, whereas nutrient concentrations play a minor role (Flombaum et al., PNAS 2013). Methodological difficulties to quantify mixing in the marine enviroments have motivated the use of indirect approaches to determine the input of nutrients into the euphotic zone, however, nutrient concentrations are not necessarily a proxy of nutrient supply. We present a large data set, including open-ocean and coastal regions, of simultaneous measurements of picoplankton abundance, temperature and irradiance, together with estimates of nutrient supply. The transport of nutrients across the nutricline was computed combining nutrient concentrations and small-scale turbulence observations collected with a microstructure profiler. Our preliminary results indicate that nutrient supply also plays a role in the distribution of functional groups of picoplankton in the ocean

Cardiorespiratory, metabolic and muscular responses during a video-recorded aerobic dance session on an air dissipation platform

Background: Aerobic dance (AD) is an appropriate physical activity for improving cardiorespiratory fitness. This study aimed to compare cardiorespiratory and metabolic responses, and muscle fatigue between an air dissipation platform (ADP) and a hard surface during a video-recorded AD session. Methods: 25 healthy young women (23.3 ± 2.5 years) completed three sessions. In session 1, participants performed an incremental test to exhaustion on a treadmill. One week after session 1, participants were randomly assigned in a crossover design to perform video-recorded AD sessions on an ADP and on a hard surface (sessions 2 and 3). Cardiorespiratory and metabolic responses were assessed during AD sessions. Muscular fatigue was measured before and after AD sessions by a countermovement jump test. Results: Significantly higher heart rate, respiratory exchange ratio, pulmonary ventilation, ventilatory oxygen equivalent, and ventilatory carbon dioxide equivalent were observed on an ADP than on a hard surface (p 0.05). Conclusions: Video-recorded AD on an ADP increased the cardioventilatory and metabolic responses compared to a hard surface, preventing further muscle fatigue

Aerobic Dance on an Air Dissipation Platform Improves Cardiorespiratory, Muscular and Cellular Fitness in the Overweight and Obese Elderly

Background: Obesity is a global health problem associated with a high number of comorbidities that decrease functional capacity, especially in elderly people. Aerobic dance is considered a viable strategy to prevent the effects of aging, mainly in obese and overweight elderly people. This study aimed to evaluate the effects of aerobic dance on an air dissipation platform (ADP) on body composition, oxidative stress and muscular and cardiorespiratory fitness in elderly people. Methods: In total, 32 elderly adults (67.1 ± 3.6) were divided into 3 groups based on body mass index: healthy (HG), overweight (OWG) and obese (OG). Training program of aerobic dance on an ADP was carried out twice a week for 12 weeks. Results: OWG (p = 0.016) and OG decreased their weight (p < 0.001). There was a significant decrease in malondialdehyde concentrations in all experimental groups (p < 0.05). OWG and OG significantly improved their peak oxygen uptake (p < 0.01). HG increased the vertical jump height (p < 0.05), and HG and OG improved the power output of the lower extremities (p < 0.05). Conclusions: The aerobic dance on an ADP may be an effective alternative to lose weight, prevent oxidative stress and improve cardiorespiratory fitness in obese and overweight elderly people