Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure.
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Catalytic converters were first fitted to light duty vehicles in the USA and Japan in 1975, in response to new emission standards, such as the US Clean Air Act Amendement (Beneman et al. 2005). Many other countries with large vehicle markets have followed since then, including South Korea (1987), Mexico (1989), the member states of the European Union (1993), Brazil (1994) and China (2000) (Kendall 2004). These devices simultaneously convert more than 90% of carbon monoxide (CO) and nitrous oxides (NOx) and 80% of unburned hydrocarbons (HCs) from exhaust emissions into less harmful carbon dioxide, nitrogen and water vapour (Onovwiona and Ugursal 2006; Twigg 2007). The catalytic converter initially employed a combination of platinum (Pt), palladium (Pd) and rhodium (Rh), with Pt and Pd being used to oxidize CO and HCs and Rh facilitating the reduction of NOx. Today, there is a wide range of possible combinations and concentrations of Pt, Pd and Rh required by car manufacturers that are used to achieve different catalyst performance features. Moreover, recently, iridium (Ir) has been incorporated into catalytic converter technology (the so called “De” catalyst) based on its capacity to drastically reduce NOx emission in the exhausts of lean burning engines (Ravindra et al. 2004).
Therefore, it is reasonable to assume in the next years a possible increase of Ir concentrations in the environment and consequently a higher exposure both for the general population and subjects occupationally exposed to vehicle traffic (Botrè et al. 2007). In fact, the rapidly changing redox conditions, high temperature, mechanical friction, abrasion and surface deterioration of the catalysts lead to Pt group elements (PGEs) emission into the various compartments of the environment at ng/km rates (Barefoot 1997; Artelt et al. 1999; Moldovan et al. 1999; Ek et al. 2004).
As in the case of the other PGEs, the recent application of Ir in the motor industry raised concerns about its increasing environmental levels and the potential adverse health effects. However, the toxicological literature concerning Ir effects on human health is very limited. Indeed, it was reported a case of contact dermatitis probably caused by exposure to a Pt and Ir alloy (Sheard 1955) and a case of contact urticarioid response with anaphylactic reactions in a worker of an electrochemical factory exposed to Ir chloride (Bergman et al. 1995). There are also some studies that, evaluating the effects of PGEs in workers of Pt refinery and catalyst manufacturing and recycling factory, revealed positive prick test reactions to Ir (Santucci et al. 2000; Cristaudo et al. 2005), while Marcusson et al. (1998) found positive reactions to Ir trichloride in 1% of 205 subjects with implanted dental alloys. These findings suggested the ability of this metal to cause immune sensitization and toxic responses in humans. In this regard, we have recently demonstrated that exposure of Wistar rats to different doses of Ir (III) chloride hydrate was able to induce an immunological imbalance, with Th1 cytokines displaying a marked dose-dependent decrease, whereas the Th2 cytokine IL-4 showed the opposite response (Iavicoli et al. 2010).
Finally, some data concerning the toxicokinetics of Ir were provided by experimental studies conducted several years ago, mostly on rats (AECD 1951a, 1951b; Casarett et al. 1960). After inhalation of metallic-Ir aqueous aerosols, metal was found in bronchi, larger bronchioles and in parenchymal regions (Casarett et al. 1960). Ir was then eliminated by lungs, with a half time of 6 h, while metal particles accumulated in the pulmonary parenchyma had a considerably slower clearance, with a half time of 22–24 days. Findings showed that the major route of excretion was via feces, for the 96% of the absorbed dose. The quantities of Ir redistributed to organs and excreted in the urine in the study of Casarett were much less than those observed by Hamilton (AECD 1951a, 1951b), probably because metal Ir is less soluble in water than Ir chloride and oxy-chloride. In more recent studies a size dependence of Ir particles distribution was observed; a predominant retention of ultrafine insoluble particles in the lung was shown 1 week after rat inhalation (Kreyling et al. 2002, 2009). The particles were then predominantly cleared via airways and larynx into the gastrointestinal tract and feces, but there was also a small traslocation from lungs to blood circulation and to secondary target organs (liver, spleen, heart, brain, and carcass). Also Semmler et al. (2004) found that the most Ir amount in rats was retained in the lungs 3 weeks after a 2 or 6 months inhalation of insoluble ultrafine Ir particles, while the clearance out of the body was solely via excretion. Moreover, the study showed that extrapulmonary particle uptake decreased with time in liver, spleen, heart and brain.
Recently a study of our group demonstrated that female Wistar rats exposed to Ir in the drinking water (from 1 to 1000 ng/ml) for 90 days displayed renal toxicity based on the elevated urinary retinol binding protein (RBP) and albumin (Iavicoli et al. 2011).
Apart from these few results, nothing is known about long-term Ir absorption, its clearance pathways out of the body and systemic uptake pathways toward secondary organs. In this context we carried out a 90-day oral administration study with female Wistar rats exposed to different Ir (III) chloride hydrate concentrations administered ad libitum in drinking water, to investigate the distribution in internal organs and the elimination routes after oral administration. This type of treatment may simulate the exposure humans receive in several environmental or occupational conditions.
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We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4′-carboxy-2,2′-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged ‘piano-stool’ configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.
To reduce the toxic side effects and circumvent intrinsic or acquired resistance of the widely used clinical anticancer drug cisplatin [1–4],new transition-metal based anticancer agents are urgently needed [5–8]. Low-spin 5d6 organo-iridium(III) complexes have attracted wide attention [9,10]. Especially promising are half-sandwich iridium complexes [(η5-Cp*)Ir(XY)Cl]+ (where Cp* is pentamethylcyclopentadienyl and XY is a chelating ligand) which have emerged as potential next-generation anticancer agents with novel redox-mediated mechanisms of action to overcome platinum resistance [11,12]. The carbon-bound Cp* ligand forms highly stable iridium(III) complexes [13–15]. We have reported that phenyl or biphenyl substituents on the Cp* ring, or a switch of the chelating ligand from N^N’ to C^N mode can have pronounced effects on the anticancer activity of these complexes. Meanwhile, the iridium centre can catalyse hydride transfer from NADH to molecular oxygen, generating hydrogen peroxide in cancer cells to trigger cell death [11,16]. However, achieving selectivity toward tumour cells over normal cells for half-sandwich iridium complexes is still To reduce the toxic side effects and circumvent intrinsic or acquired challenging and worthy of further investigation [17–20].
Ruiz et al. have designed a half-sandwich Cp* iridium steroid hormone conjugate targeted to steroidal receptors, which displayed 6-fold and 2-fold greater potency than cisplatin and a non-steroidal analogue, respectively [21]. Recently, Liu et al. have further developed a series of half-sandwich iridium anticancer complexes with lysosome-targeting properties [22]. In addition, Perrier et al. have used a cyclic peptide—polymer nanotube to deliver a Cp* iridium anticancer complex, with remarkable selectivity toward cancer cells as well as higher activity toward human ovarian cancer cells compared to the free iridium complex [23].
Tumour-targeting peptides can also be used as vectors [24] and have the potential to provide alternative efficient therapeutic benefit over the drug on its own [25]. The sequence RWY (Arg-Trp-Tyr) within the cyclic peptide of sequence c(CRWYDENAC) has a high affinity and specificity for the integrin α6 receptor on the surface of nasopharyngeal carcinoma [26]. Conjugation of this peptide to the periphery of a PtIVprodrug encapsulated in nanoparticles has resulted in a 100-fold increase in cytotoxicity over free cisplatin in vitro [26]. Furthermore, we have recently reported that photoactive PtIV prodrugs conjugated to this cyclic peptide exhibit higher photocytotoxicity and cellular Pt accumulation than the parent complex upon light irradiation [27].
However, it is well known that peptides with specific amino acid residues such as histidine, cysteine, tryptophan, and glutamic acid are natural chelating ligands for metal ions [28,29]. Conventional peptide conjugation methods suffer from poor site-specificity and hetero-geneous products related to the ratios of conjugation sites. To improve the site-specific conjugation as well as batch-to-batch reproducibility, “click” chemistry has proved to be a highly successful tool [30–32]. While the classic click Cu(I)-catalysed azide-alkyne cycloadditions have been a benchmark in many areas of recent synthetic chemistry, side reactions and toxicity of the copper catalyst often limit its utilization in biological applications [33,34]. By replacing terminal alkynes with strain-promoted cycloalkynes, copper-free azide-alkyne cycloadditions can be achieved under mild conditions without disrupting the function of the biomolecules, including selective derivatization of proteins, sugars, lipids, DNA and RNA [35]. The simplicity and orthogonality of strain-promoted azide-alkyne cycloadditions, have been widely used in a bioorthogonal fashion at the level of living cells as well as multicellular organisms [36–38].
Here we have synthesized a half-sandwich iridium complex [(Cp*)Ir (4-methyl-4′-carboxy-2,2′-bipyridine)Cl]PF6 (Ir-I) and its conjugate (Ir-CP) with a tumour-targeting cyclic peptide of sequence c(CRWYDENAC). The conjugation is achieved by an amide formation reaction first affording the precursor complex Ir-II for the subsequent strain-promoted copper-free azide-alkyne cycloaddition reaction between Ir-II and azide functionalised-cyclic peptide to generate the final Ir-CP. Ir-I and Ir-II are novel and have been characterized by 1H and 13C NMR, high resolution ESI-MS, HPLC and X-ray crystallography. The cytotoxicity of Ir-I and Ir-II has been screened against the human ovarian A2780 cancer cell line. The successful synthesis of the peptide conjugate Ir-CP has been verified by high resolution ESI-MS, HPLC, and UV–vis spectroscopy.
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