Bioorthogonal catalytic patch.

Bioorthogonal catalysis mediated by transition metals has inspired a new subfield of artificial chemistry complementary to enzymatic reactions, enabling the selective labelling of biomolecules or in situ synthesis of bioactive agents via non-natural processes. However, the effective deployment of bioorthogonal catalysis in vivo remains challenging, mired by the safety concerns of metal toxicity or complicated procedures to administer catalysts. Here, we describe a bioorthogonal catalytic device comprising a microneedle array patch integrated with Pd nanoparticles deposited on TiO2 nanosheets. This device is robust and removable, and can mediate the local conversion of caged substrates into their active states in high-level living systems. In particular, we show that such a patch can promote the activation of a prodrug at subcutaneous tumour sites, restoring its parent drug's therapeutic anticancer properties. This in situ applied device potentiates local treatment efficacy and eliminates off-target prodrug activation and dose-dependent side effects in healthy organs or distant tissues.

Mechanistic simulation of bioconcentration kinetics of waterborne Cd, Ag, Pd, and Pt in the zebra mussel Dreissena polymorpha.

Mechanistic models based on chemical properties of metals and body size have received substantial attention for their potential application to various metals and to different conditions without required calibration. This advantage has been demonstrated for a number of metals, such as Cd and Ag. However, the capacity of metal-specific chemical properties to explain variations in the accumulation for platinum-group elements (PGEs) has not been investigated yet, although emission of these metals is of increasing concern. Once being released, PGEs exist in the environment in mixtures with other metals. The present study attempted to model the accumulation of Pd and Pt in mixtures with Ag and Cd in the zebra mussel (Dreissena polymorpha) from the aqueous phase; and to investigate the potential application of mechanistic models to Pd and Pt. The present study showed statistically insignificant differences in metal accumulation among size groups in a narrow range of shell length (16-22 mm). Kinetic models could simulate well the accumulation of Cd, Ag, and Pt when metal-specific responses of zebra mussels are taken into consideration. These responses include enhanced immobilisation as a detoxifying mechanism and exchange between soft tissues and shells via the extrapallial fluid. Environmental conditions, e.g. the presence of abiotic ligands such as chloride, might also play an important role in metal accumulation. Significant relationships between the absorption efficiency and the covalent index indicate the potential application of mechanistic models based on this chemical property to Pt.

Intratumoral Injection of Low-Energy Photon-Emitting Gold Nanoparticles: A Microdosimetric Monte Carlo-Based Model.

Gold nanoparticles (Au NPs) distributed in the vicinity of low-dose rate (LDR) brachytherapy seeds could multiply their efficacy thanks to the secondary emissions induced by the photoelectric effect. Injections of radioactive LDR gold nanoparticles (LDR Au NPs), instead of conventional millimeter-size radioactive seeds surrounded by Au NPs, could further enhance the dose by distributing the radioactivity more precisely and homogeneously in tumors. However, the potential of LDR Au NPs as an emerging strategy to treat cancer is strongly dependent on the macroscopic diffusion of the NPs in tumors, as well as on their microscopic internalization within the cells. Understanding the relationship between interstitial and intracellular distribution of NPs, and the outcomes of dose deposition in the cancer tissue is essential for considering future applications of radioactive Au NPs in oncology. Here, LDR Au NPs (103Pd:Pd@Au-PEG NPs) were injected in prostate cancer tumors. The particles were visualized at time-points by computed tomography imaging ( in vivo), transmission electron microscopy ( ex vivo), and optical microscopy ( ex vivo). These data were used in a Monte Carlo-based dosimetric model to reveal the dose deposition produced by LDR Au NPs both at tumoral and cellular scales. 103Pd:Pd@Au-PEG NPs injected in tumors produce a strong dose enhancement at the intracellular level. However, energy deposition is mainly confined around vesicles filled with NPs, and not necessarily close to the nuclei. This suggests that indirect damage caused by the production of reactive oxygen species might be the leading therapeutic mechanism of tumor growth control, over direct damage to the DNA.

In vitro cytotoxicity study of dual drug loaded chitosan/palladium nanocomposite towards HT-29 cancer cells.

Conjugated drug delivery has gained immense interest due to the possibility of overcoming the resistance of cancer cells to a specific drug when treated using it for a period of time. In the present study, CS/Pd nanocomposite has been prepared using cost effective chemical reduction method and has been used for the delivery of curcumin (CUR) and 5-Fluorouracil (5-FU) separately and in a conjugated form. The prepared nanocomposite before and after drug encapsulation have been studied using various characterization techniques. The release of drugs from the nanocomposite with respect to time has been analyzed and the release kinetics has also been studied. The release profile is mostly seen to adhere to zero order kinetics which represents the constant release of drugs from drug delivery system. This is the most favored release kinetic as this leads to the prolonged release of the drug, thus leading to a reduction in the number of doses administered. The cytotoxicity of the drug loaded nanocomposites on colon cancer cells has been studied, which shows the effectiveness of the composite system towards successfully inhibiting the growth of cancer cells.

Quantitative bioimaging of platinum group elements in tumor spheroids.

Limited drug penetration into tumor tissue is a significant factor to the effectiveness of cancer therapy. Tumor spheroids, a 3D cell culture model system, can be used to study drug penetration for pharmaceutical development. In this study, a method for quantitative bioimaging of platinum group elements by laser ablation (LA) coupled to inductively coupled plasma mass spectrometry (ICP-MS) is presented. Different matrix-matched standards were used to develop a quantitative LA-ICP-MS method with high spatial resolution. To investigate drug penetration, tumor spheroids were incubated with platinum complexes (Pt(II)acetylacetonate, cisplatin) and the palladium tagged photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP). Distribution and accumulation of the pharmaceuticals were determined with the developed method.

Palladium nanoparticles exposure: Evaluation of permeation through damaged and intact human skin.

The intensified use of palladium nanoparticles (PdNPs) in many chemical reactions, jewellery, electronic devices, in car catalytic converters and in biomedical applications lead to a significant increase in palladium exposure. Pd can cause allergic contact dermatitis when in contact with the skin. However, there is still a lack of toxicological data related to nano-structured palladium and information on human cutaneous absorption. In fact, PdNPs, can be absorbed through the skin in higher amounts than bulk Pd because NPs can release more ions. In our study, we evaluated the absorption of PdNPs, with a size of 10.7 ± 2.8 nm, using intact and damaged human skin in Franz cells. 0.60 mg cm(-2) of PdNPs were applied on skin surface for 24 h. Pd concentrations in the receiving solutions at the end of experiments were 0.098 ± 0.067 µg cm(-2) and 1.06 ± 0.44 µg cm(-2) in intact skin and damaged skin, respectively. Pd flux permeation after 24 h was 0.005 ± 0.003 µg cm(-2) h(-1) and 0.057 ± 0.030 µg cm(-2) h(-1) and lag time 4.8 ± 1.7 and 4.2 ± 3.6 h, for intact and damaged skin respectively. This study indicates that Pd can penetrate human skin.

64Cu-Doped PdCu@Au Tripods: A Multifunctional Nanomaterial for Positron Emission Tomography and Image-Guided Photothermal Cancer Treatment.

This article reports a facile synthesis of radiolabeled PdCu@Au core-shell tripods for use in positron emission tomography (PET) and image-guided photothermal cancer treatment by directly incorporating radioactive (64)Cu atoms into the crystal lattice. The tripod had a unique morphology determined by the PdCu tripod that served as a template for the coating of Au shell, in addition to well-controlled specific activity and physical dimensions. The Au shell provided the nanostructure with strong absorption in the near-infrared region and effectively prevented the Cu and (64)Cu atoms in the core from oxidization and dissolution. When conjugated with D-Ala1-peptide T-amide (DAPTA), the core-shell tripods showed great enhancement in targeting the C-C chemokine receptor 5 (CCR5), a newly identified theranostic target up-regulated in triple negative breast cancer (TNBC). Specifically, the CCR5-targeted tripods with an arm length of about 45 nm showed 2- and 6-fold increase in tumor-to-blood and tumor-to-muscle uptake ratios, respectively, relative to their nontargeted counterpart in an orthotopic mouse 4T1 TNBC model at 24 h postinjection. The targeting specificity was further validated via a competitive receptor blocking study. We also demonstrated the use of these targeted, radioactive tripods for effective photothermal treatment in the 4T1 tumor model as guided by PET imaging. The efficacy of treatment was confirmed by the significant reduction in tumor metabolic activity revealed through the use of (18)F-fluorodeoxyglucose PET/CT imaging. Taken together, we believe that the (64)Cu-doped PdCu@Au tripods could serve as a multifunctional platform for both PET imaging and image-guided photothermal cancer therapy.

Optimization of Surface Coating on Small Pd Nanosheets for in Vivo near-Infrared Photothermal Therapy of Tumor.

Palladium nanosheets with strong near-infrared absorption have been recently demonstrated as promising photothermal agents for photothermal therapy (PTT) of cancers. However, systematic assessments of their potential risks and impacts to biological systems have not been fully explored yet. In this work, we carefully investigate how surface coatings affect the in vivo behaviors of small Pd nanosheets (Pd NSs). Several biocompatible molecules such as carboxymethyl chitosan (CMC), PEG-NH2, PEG-SH, and dihydrolipoic acid-zwitterion (DHLA-ZW) were used to coat Pd NSs. The blood circulation half-lives, biodistribution, potential toxicity, clearance, and photothermal effect of different surface-coated Pd NSs in mice after intravenous injection were compared. PEG-SH-coated Pd NSs (Pd-HS-PEG) were found to have ultralong blood circulation half-life and show high uptake in the tumor. We then carry out the in vivo photothermal therapeutic studies on the Pd-HS-PEG conjugate and revealed its outstanding efficacy in in vivo photothermal therapy of cancers. Our results highlight the importance of surface coatings to the in vivo behaviors of nanomaterials and can provide guidelines to the future design of Pd NSs bioconjugates for other in vivo applications.

Intracellular surface-enhanced Raman scattering (SERS) with thermally stable gold nanoflowers grown from Pt and Pd seeds.

SERS provides great sensitivity at low concentrations of analytes. SERS combined with near infrared (NIR)-resonant gold nanomaterials are important candidates for theranostic agents due to their combined extinction properties and sensing abilities stemming from the deep penetration of laser light in the NIR region. Here, highly branched gold nanoflowers (GNFs) grown from Pd and Pt seeds are prepared and their SERS properties are studied. The growth was performed at 80 °C without stirring, and this high temperature growth method is assumed to provide great shape stability of sharp tips in GNFs. We found that seed size must be large enough (>30 nm in diameter) to induce the growth of those SERS-active and thermally stable GNFs. We also found that the addition of silver nitrate (AgNO3) is important to induce sharp tip growth and shape stability. Incubation with Hela cells indicates that GNFs are taken up and reside in the cytoplasm. SERS was observed in those cells incubated with 1,10-phenanthroline (Phen)-loaded GNFs.

Development of a spray-drying method for the formulation of respirable microparticles containing ofloxacin-palladium complex.

The purpose of this study was to produce low-releasing spray-dried polymeric microparticles (MP) useful to target alveolar macrophages in tuberculosis (TB) inhalation therapy. Ofloxacin (Ofx) was encapsulated as ofloxacin-palladium (Ofx-Pd) complex into poly DL-lactide (PLA) MP by spray-drying. Ofx-Pd was prepared according to a method previously reported. A D-optimal design was employed to optimize drug content (DC), aerodynamic diameter (d(ae)) and span. d(ae) was calculated coupling tap-density to particle size analysis. The MP were characterized by SEM, UV spectrophotometry, and DSC. In vitro drug release was performed in comparison to Ofx loaded PLA MP. The Ofx-Pd complex formed spontaneously with a 1:1 stoichiometry. Inlet temperature, drug loading and polymer concentration resulted the most influential. Optimal MP had span of 0.9, a round shape, d(ae) of 2.5 µm, and DC of 30% (w/w). DSC and SEM analyses correlated with particle size. The optimized MP formulation showed a very low release at pH 7.4 compared to spray-dried Ofx loaded MP, the release increased slightly at lower pHs. Potentially inhalable MP were obtained by an optimized spray-drying process. The very low initial drug release at physiologic pH could be useful to target alveolar macrophages and to avoid systemic exposure.

Tailoring of Pd-Pt bimetallic clusters with high stability for oxygen reduction reaction.

The composition-dependent equilibrium structure and thermal stability of Pd-Pt clusters with the size of 55 atoms, and CO, O, OH, and O(2) adsorption on these clusters have been studied using molecular simulation based on the Gupta empirical potential and density functional theory (DFT) calculations. It is found that Pd(43)Pt(12) with a three-shell onionlike structure (TS-cluster) exhibits the highest relative stability in both DFT and Gupta levels and also the highest melting point at the Gupta level among these Pd-Pt clusters. In addition, the Pd(43)Pt(12) TS-cluster possesses the weakest CO, O, OH, and O(2) adsorption strength, compared to the Pt(55), Pd(55), and Pd(13)Pt(42) clusters, indicating good catalytic activities toward the oxygen reduction reaction (ORR) among these Pd-Pt clusters considered. We expect that this kind of DFT-guided strategy by controlling the composition could provide a simple way for possibly searching new electrocatalysts.

Synthesis, X-ray crystal structure, DNA binding, antioxidant and cytotoxicity studies of Ni(ii) and Pd(ii) thiosemicarbazone complexes.

New complexes, [Ni(HL)(PPh(3))]Cl (1), [Pd(L)(PPh(3))](2), and [Pd(L)(AsPh(3))](3), were synthesized from the reactions of 4-chloro-5-methyl-salicylaldehyde thiosemicarbazone [H(2)L] with [NiCl(2)(PPh(3))(2)], [PdCl(2)(PPh(3))(2)] and [PdCl(2)(AsPh(3))(2)]. They were characterized by IR, electronic, (1)H-NMR spectral data. Further, the structures of the complexes have been determined by single crystal X-ray diffraction. While the thiosemicarbazone coordinated as binegative tridentate (ONS) in complexes 2 and 3, it is coordinated as mono negative tridentate (ONS) in 1. The interactions of the new complexes with calf thymus DNA was examined by absorption and emission spectra, and viscosity measurements. Moreover, the antioxidant properties of the new complexes have also been tested against DPPH radical in which complex 1 exhibited better activity than that of the other two complexes 2 and 3. The in vitro cytotoxicity of complexes 1-3 against A549 and HepG2 cell lines was assayed, and the new complexes exhibited higher cytotoxic activity with lower IC(50) values indicating their efficiency in killing the cancer cells even at very low concentrations.

First determination of the levels of platinum group metals in Manta birostris (manta ray) caught along the Ghanaian coastline.

Tissues from Manta birostris caught by fishermen from Dixcove in the western part of Ghana were analyzed for their Platinum, palladium and rhodium concentrations (PGM). The use of chondrichthyan fish has permitted the study of trace levels of Platinum group metals (PGMs) which have travelled very far into the sea. The analysis showed that Ghana's coastline is fairly polluted with these platinum group metals (PGMs). PGM concentration in manta ray recorded a range of (0.15-0.85) microg/g for Pt, (0.033-0.67) microg/g for Pd and (0.007-0.145) microg/g for Rh. Comparing these values to the UK dietary intake of 0.2 microg/day for Pt and Rh and 1.0 microg/day for Pd, its indicates that the values obtained from the analysis for Pt was above the required level. This is the first study to show the accumulation of PGM in chondrichthyan fish, although the sources of this pollution are not clear as manta birostris is migratory and therefore need to be investigated further. The presence of the PGM is very significant, since manta ray meat is consumed in Ghana. This may presents a health risk, due to a possible accumulation of PGMs in humans.

Distribution and elimination of palladium in rats after 90-day oral administration.

This study determined the distribution in internal organs and the elimination routes in rats after oral administration of potassium hexachloro-palladate. Forty male Wistar rats were exposed for 90 days to 0, 10, 100 and 250 ng/mL of the palladium (Pd) salt in drinking water. Samples of urine and feces were collected on days 1, 30, 60 and 90, while organs (kidney, liver, lung, spleen and bones) and blood were collected at the end of the experiment. Quantification method was based on the sector-field inductively coupled plasma mass spectrometry. Results indicated that Pd ions were rapidly eliminated from the body. The principal excretion was through the feces (650 +/- 72.7 ng/g dry weight, at the Pd dose of 250 ng/mL), but at the higher dosing Pd was also eliminated through the urine (6.16 +/- 1.91 ng/mL for the Pd intake of 250 ng/mL). A clear relationship between the Pd ingested dose and the Pd excretion amount was observed mainly in the feces. Absorbed Pd was mostly found in the kidney of rats (124.4 +/- 23.0 ng/g dry weight, following the highest dose), while liver, lung, spleen and bones did not accumulate the metal. At the higher dosing, Pd content in the kidney raised proportionally with the Pd dose. Our findings may be useful to help in the understanding of the health impact of Pd dispersed in the environment as well as in identifying appropriate biological indices of Pd exposure.

[Pharmacokinetic and dosimetric characteristics of new radiopharmaceutical based on complexes of 103Pd and albumin microspheres].

Results of the study of absorbed dose formed in organs and tissues of mice after administration of new therapeutic radiopharmaceutical on the base of 103Pd and albumin microspheres (MSA) are presented. Pharmacokinetic parameters of preparation distribution in the body of animals were experimentally determined and then absorbed doses were calculated using MCNP code for the developed mathematical model of mouse. It was shown that absorption of 103Pd-MSA in tumor, physical properties of 103Pd and daughter radionuclide 103mRh provide a targeted irradiation of tumor as compared with the adjusting tissues and critical organs. In administration to tumor muscle tissue of the leg of experimental animals after 15 days following the injection of 103Pd-MSA the accumulated absorbed dose was 15 times less than corresponding one in tumor. In a critical organ (kidneys) the accumulated absorbed dose was 20 times less than in tumor. The work performed as a stage of pre-clinical testing of the radiopharmaceutical.

Airborne particulate matter, platinum group elements and human health: a review of recent evidence.

Environmental concentrations of the platinum group elements (PGE) platinum (Pt), palladium (Pd) and rhodium (Rh) have been on the rise, due largely to the use of automobile catalytic converters which employ these metals as exhaust catalysts. It has generally been assumed that the health risks associated with environmental exposures to PGE are minimal. More recent studies on PGE toxicity, environmental bioavailability and concentrations in biologically relevant media indicate however that environmental exposures to these metals may indeed pose a health risk, especially at a chronic, subclinical level. The purpose of this paper is to review the most recent evidence and provide an up-to-date assessment of the risks related to environmental exposures of PGE, particularly in airborne particulate matter (PM). This review concludes that these metals may pose a greater health risk than once thought for several reasons. First, emitted PGE may be easily mobilised and solubilised by various compounds commonly present in the environment, thereby enhancing their bioavailability. Second, PGE may be transformed into more toxic species upon uptake by organisms. The presence of chloride in lung fluids, for instance, may lead to the formation of halogenated PGE complexes that have a greater potential to induce cellular damage. Third, a significant proportion of PGE found in airborne PM is present in the fine fraction that been found to be associated with increases in morbidity and mortality. PGE are also a concern to the extent that they contribute to the suite of metals found in fine PM suspected of eliciting a variety of health effects, especially in vulnerable populations. All these factors highlight the need to monitor environmental levels of PGE and continue research on their bioavailability, behaviour, speciation and associated toxicity to enable us to better assess their potential to elicit health effects in humans.

Distribution and elimination of palladium in male wistar rats following 14-day oral exposure in drinking water.

The Pd tissue distribution and elimination in rats following oral exposure in drinking water of dipotassium hexachloropalladate at doses of 100 or 250 ng/ml for 14 d were determined. The sector field inductively coupled plasma mass spectrometry used for Pd quantification showed the adequate sensitivity (10 ng/l) and accuracy (96-105%), and all the more in consideration of the very low levels of Pd accumulated. Tissues were taken and analyzed after 14 d. The tissue containing the highest Pd concentration was the kidney (4 ng/g dry weight in controls and 75 ng/g dry weight at the maximum dose), with left and right kidneys showing a comparable accumulation. The Pd kidney levels rose, but not significantly, with the administered dose. None of the other organs (liver, lung, spleen, adrenal glands, and bones) appeared to accumulate Pd, even at the highest dose. At the 250-ng/ml dose, small amounts of Pd were found in serum (0.27 ng/ml vs. 0.19 ng/ml in controls), while they were higher in urine (1.2 ng/ml vs. 0.16 ng/ml in controls) and in feces (3,231 ng/g dry weight vs. 69 ng/g dry weight in controls). Feces were the main excretion route for Pd, with a significant linear correlation with exposed dose, which is likely due to low intestinal absorption of Pd.

Metallothionein (MT) response after chronic palladium exposure in the zebra mussel, Dreissena polymorpha.

The effects of different exposure concentrations of palladium (Pd) on relative metallothionein (MT) response and bioaccumulation were investigated in zebra mussels (Dreissena polymorpha). The mussels were exposed to 0.05, 5, 50, and 500 microg/L Pd2+ for 10 weeks under controlled temperature and fasting conditions. Relative MT contents were assessed by a modified Ag-saturation method, which allows to discriminate between MT bound to Pd (Pd-MT) and MT bound to unidentified metals (Ag-MT). Determination of metal contents resulted from atomic absorption spectrometry following a microwave digestion. For unexposed mussels and mussels exposed to 0.05 microg/L Pd no metal accumulation could be detected. All other exposure concentrations resulted in detectable Pd accumulation in mussels with final tissue concentrations of 96 microg/g (500 microg/L), 45 microg/g (50 microg/L), and 9 microg/g (5 microg/L). Compared with initial levels Pd-MT concentrations at the end of the exposure period were 600 (500 microg/L), 160 (50 microg/L), and 27 (5 microg/L) times higher. These results show that an increase in MTs in D. polymorpha already occurs at relatively low aqueous Pd concentrations indicating that there is the need for detoxification of Pd in the mussel. Furthermore, correlations between Ag-MT and Pd accumulation indicate that higher exposure concentrations are associated with adverse effects on the mussels. Thus, harmful effects of chronic Pd exposure of organisms even in lowest concentrations cannot be excluded in the environment.

Influence of synthetic surfactants on the uptake of Pd, Cd and Pb by the marine macroalga, Ulva lactuca.

Uptake of Pd, Cd and Pb by the marine macroalga, Ulva lactuca, has been studied in the presence of an anionic (sodium dodecyl sulphate, SDS), cationic (hexadecyltrimethylammonium bromide; HDTMA) and non-ionic (Triton X-100; TX) surfactant. Compared with the surfactant-free system, metal sorption was reduced in the presence of SDS or TX. Neither surfactant, however, had any measurable impact on cell membrane permeability, determined by leakage of dissolved free amino acids (DFAA), or on metal internalisation. We attribute these observations to the stabilisation of aqueous Cd and Pb by SDS and the shielding of otherwise amenable sorption sites by TX. Presence of HDTMA resulted in a reduction in the extent of both sorption and internalisation of all metals and a significant increase in the leakage of DFAA. Thus, by enhancing membrane permeability, HDTMA exerts the greatest influence on metal behaviour in the presence of U. lactuca.

Palladium alters cigarette smoke toxicological profile, but accumulates in the lungs of rats during inhalation exposure.

The use of a palladium (Pd) catalyst has been proposed to promote combustion of tobacco, thereby reducing concentrations of certain toxic components of smoke, including polyaromatic hydrocarbons (PAHs). In the present work, toxicological comparisons were made using experimental cigarettes containing no added Pd, against otherwise similar cigarettes containing three different amounts of Pd as potassium tetrachloropalladate added to the tobacco. A full analysis of smoke chemistry was made, along with a subchronic 90-day inhalation study with mainstream smoke (rats exposed to 150 mg/m(3) of total particulate matter, 6 h/day for 90 consecutive days) and in vitro evaluations of Salmonella mutagenicity, cytotoxicity, and in vivo clastogenicity (micronucleus). Addition of Pd to the tobacco resulted in 20-30% reductions in the concentrations of 6 PAHs and 2 aromatic amines, but it also resulted in transfer of Pd to smoke and in 10-50% increases in concentrations of several tobacco-specific nitrosamines. Mutagenicity was reduced by about 50% in 2 of 5 strains of Salmonella (with S9 only), while the cytotoxicity and micronucleus assays showed no changes. Histopathology responses were similar across the four smoke inhalation groups. Smoke Cd was reduced by 40-70% in the smoke, leading to lower lung concentrations; however, the presence of Pd in smoke led to accumulation of Pd in the lungs increasing in both a dose-and an exposure-related manner. While catalysts such as Pd addition may alter the typical chemical/toxicological profile of smoke, a concern arises regarding the "risk-benefit" of the addition of such chemically active materials as Pd to cigarette tobacco, leading to potential pulmonary accumulation with unknown consequences.