Folic acid conjugated chitosan encapsulated palladium nanoclusters for NIR triggered photothermal breast cancer treatment.

This study developed folic acid (FA) conjugated chitosan (CS) encapsulated rutin (R) synthesized palladium nanoclusters (Pd NCs) for NIR triggered and folate receptor (FR) targeted triple-negative breast cancer (MDA-MB 231 cells) treatment. R-Pd NCs exhibited flower-shaped particles with an average size of <100 nm. FA-CS encapsulation concealed the flower shape of R-Pd NCs with a positive charge. The XRD spectrum confirmed the cubic crystalline structure of Pd. The FA conjugation on CS improved the cellular uptake of R-Pd NCs in MDA-MB 231 cells was confirmed by TEM. FA-CS-R-Pd NCs (+NIR) treatment was considerably inhibited the MDA-MB 231 cells proliferation evidenced by cell viability, fluorescent staining, and flow cytometry analysis. Further, in vitro hemolysis assay and in Ovo model confirmed the non-toxic nature of FA-CS-R-Pd-NCs with or without NIR radiation. Hence, this study concluded that FA-CS-R-Pd NCs can be applied for the treatment of drug-resistant breast cancer.

meso-Tetra-(4-pyridyl)porphyrin/palladium(II) complexes as anticancer agents.

This study reports the synthesis, structural characterization and cytotoxic activity of four new palladium/pyridylporphyrin complexes, with the general formula {TPyP[PdCl(P-P)]4}(PF6)4, where P-P is 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb) or 1,1'-bis(diphenylphosphino)ferrocene (dppf). The complexes were characterized by elemental analysis, and by FT-IR, UV/Vis, 1H and 31P{1H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)]4}(PF6)4 (in an excess of NaBF4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P21/a space group. The cytotoxicity of the complexes against MDA-MB-231 (breast cancer cells) and MCF-10A (non-tumor breast cancer cells), was determined by the colorimetric MTT method, which revealed that all four complexes show selective indexes close to 1.2, lower than that of cisplatin for the same cells (12.12). The interaction of the complexes with CT-DNA was evaluated by UV-visible and viscosity measurements and it was determined that the complexes interact moderately with CT-DNA, probably by H-bonding/π-π stacking and electrostatic interactions.

Patch test-relevant concentrations of metal salts cause localized cytotoxicity, including apoptosis, in skin ex vivo.

BACKGROUND: Metal alloys containing contact sensitizers (nickel, palladium, titanium) are extensively used in medical devices, in particular dentistry and orthopaedic surgery. The skin patch test is used to test for metal allergy. OBJECTIVE: To determine whether metal salts, when applied to freshly excised skin at patch test-relevant concentrations and using a method which mimics skin patch testing, cause in changes in the epidermis and dermis. METHODS: Tissue histology, apoptosis, metabolic activity, and inflammatory cytokine release were determined for two nickel salts, two palladium salts, and four titanium salts. RESULTS: Patch test-relevant concentrations of all metal salts caused localized cytotoxicity. This was observed as epidermis separation at the basement membrane zone, formation of vacuoles, apoptotic nuclei, decreased metabolic activity, and (pro)inflammatory cytokine release. Nickel(II) sulfate hexahydrate, nickel(II) chloride hexahydrate, titanium(IV) bis(ammonium lactato)dihydroxide, and calcium titanate were highly cytotoxic. Palladium(II) chloride, sodium tetrachloropalladate(II), titanium(IV) isopropoxide, and titanium(IV) dioxide showed mild cytotoxicity. CONCLUSION: The patch test in itself may be damaging to the skin of the patient being tested. These results need further verification with biopsies obtained during clinical patch testing. The future challenge is to remain above the elicitation threshold at noncytotoxic metal concentrations.

Patch testing with aluminium Finn Chambers could give false-positive reactions in patients with contact allergy to aluminium.

BACKGROUND: Earlier laboratory studies have shown that sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride trigger the release of aluminium (Al) from Finn Chambers (FC). OBJECTIVES: To investigate whether aluminium realease from FC could influence the diagnostic outcome of patch testing with FC. METHOD: A retrospective analysis of patch test results from 2010 to 2019 was performed. A two-sided Fisher's exact test was used to calculate any overrepresentation of contact allergy to Al among patients with positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride. RESULTS: A total of 5446 patients had been tested with FC during the study period. There was a significant overrepresentation of contact allergy to Al among patients with positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride. Patients with a strong Al allergy had significantly higher amounts of concomitant reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride compared to patients with weak Al allergy. These results were not seen for patients tested with Finn Chambers AQUA. CONCLUSION: In patients with contact allergy to Al, patch testing with Finn chambers could give false-positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride.

Synthesis and characterization of palladium nanoparticles by chemical and green methods: A comparative study on hepatic toxicity using zebrafish as an animal model.

Nanoparticles synthesized by chemical methods are of a matter of concern, whereas, the green methods are said to be eco-friendly and environmentally safe. In this study, the toxicity of palladium nanoparticles (Pd NPs) synthesized through chemical co-precipitation and green route method using Annona squamosa seed kernels (As-Pd NPs) were evaluated using zebrafish as an animal model. The synthesized nanoparticles (NPs) were characterized using UV-Visible spectroscopy, Field Emission Scanning Electron Microscopy (FE-SEM), Energy Dispersive X-ray (EDX), Fourier Transform Infrared Spectroscopy (FTIR), Dynamic Light Scattering (DLS) and Zeta potential. Zebrafish (Danio rerio) were exposed to 0.4 ng/L of Pd NPs and As-Pd NPs for 96-h, further oxidative stress parameters and histological changes were evaluated. The superoxide dismutase (SOD), catalase (CAT) activity and the lipid peroxidation (LPO) levels were elevated in the Pd NPs groups. But in the As-Pd NPs group, the SOD activity showed a biphasic nature while the CAT activity gradually declined till the 96-h compared to the control and Pd NPs groups. The LPO levels in the As-Pd NPs groups showed a measurable increase till 72-h and sudden decline at the end of 96-h. Anomalies in the histological changes such as ruptured hepatocytes, sinusoidal congestion, vacuolation and accumulation of erythrocytes were observed in both the NPs treated groups but As-Pd NPs exhibited lesser lesions than the control and Pd NPs groups. However, our present study reveals the possible reliability of the nanoparticles and the mechanism of scavenging activity suggesting that the As-Pd NPs synthesized by green route are less toxic comparing to the chemically synthesized Pd NPs.

Palladium-Induced Temporal Internalization of MHC Class I Contributes to T Cell-Mediated Antigenicity.

Palladium (Pd) is a widely used metal and extremely important biomaterial for the reconstruction of occlusions during dental restorations. However, metallic biomaterials can cause serious allergic reactions, such as Pd-related oral mucositis seen in dentistry. Metal allergy is categorized as a type IV allergy and we demonstrated that CD8 T cells play an important role in Pd allergy previously. As TCR of CD8 T cells recognizes MHC class I/peptide complex, the antigen specificity to this complex seems to be generated during Pd allergy. However, it remains unknown if Pd affects the MHC class I/peptide complex. In this study, we investigated the behavior of the MHC class I/peptide complex in response to Pd treatment. We found that PdCl2 treatment altered peptide presentation on MHC class I and that co-culture with Pd-treated DC2.4 cells induced activation of Pd-responsive TCR-expressing T cell line. Furthermore, PdCl2 treatment induced temporal MHC class I internalization and inhibition of membrane movement suppressed Pd-induced T cell-mediated antigenicity. These data suggest that Pd-induced MHC class I internalization is critical for generation of antigenicity through a mechanism including differential peptide loading on MHC class I, which results in Pd allergy.

Nondestructive production of exosomes loaded with ultrathin palladium nanosheets for targeted bio-orthogonal catalysis.

The use of exosomes as selective delivery vehicles of therapeutic agents, such as drugs or hyperthermia-capable nanoparticles, is being intensely investigated on account of their preferential tropism toward their parental cells. However, the methods used to introduce a therapeutic load inside exosomes often involve disruption of their membrane, which may jeopardize their targeting capabilities, attributed to their surface integrins. On the other hand, in recent years bio-orthogonal catalysis has emerged as a new tool with a myriad of potential applications in medicine. These bio-orthogonal processes, often based on Pd-catalyzed chemistry, would benefit from systems capable of delivering the catalyst to target cells. It is therefore highly attractive to combine the targeting capabilities of exosomes and the bio-orthogonal potential of Pd nanoparticles to create new therapeutic vectors. In this protocol, we provide detailed information on an efficient procedure to achieve a high load of catalytically active Pd nanosheets inside exosomes, without disrupting their membranes. The protocol involves a multistage process in which exosomes are first harvested, subjected to impregnation with a Pd salt precursor followed by a mild reduction process using gas-phase CO, which acts as both a reducing and growth-directing agent to produce the desired nanosheets. The technology is scalable, and the protocol can be conducted by any researcher having basic biology and chemistry skills in ~3 d.

Analysis of Spatial Dose-Volume Relationships and Decline in Sexual Function Following Permanent Brachytherapy for Prostate Cancer.

OBJECTIVE: To explore relationships between dose to periprostatic anatomic structures and erectile dysfunction (ED) outcomes in an institutional cohort treated with prostate brachytherapy. METHODS: The Sexual Health Inventory for Men (SHIM) instrument was administered for stage cT1-T2 prostate cancer patients treated with Pd-103 brachytherapy over a 10-year interval. Dose volume histograms for regional organs at risk and periprostatic regions were calculated with and without expansions to account for contouring uncertainty. Regression tree analysis clustered patients into ED risk groups. RESULTS: We identified 115 men treated with definitive prostate brachytherapy who had 2 years of complete follow-up. On univariate analysis, the subapical region (SAR) caudal to prostate was the only defined region with dose volume histograms parameters significant for potency outcomes. Regression tree analysis separated patients into low ED risk (mean 2-year SHIM 20.03), medium ED risk (15.02), and high ED risk (5.54) groups. Among patients with good baseline function (SHIM ≥ 17), a dose ≥72.75 Gy to 20% of the SAR with 1 cm expansion was most predictive for 2-year potency outcome. On multivariate analysis, regression tree risk group remained significant for predicting potency outcomes even after adjustment for baseline SHIM and age. CONCLUSION: Dose to the SAR immediately caudal to prostate was predictive for potency outcomes in patients with good baseline function. Minimization of dose to this region may improve potency outcomes following prostate brachytherapy.

NIR-II Driven Plasmon-Enhanced Catalysis for a Timely Supply of Oxygen to Overcome Hypoxia-Induced Radiotherapy Tolerance.

Hypoxia, as a characteristic feature of solid tumor, can significantly adversely affect the outcomes of cancer radiotherapy (RT), photodynamic therapy, or chemotherapy. In this study, a strategy is developed to overcome tumor hypoxia-induced radiotherapy tolerance. Specifically, a novel two-dimensional Pd@Au bimetallic core-shell nanostructure (TPAN) was employed for the sustainable and robust production of O2 in long-term via the catalysis of endogenous H2 O2 . Notably, the catalytic activity of TPAN could be enhanced via surface plasmon resonance (SPR) effect triggered by NIR-II laser irradiation, to enhance the O2 production and thereby relieve tumor hypoxia. Thus, TPAN could enhance radiotherapy outcomes by three aspects: 1) NIR-II laser triggered SPR enhanced the catalysis of TPAN to produce O2 for relieving tumor hypoxia; 2) high-Z element effect arising from Au and Pd to capture X-ray energy within the tumor; and 3) TPAN affording X-ray, photoacoustic, and NIR-II laser derived photothermal imaging, for precisely guiding cancer therapy, so as to reduce the side effects from irradiation.

Platinum and palladium nanoparticle-containing mixture, PAPLAL, does not induce palladium allergy.

Palladium (Pd) is a common metal found in jewellery and dental appliances, but it has been shown to be likely to cause metal allergy. We previously reported that platinum (nPt) and palladium (nPd) nanoparticle-containing mixture (PAPLAL) has both superoxide dismutase and catalase activities and that the topical application of PAPLAL improved skin atrophy induced by chronic oxidative damage in an ageing mouse model. However, the safety of PAPLAL for preventing Pd allergy remains unclear. In the present study, we investigated whether or not PAPLAL induces Pd allergy. We found that PAPLAL treatment caused no skin inflammation, while nPd administration caused only slight skin inflammation compared to the palladium chloride-induced severe reaction in an experimental metal allergy model. A gene expression analysis revealed that PAPLAL treatment significantly suppressed the expression of Inf-γ, Il-1ß and Tnfα genes. Even in human clinical trials using patches containing metal nanoparticles, nPd and PAPLAL failed to induce significant skin inflammation. These results suggest that mixing with nPt in PAPLAL suppresses the inflammation response of nPd. PAPLAL can be expected to be applied to various skin treatments as a safe topical substance.

Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer's disease.

Oxidative stress-induced mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer's disease (AD). Hydrogen molecule, a special antioxidant, can selectively scavenge highly cytotoxic reactive oxygen species such as ·OH, exhibiting a potential to treat AD by reducing oxidative stress. However, there is no effective route to realize the continuous and efficient accumulation of administrated hydrogen in AD brain owing to its low solubility. Here, we develop the small-sized Pd hydride (PdH) nanoparticles for high payload of hydrogen and in situ sustained hydrogen release in AD brain. By virtue of the catalytic hydrogenation effect of Pd, the released hydrogen from PdH nanoparticles exhibits high bio-reductivity in favor of effectively scavenging cytotoxic ·OH in a self-catalysis way. Bio-reductive hydrogen is able to recover mitochondrial dysfunction, inhibit Aß generation and aggregation, block synaptic and neuronal apoptosis and promote neuronal energy metabolism by eliminating oxidative stress and activating the anti-oxidative pathway, consequently ameliorating the cognitive impairment in AD mice. The proposed hydrogen-releasing nanomedicine strategy would open a new window for the treatment of AD.

Transferrin-conjugated pH-sensitive platform for effective delivery of porous palladium nanoparticles and paclitaxel in cancer treatment.

Porous palladium (Pd) nanoparticles have garnered great research attention due to their potential anticancer activity and photothermal effect. In this study, a transferrin-conjugated pH-sensitive platform (Tf-PPP), comprising porous Pd nanoparticles (PdNPs) and paclitaxel (PTX), was successfully developed for combined chemo-phototherapy. Tf-PPPs have a small size of 164.6 ± 8.7 nm, PDI of 0.278 ± 0.029, and negative charge (-13.2 ± 1.8 mV). Poly(acrylic acid)-poly(ethylene oxide) (PAA-PEO), a pH sensitive polymer, was used to achieve pH-dependent drug release from nanoparticles. Transferrin (Tf) conjugated on the surface of nanoplatforms could enhance the cellular uptake and prolong nanoparticle accumulation in the tumor site. The combination of phototherapy induced by PdNPs and chemotherapeutic agent (PTX) could exhibit synergistic anticancer activities. Consistent findings were observed in both in vitro experiments including cytotoxicity, live/dead assay, and assessment of apoptotic protein levels, and in vivo antitumor study in MCF-7 tumor-bearing mice, with results decreasing in the following order: Tf-PPPs + NIR > Tf-PPPs > PPPs + NIR > PPPs > PTX > PdNPs. These findings suggest that the administration of Tf-PPPs, followed by NIR irradiation could be a promising strategy in the treatment of cancer.

Phase II study of intraoperative dosimetry for prostate brachytherapy using registered ultrasound and fluoroscopy.

PURPOSE: To assess the performance of a system of intraoperative dosimetry and obtain estimates of dosimetry outcomes achieved when utilizing the system in a Phase II clinical trial. METHODS AND MATERIALS: Forty-five patients undergoing permanent Pd-103 seed implantation for prostate cancer were prospectively enrolled. Seed implantation was performed and dose was tracked intraoperatively using intraoperative registered ultrasound and fluoroscopy (iRUF). Three-dimensional seed locations were computed from X-rays and registered to ultrasound for intraoperative dosimetry, followed by adaptive plan modification to achieve prostate V100 ≥95% and ≥95% D90. Time required for iRUF was recorded. Postoperative CT/MRI scans were performed 1 day after the implantation and used as reference for dosimetric analysis. Dosimetric parameters for the prostate and urethra were compared between standard ultrasound-based dosimetry (USD), iRUF, and postoperative CT/MRI. RESULTS: Mean total time for iRUF was <30 min. A mean of four seeds (0-12) were added per implant to correct cold spots discovered by iRUF. Day 1 CT/MRI prostate V100 was ≥95% for 44/45 patients; 1 patient had Day 1 V100 93%. No patient had rectal V100 exceeding 1 cc. Compared to CT/MRI, iRUF dosimetry had significantly smaller mean differences and higher correlations for all prostate and urethral dosimetric parameters examined than USD. Both USD and iRUF tended to overestimate dose, but with less bias in iRUF than USD. CONCLUSIONS: Intraoperative dosimetry utilizing iRUF was associated with acceptable increase in procedure time and enabled very high rates of achieving excellent prostate dose coverage. iRUF intraoperative dosimetry approximated postoperative CT/MRI dosimetry to a greater degree than USD for the prostate and urethra.

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.

Comparative outcomes and toxicities for ruthenium-106 versus palladium-103 in the treatment of choroidal melanoma.

For the treatment of choroidal melanoma, palladium-103 (Pd) and ruthenium-106 (Ru) plaque brachytherapy shows reduced toxicity compared with the historical standard iodine-125. No report has directly compared the clinical outcomes between Pd and Ru, and the reasons for the selection of one over the other remain purely theoretical. Patients with choroidal melanoma with apical tumor height up to 5 mm were included. Patients from Emory University were treated with Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. Pd patients (n=124) and Ru patients (n=42) had a median follow-up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes, but Ru had lower grades of retinopathy (P=0.006). Pd was associated with worse VA preservation (≥20/40) by year 3 (odds ratio: 3.8; 95% confidence interval: 1.01-14.31, P=0.048). Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (hazard ratio: 0.10; 95% confidence interval: 0.02-0.38; P<0.001). Ru had lower grades of radiation retinopathy and improved long-term VA preservation, but also inferior DMFS, compared with Pd. Because of the inherent limitations of a retrospective analysis, the significance of the inferior DMFS for Ru remains unclear, although the suggestion of a slight inferiority in terms of DMFS for Ru is consistent with the other limited literature. On the basis of this study, we believe that both radioisotopes remain appropriate for the treatment of small choroidal melanomas up to 5 mm in apical height.

Thermosensitive chitosan/phosphate hydrogel-composites fortified with Ag versus Ag@Pd for biomedical applications.

INTRODUCTION: Thermo-responsive hydrogels are promising biomedical systems as their gelation is triggered by temperature changes. Greenly synthesized noble metallic nanoparticles are a growing research area assessing their potential applications in nanomedicine. MATERIALS AND METHODS: Chitosan/phosphate thermosensitive gels were successfully achieved. The developed composite scaffolds were functionalized with the greenly synthesized Ag or Ag@Pd targeting improved bactericidal activity and biocompatibility performance. The physicochemical characterization was assessed through TGA, DSC, FESEM, HRTEM, XRD and FTIR. Bactericidal activities were tested against gram- positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa. Their biodegradability upon DMEM immersion was followed up to seven days through measuring ionic concentrations of Ca, P, Ag and Pd successively. KEY FINDINGS: The newly developed phosphatic layers over the scaffold surfaces post-immersion assessed their osteogenic ability. Further, their promising and differentiated bactericidal activities due to the noble metals incorporation were proved. Cytotoxicity assessment demonstrated their high biocompatibility since no toxic effect was recorded. SIGNIFICANCE: Consequently, they can be successfully and directly applied in biomedical and dental surgeries.

Folate receptor-targeted multimodal fluorescence mesosilica nanoparticles for imaging, delivery palladium complex and in vitro G-quadruplex DNA interaction.

New folic acid-conjugated mesoporous silica nanoparticles were synthesized. The effect of calcination at 400°C on the fluorescence characteristics of mesoporous silica nanoparticles were studied in this work. The formed carbon dots (CDs) from calcination were used as the source of fluorescence. 3-Aminopropyltriethoxysilane was then used to amine-functionalized the fluorescent surface of mesoporous silica nanoparticles. The amine fluorescence mesoporous silica nanoparticles (amine-FMSNs) were coupled with folic acid (FA) as the target ligand (FA-amine-FMSNs). A palladium complex was also synthesized and encapsulated in the FA-amine-FMSNs yielded fluorescent property with therapeutic effect. The in vitro release of an entrapped palladium complex from FA-amine-FMSNs was studied under physiological conditions. According to the cell viability assay on HeLa (positive FR) and Hep-G2 (negative FR) cells, the targeted delivery system inhibited the growth of positive FR with higher selectivity compared with negative FR cells. Also, the emission CDs were used for fluorescence microscopic imaging. To confirm anti-cancer activity of the palladium complex, the interaction between palladium complex and G-quadruplex DNA were investigated with multi-spectroscopic methods and molecular modeling. The molecular docking studies showed a partial intercalation mode with a 4.27 × 105 M-1 binding constant.

Nano-palladium is a cellular catalyst for in vivo chemistry.

Palladium catalysts have been widely adopted for organic synthesis and diverse industrial applications given their efficacy and safety, yet their biological in vivo use has been limited to date. Here we show that nanoencapsulated palladium is an effective means to target and treat disease through in vivo catalysis. Palladium nanoparticles (Pd-NPs) were created by screening different Pd compounds and then encapsulating bis[tri(2-furyl)phosphine]palladium(II) dichloride in a biocompatible poly(lactic-co-glycolic acid)-b-polyethyleneglycol platform. Using mouse models of cancer, the NPs efficiently accumulated in tumours, where the Pd-NP activated different model prodrugs. Longitudinal studies confirmed that prodrug activation by Pd-NP inhibits tumour growth, extends survival in tumour-bearing mice and mitigates toxicity compared to standard doxorubicin formulations. Thus, here we demonstrate safe and efficacious in vivo catalytic activity of a Pd compound in mammals.