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The precise and safe treatment of bioorthogonal prodrug system is hindered by separate administration of prodrug and its activator, which often results in poor therapeutic effects and severe side effects. To address above issues, we herein construct a single bioorthogonal-activated co-delivery system for simultaneous PROTAC prodrug (proPROTAC) delivery and controlled, site-specific activation for tumor-specific treatment. In this co-delivery system (termed AuPLs), prodrug (proPROTAC) and water-soluble Pd-catalyst are first encapsulated by gold nanocubes (AuNCs), which are further coated with a layer of phase-change material (lauric acid/stearic acid, LA/SA). Below 39 °C, the solid state of LA/SA prevents the activation of Pd-mediated bioorthogonal reaction due to the solidification of Pd-catalyst and proPROTAC. Nevertheless, once over 42 °C, the phase change of LA/SA into liquid state, enabled by the photothermal effect of AuNCs, triggers the simultaneous release of proPROTAC and Pd-catalyst and initiates the in situ bioorthogonal reaction for proPROTAC activation. In the tumor-bearing mouse models, the systemic administration of AuPLs results in the accumulation in tumor region, where the photothermal effect activates and controls the tumor-specific bioorthogonal reaction to degrade BRD4 protein, leading to anti-tumor effects with minimized side effects. Overall, the co-delivery proPROTAC and Pd-catalyst and controlled activation by photothermal effects provide a precise way for biorthogonal-based anticancer prodrugs., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure. Selection of appropriate radionuclides is required. This work highlights the potential of 103 Pd (T 1/2 = 16.991 d) which decays to 103m Rh (T 1/2 = 56.12 min) then to stable 103 Rh with emission of Auger and conversion electrons. Methods: The Monte Carlo track structure code CELLDOSE was used to assess absorbed doses in single cells (14-μm diameter; 10-μm nucleus) and clusters of 19 cells. The radionuclide was distributed on the cell surface, within the cytoplasm, or in the nucleus. Absorbed doses from 103 Pd, 177 Lu and 161 Tb were compared after energy normalization. The impact of non-uniform cell targeting, and the potential benefit from dual-targeting was investigated. Additional results related to 103m Rh, if used directly, are provided. Results: In the single cell, and depending on radionuclide distribution, 103 Pd delivered 7- to 10-fold higher nuclear absorbed dose and 9- to 25-fold higher membrane dose than 177 Lu. In the 19-cell clusters, 103 Pd absorbed doses also largely exceeded 177 Lu. In both situations, 161 Tb stood in-between 103 Pd and 177 Lu. Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity. For example, with intranuclear 103 Pd, unlabeled cells received only 14% of the expected nuclear dose. Targeting with two 103 Pd-labeled radiopharmaceuticals minimized dose heterogeneity. Conclusion: 103 Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than 177 Lu to single tumor cells and cell clusters. This may open new horizons for the use of TRT in adjuvant or neoadjuvant settings, or for targeting minimal residual disease., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The low oxidation level and immunosuppressive microenvironment within hypoxic tumor tissue are critical factors contributing to the inefficacy of various anti-tumor strategies. Herein, we have designed a novel intravenous injection nanoplatform to conduct electro-immunotherapy, based on phospholipid-modified PtPd nanocrystals loaded with the immunoregulator IPI549 (LP@Pt-Pd@IPI549 nanoparticles, LPPI). LPPI responds to reactive oxygen species (ROS), triggering a cascade of therapeutic effects that overcome hypoxia-related resistance and effectively eradicate hypoxic tumors. Firstly, under electric field exposure, LPPI relied on water rather than oxygen to generate abundant ROS under hypoxic conditions for tumor electrodynamic therapy (EDT). Moreover, the generated ROS further induced the disintegration of the outer phospholipid membrane of LPPI, leading to the release of the immunoregulator and inhibition of myeloid-derived suppressor cells (MDSCs), triggering cascade immune responses. Additionally, the immunomodulatory effects of IPI549, in synergy with the immunogenic cell death (ICD) induced by EDT, reversed the immunosuppressive microenvironment contributing to tumor resistance. In summary, EDT transiently killed tumor cells while simultaneously generating antigen release, instigating an adaptive immune response for electro-immunotherapy, resulting in a potent and long-lasting tumor inhibition effect., 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 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021. Published by Elsevier Ltd.)

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 PdCl 2 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, PdCl 2 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer N.S has declared a shared affiliation with some of the authors KI, NH, KO to the handling editor at the time of review., (Copyright © 2021 Ito, Kanaseki, Tokita, Torigoe, Hirasawa and Ogasawara.)

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 }(PF 6 ) 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, 1 H and 31 P{ 1 H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)] 4 }(PF 6 ) 4 (in an excess of NaBF 4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P 2 1 / 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.

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., (© 2021 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

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., (© 2021 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: D.S. receives royalties from UpToDate (Wolters Kluwer Health). C.B.M. has no funding or conflicts of interest to declare.

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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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 O 2 in long-term via the catalysis of endogenous H 2 O 2 . Notably, the catalytic activity of TPAN could be enhanced via surface plasmon resonance (SPR) effect triggered by NIR-II laser irradiation, to enhance the O 2 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 O 2 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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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-1β 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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 Aβ 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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 × 10 5  M -1 binding constant.

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., (Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

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.

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 ( 103 Pd: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. 103 Pd: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.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

A metabolomics study of Pd 2 Spermine(Spm) on osteosarcoma MG-63 and osteoblastic HOb cells is presented to assess the impact of the potential palladium drug on cell metabolism compared with cisplatin (cDDP). Despite its higher cytotoxicity, Pd 2 Spm induced lower (and reversible) metabolic impact on MG-63 cells and the absence of apoptosis; conversely, it induced significant deviations in osteoblastic amino acid metabolism. However, when in combination with doxorubicin and methotrexate, Pd 2 Spm induced strong metabolic deviations on lipids, choline compounds, amino acids, nucleotides, and compounds related to antioxidative mechanisms (e.g., glutathione, inositol, hypoxanthine), similarly to the cDDP cocktail. Synergetic effects included triggering of lipid biosynthesis by Pd 2 Spm in the presence of doxorubicin (and reinforced by methotrexate) and changes in the glycosylation substrate uridine diphosphate acetylgalactosamine and methionine and serine metabolisms. This work provides promising results related to the impact of Pd 2 Spm on osteosarcoma cellular metabolism, particularly in drug combination protocols. Lipid metabolism, glycosylation, and amino acid metabolisms emerge as relevant features for targeted studies to further understand a potential anticancer mechanism of combined Pd 2 Spm.

Selenium and palladium containing compounds separately exert multifunctional effects on cells. While selenium containing compounds usually exert antioxidative properties, palladium(II) containing compounds are cytotoxic and prooxidative. Here we investigated biological effects of bicyclic seleno-hydantoin cis-7a-ethyl-5-methyl-5-phenylselanylmethyl-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (Hid-Se), and its palladium(II) complex, trans-bis-(cis-7a-ethyl-5-methyl-5-phenylselanylmethyl-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dionato) palladium(II) chloride ((Hid-Se)2Pd) on human colon HCT-116 and breast MDA-MB-231 cancer cell lines. Hid-Se and (Hid-Se)2Pd showed prooxidative and cytotoxic character. In all performed experiments (Hid-Se)2Pd proved to be more active, i.e. this substance exerted greater prooxidative effect, cytotoxicity and influence on cell migration potential. Even though Hid-Se and (Hid-Se)2Pd enhanced migration of HCT-116 cells, very important feature of these substances is the strong antimigratory potential on metastatic MDA-MB-231 cells.

Metal-based chemotherapeutics such as cisplatin are widely used treatment of lung cancer which is the major cause of cancer-related mortality worldwide. Recent studies demonstrated that novel metal-based compounds have strong cytotoxic activity in a similar way as cisplatin. Therefore, metal-based compounds have been synthesized and investigated in order to determine their cytotoxic activities. It has been also reported curcumin, which has been derived from turmeric plant, has powerful cytotoxic effect on various cancer cell lines. In the light of these data, it has been investigated the cytotoxic effects of combination of curcumin (0.78-100μM) and palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine [Pd(II) complex] (0.39-50μM) against non small lung cancer cell lines, A549 and H1299. It has been found that combination of Pd(II) complex and curcumin enhanced the cytotoxic activity and apoptotic cell death at 48h, compared to single use of each agent, only in H1299 cell line (combination index <1). Apoptosis was evident by annexin v staining positivity, increased caspase 3/7 activity and the presence of pyknotic nuclei. Pro-apoptotic genes of TNFRSF10A and HRK were found to be involved in apoptotic cell death. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of lung cancer due to its promising cytotoxic and apoptotic effect., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Catheter-associated urinary tract infection (CAUTI) is the most common healthcare-associated infection. The primary aim of this study was to investigate whether the use of a silicone catheter coated with an ultrathin layer of a combination of the noble metals gold, palladium and silver (BIP™-silicone catheter) could reduce the incidence of CAUTI and antibiotic prescription compared with a standard silicone catheter in a cohort of acute neurological patients suffering primarily from stroke. At the same time, all infectious events requiring prescription of an antimicrobial agent were registered and are reported., Materials and Methods: The study was designed as a crossover cohort study enrolling men and women aged over 18 years, requiring emergency management for stroke including the insertion of an indwelling catheter. Data on patient characteristics, urinary tract infections (UTIs), other infectious events and all antibiotic prescriptions were recorded prospectively., Results: The patients' characteristics differed in the two centres in terms of age but not in diagnosis distribution. UTIs were recorded in 78 (24.2%) of the patients, ahead of pulmonary tract infections (n = 65; 20.2%). There was no difference in terms of CAUTI in the two catheter groups, even in subgroups with catheter treatment for 1 week or less. The patients with a diagnosed UTI required 3.5 more days of hospitalization than those without a UTI., Conclusion: CAUTIs were the most frequent healthcare-associated infections, slightly ahead of pulmonary tract infections. No advantages of the coated catheter could be found in this cohort of critically ill patients.

New Cu(II), Pd(II) and Pt(II) complexes, (Cu(L)(H₂O)₂(OAc)) (1), (Cu(HL)(H₂O)₂(SO₄)) (2), (Cu(L)(H₂O)₂(NO₃)) (3), (Cu(L)(H₂O)₂(ClO₄)) (4), (Cu(L)₂(H₂O)₂) (5), (Pd(L)(OAc))H₂O (6), and (Pt(L)₂) (7) were synthesized from 8-ethyl-2-hydroxytricyclo(7.3.1.0(2,7))tridecan-13-one thiosemicarbazone (HL). The ligand and its metal complexes were characterized by IR, ¹H-NMR, (13)C-NMR, UV-Vis, FAB, EPR, mass spectroscopy, elemental and thermal analysis, magnetic susceptibility measurements and molar electric conductivity. The free ligand and the metal complexes have been tested for their antimicrobial activity against E. coli, S. enteritidis, S. aureus, E. faecalis, C. albicans and cytotoxicity against the NCI-H1573 lung adenocarcinoma, SKBR-3 human breast, MCF-7 human breast, A375 human melanoma and HL-60 human promyelocytic leukemia cell lines. Copper complex 2 exhibited the best antiproliferative activities against MCF-7 human breast cancer cells. A significant inhibition of malignant HL-60 cell growth was observed for copper complex 2, palladium complex 6 and platinum complex 7, with IC50 values of 1.6 µM, 6.5 µM and 6.4 µM, respectively.

Purpose: Examine modifications to seed placement and target margins necessary to accomplish focal brachytherapy with (103)Pd., Methods: Our proposed focal brachytherapy program will be primarily favorable intermediate-risk patients with a unilateral index lesion confirmed by transperineal template-guided mapping biopsies (TTMB). The dimensions and location of the TTMB core with the index lesion were placed within the 3-D ultrasound planning volume. Implants were planned for the prostate and the focal targets with generous margins. Planning goals were to cover the target with the 125Gy prescription dose and keep D90 (minimum dose covering 90% of the target) between 125% and 150% of the prescription while minimizing urethral and rectal hot spots. Radiobiological parameters - biologically effective dose (BED) and tumor control probability - were integrated over fractional sub-volumes and focal plans compared to whole gland brachytherapy., Results: A typical 30.1cm(3) prostate was expanded to create a 50.6cm(3) planning target volume (PTV) and needed 22 needles containing 86 (103)Pd seeds of strength 3.20U to deliver the prescribed dose. The hemi-prostate required 39 seeds in 12 needles, and the focal core expanded to a target volume of 11.6cm(3) required 29 seeds in 8 needles. All cancerous PTVs and sub volumes had a tumoricidal BED while organs at risk (OAR) met the dose constraints minimizing morbidity., Conclusions: For this single case study, both hemi-prostate and focal brachytherapy using (103)Pd seeds met the same target dosimetric goals and OAR constraints as whole prostate plans but with the expected reduction in number of seeds and needles., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: Information currently available on the impact of palladium on the immune system mainly derives from studies assessing the biological effects of palladium salts. However, in the last years, there has been a notable increase in occupational and environmental levels of fine and ultrafine palladium particles released from automobile catalytic converters, which may play a role in palladium sensitization. In this context, the evaluation of the possible effects exerted by palladium nanoparticles (Pd-NPs) on the immune system is essential to comprehensively assess palladium immunotoxic potential., Aim: Therefore, the aim of this study was to investigate the effects of Pd-NPs on the immune system of female Wistar rats exposed to this xenobiotic for 14 days, by assessing possible quantitative changes in a number of cytokines: IL-1α, IL-2, IL-4, IL-6, IL-10, IL-12, GM-CSF, INF-γ and TNF-α., Methods: Twenty rats were randomly divided into four exposure groups and one of control. Animals were given a single tail vein injection of vehicle (control group) and different concentrations of Pd-NPs (0.012, 0.12, 1.2 and 12 μg/kg). A multiplex biometric enzyme linked immunosorbent assay was used to evaluate cytokine serum levels., Results: The mean serum concentrations of all cytokines decreased after the administration of 0.012 μg/kg of Pd-NPs, whereas exceeded the control levels at higher exposure doses. The highest concentration of Pd-NPs (12 μg/kg) induced a significant increase of IL-1α, IL-4, IL-6, IL-10, IL-12, GM-CSF and INF-γ compared to controls., Discussion and Conclusions: These results demonstrated that Pd-NP exposure can affect the immune response of rats inducing a stimulatory action that becomes significant at the highest administered dose. Our findings did not show an imbalance between cytokines produced by CD4+ T helper (Th) cells 1 and 2, thus suggesting a generalized stimulation of the immune system with a simultaneous activation and polarization of the naïve T cells towards Th1 and Th2 phenotype.

The innovative applications of engineered nanoparticles (NPs) in medicine, such as diagnosis and therapy, have attracted considerable attention. It is highly important to predict the interactions between engineered NPs and the complex biological system as well as the impacts on the subsequent behaviors in living subjects. Herein, we report the use of T1 contrast-enhanced magnetic resonance imaging (MRI) to monitor the in vivo behaviors of NPs in a real-time manner. We chose ultrasmall Pd nanosheets (SPNSs) as the object of NPs because of their promise in theranostics and fitness for diverse surface chemistry. SPNSs were modified with different surface coating ligands (e.g., polyethylene glycol, zwitterionic ligands, polyethylenimine) and functionalized with Gd-chelates to render T1 contrast-enhanced capability. MRI real-time monitoring recorded the location and accumulation of SPNSs in small animals and revealed the prominent roles of surface coating ligands in pharmacokinetics. These results highlighted the significance of selecting proper surface coating for particular biomedical assignment. Moreover, we demonstrated a powerful and noninvasive means to predict and detect the behaviors of NPs in living subjects, which may be helpful for rational design and screening of engineered NPs in biomedical applications.

Purpose: In clinical practice, specific air kerma strength (SK) value is used in treatment planning system (TPS) permanent brachytherapy implant calculations with (125)I and (103)Pd sources; in fact, commercial TPS provide only one SK input value for all implanted sources and the certified shipment average is typically used. However, the value for SK is dispersed: this dispersion is not only due to the manufacturing process and variation between different source batches but also due to the classification of sources into different classes according to their SK values. The purpose of this work is to examine the impact of SK dispersion on typical implant parameters that are used to evaluate the dose volume histogram (DVH) for both planning target volume (PTV) and organs at risk (OARs)., Methods: The authors have developed a new algorithm to compute dose distributions with different SK values for each source. Three different prostate volumes (20, 30, and 40 cm(3)) were considered and two typical commercial sources of different radionuclides were used. Using a conventional TPS, clinically accepted calculations were made for (125)I sources; for the palladium, typical implants were simulated. To assess the many different possible SK values for each source belonging to a class, the authors assigned an SK value to each source in a randomized process 1000 times for each source and volume. All the dose distributions generated for each set of simulations were assessed through the DVH distributions comparing with dose distributions obtained using a uniform SK value for all the implanted sources. The authors analyzed several dose coverage (V100 and D90) and overdosage parameters for prostate and PTV and also the limiting and overdosage parameters for OARs, urethra and rectum., Results: The parameters analyzed followed a Gaussian distribution for the entire set of computed dosimetries. PTV and prostate V100 and D90 variations ranged between 0.2% and 1.78% for both sources. Variations for the overdosage parameters V150 and V200 compared to dose coverage parameters were observed and, in general, variations were larger for parameters related to (125)I sources than (103)Pd sources. For OAR dosimetry, variations with respect to the reference D0.1cm(3) were observed for rectum values, ranging from 2% to 3%, compared with urethra values, which ranged from 1% to 2%., Conclusions: Dose coverage for prostate and PTV was practically unaffected by SK dispersion, as was the maximum dose deposited in the urethra due to the implant technique geometry. However, the authors observed larger variations for the PTV V150, rectum V100, and rectum D0.1cm(3) values. The variations in rectum parameters were caused by the specific location of sources with SK value that differed from the average in the vicinity. Finally, on comparing the two sources, variations were larger for (125)I than for (103)Pd. This is because for (103)Pd, a greater number of sources were used to obtain a valid dose distribution than for (125)I, resulting in a lower variation for each SK value for each source (because the variations become averaged out statistically speaking).

Background: Recently, sodium tetrachloropalladate (Na2 PdCl4 ) was found to be a more sensitive palladium patch test allergen than palladium dichloride (PdCl2 )., Objectives: To determine the optimal test concentration of Na2 PdCl4 , to evaluate the prevalence of palladium sensitization with Na2 PdCl4 and PdCl2 , and to compare the results with nickel sensitization in a European multicentre study., Materials and Methods: In addition to the European or national baseline series including NiSO4 ·6H2 0 5% pet., consecutive patients were tested with PdCl2 and Na2 PdCl4 2%, 3% and 4% pet. in eight European dermatology clinics. The age and sex distributions were also evaluated in patients sensitized to nickel and palladium., Results: In total, 1651 patients were tested. Relative to 3% Na2 PdCl4 , 4% Na2 PdCl4 did not add any information. Two per cent Na2 PdCl4 resulted in more doubtful reactions and showed suboptimal reactivity. The prevalence of palladium sensitization doubled with Na2 PdCl4 and was similar to that of nickel. Interestingly, in contrast to nickel sensitization, palladium sensitization was not related to female sex., Conclusions: Three per cent Na2 PdCl4 pet. is the most suitable patch test concentration. Sensitization to palladium is almost as prevalent as sensitization to nickel. The sex distribution is different between nickel-sensitized and palladium-sensitized patients, suggesting different sources of exposure., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage.

There is concern about the possible toxicity of palladium nanoparticles (Pd-NP), as they are released in the environment through many applications. We previously studied the toxicity of Pd-NP at high concentrations; here we address the possible toxicity of Pd-NP at low, subtoxic doses. In particular, we have exposed normal human PBMC entering into the first in vitro mitotic division to Pd-NP and to Pd(IV) ions to evaluate ROS generation and cell cycle progression. We have measured a statistically significant increase of intracellular ROS in Pd(IV) exposed cells, but not in Pd-NP exposed cells. TEM revealed accumulation of lipid droplets and autophagic and mitophagic vacuoles, which appeared more conspicuous in cells exposed to Pd(IV) ions than to Pd-NP. Pd-NP were visible in the cytoplasm of Pd-NP exposed cells. Pd-NP addition was associated with a significant increase of cells within the G0/G1-phase and a significant reduction in GS- and G2/M-phases. Cells exposed to Pd(IV) ions showed a significant amplification of these cell cycle alterations. These results suggest that ions, per se or released by NPs, are the true inducers of Pd toxicity. It will be essential to verify whether the observed disturbance represents a temporary response or might result in permanent alterations.

Background: Since the EU Nickel Directive came into force, concern has been raised that palladium may increasingly replace nickel in alloys used in jewellery and dentistry, and that it may cause as many allergy problems as nickel., Objectives: (i) To investigate the clinical relevance of contact allergy to palladium resulting from the wearing of palladium-coated earrings, and (ii) to evaluate the concordance in test results between palladium chloride (PdCl2 ), sodium tetrachloropalladate (Na2 PdCl4 ), and nickel(II) sulfate hexahydrate (NiSO4 .6H2 O), as well as variability in patch test reactivity., Materials/methods: Forty female patients with pierced earlobes and previously known contact allergy to palladium and nickel were patch tested with dilution series of nickel and palladium salts. They wore earrings covered with palladium and titanium for 9 weeks to monitor the appearance of any clinical manifestations., Result/conclusion: There is a low risk of eczema in palladium-allergic and nickel-allergic individuals when they wear jewellery coated with pure palladium, but further studies are needed to determine whether palladium, when present in alloys, could cause allergic reactions. PdCl2 , like NiSO4 .6H2 O, shows variability in patch test reactivity over time. Furthermore, Na2 PdCl4 seems to be a more sensitive test substance than PdCl2 for the detection of palladium allergy., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A multicomponent reaction is reported generating highly enantioenriched and diastereomerically pure quaternary amino acid derivatives via 1,4-addition of azlactones to enones. The azlactone intermediates are generated in situ from unprotected α-amino acids and acetic anhydride. Previous attempts using bis-palladacycle catalysts required the use of a large excess of benzoic anhydride (which is very difficult to remove from the products), since acetic anhydride provided regioisomeric product mixtures. Key for the high regioselectivity is a pentaphenylferrocene monopalladacycle catalyst.

A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)(2)BC and corresponding zinc chelate (NC)(2)BC-Zn and palladium chelate (NC)(2)BC-Pd were studied. Direct dilution of a solution of bacteriochlorin in an organic solvent (N,N-dimethylacetamide) into serum-containing medium was compared with the dilution of bacteriochlorin in Cremophor EL (CrEL; polyoxyethylene glycerol triricinoleate) micelles into the same medium. CrEL generally reduced aggregation (as indicated by absorption and fluorescence) and increased activity up to tenfold (depending on bacteriochlorin), although it decreased cellular uptake. The order of PDT activity against HeLa human cancer cells after 24 h incubation and illumination with 10 J cm(-2) of near-infrared (NIR) light is (NC)(2)BC-Pd (LD(50)=25 nM) > (NC)(2)BC > (NC)(2)BC-Zn ≈ BC. Subcellular localization was determined to be in the endoplasmic reticulum, mitochondria and lysosomes, depending on the bacteriochlorin. (NC)(2)BC-Pd showed PDT-mediated damage to mitochondria and lysosomes, and the greatest production of hydroxyl radicals as determined using a hydroxyphenylfluorescein probe. The incorporation of cyano substituents provides an excellent motif for the enhancement of the photoactivity and photostability of bacteriochlorins as PDT photosensitizers., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this study, synergism in activity from the sequenced combinations of three trans-palladiums (denoted as TH5, TH6 and TH7) with green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), as well as that with cisplatin, was investigated in a number of human ovarian tumour models as a function of sequence of administration. Cellular accumulation of platinum and palladium, and the levels of platinum-DNA and palladium-DNA binding were also determined for the 0/4 h and 0/0 h sequences of administration. The results of the study show that co-administration of cisplatin with EGCG (0/0 h) produces weak synergism in both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780(cisR)) cell lines whereas (0/4 h) administration produces pronounced synergism in both. In contrast, bolus administration of EGCG with TH5, TH6 and TH7 produces marked antagonism except that with TH5, in the A2780(cisR) cell line, where a mild synergism is observed. In the case of TH5, TH6 and TH7, administration of drugs with a time gap (0/4 h or 4/0 h combinations) produces sequence-dependent synergism in both A2780 and A2780(cisR) cell lines, whereas in the case of cisplatin, marked antagonism is observed with the 4/0 h sequence of administration in the A2780 cell line. Whereas the highly synergistic 0/4 h sequence of combination of cisplatin with EGCG is found to be associated with pronounced cellular accumulation of platinum and a high level of platinum-DNA binding, no such clear trend can be seen for any of the combinations of TH5, TH6 and TH7 with EGCG. The results of the present study provide support to the idea that sequenced combinations of platinum drugs and tumour-active palladium compounds with selected phytochemicals such as EGCG may provide a means of overcoming drug resistance.

Aim: Radiolabeled porphyrin derivatives could be envisaged as potential agents for targeted tumor therapy owing to the inherent tumor accumulation property exhibited by porphyrins. However, to achieve adequately high tumor accumulation and retention therein along with fast clearance from all non-target organs, an optimum balance between the hydrophilicity and lipophilicity must be achieved. Based on our prior experiences of working with (109)Pd-labeled porphyrins with variable lipophilicity and hydrophilicity, we have envisioned a suitable porphyrin derivative which could be expected to have the required balance between lipophilicity and hydrophilicity when complexed with (109)Pd. Towards this, 5,10,15,20- tetrakis[4-carboxymethyleneoxyphenyl]porphyrin (PHBEPH) was synthesized, radiolabeled with (109)Pd and its biological behavior in small animal model was studied., Experimental: The porphyrin derivative was synthesized and characterized following the reported procedure and radiolabeled with (109)Pd [E β(max) = 1.12 MeV, E γ = 88 keV (3.6%), T1/2 = 13.7 h], which was produced by the thermal neutron bombardment on enriched (98% in (108)Pd) metallic Pd target at a flux of 3x1013 n/cm2.s for 3 d. Biological behavior of the radiolabeled agent was studied by biodistribution studies in Swiss mice bearing fibrosarcoma tumors., Results: (109)Pd was produced with a specific activity of ∼1.85 GBq/mg (50 mCi/mg) and radionuclidic purity of 100%. (109)Pd complex of the synthesized porphyrin derivative was prepared with excellent radiochemical purity ( > 98%) and the complex was observed to exhibit Log P value of -1.29. Biodistribution studies revealed good tumor uptake [(3.55±0.49)% injected activity (IA)/g] within 30 min post-injection (p.i.) and retention therein till 24 h [(2.56±0.25)% IA)/g], upto which the study was continued. The complex exhibited fast clearance from the non-target organs with favorable tumor/blood and tumor/muscle ratios [(5.09±0.18)% and (284.44±3.25)% at 24 h p.i.]., Conclusion: The complex exhibited good uptake and retention in the tumor along with encouraging target to non-target ratio. Preliminary biological studies indicated the promising attributes of the agent towards its use for targeted radiotherapy.

Background: To investigate the effect of (103)Pd radioactive stent on Caspase-9, cholangiocarcinoma cell growth and its radiosensitivity., Methods: Cholangiocarcinoma was treated with (103)Pd radioactive stent at different period. Radiosensitivity of the cells was detected by methyl thiazolyl tetrazolium (MTT) method. Apoptosis of cholangiocarcinoma cells was detected by immunohistochemistry and electron microscope. The activity of Caspase-9 was detected by non-radioimmunoprecipitation, while its protein expression was detected by Western blot., Results: (103)Pd radioactive stent had significant inhibitive effect on cholangiocarcinoma cells and it could induce apoptosis. After treatment by (103)Pd radioactive stent for 10 days, the activity of Caspase-9 was gradually enhanced, which was markedly decreased in common stent group. Cholangiocarcinoma cells had relatively high sensitivity to (103)Pd radiation., Conclusion: (103)Pd radioactive stent can activate caspase-9 gene to induce apoptosis of cholangiocarcinoma cell, inhibit its growth and enhance its radiosensitivity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: Postoperative dosimetry is integral to quality assurance for prostate brachytherapy. Images on Day 0 are typically obtained with a contrast-filled urinary catheter in place for urethral dose calculations. However, expansion of the urethra and perhaps the prostate by the catheter may affect target coverage. We assessed the effect of urinary catheterization on target dosimetry after implantation with palladium-103 ((103)Pd) or iodine-125 ((125)I) seeds., Methods and Materials: Patients were 29 consecutive men with postimplant dosimetry calculated with and without a urinary catheter after brachytherapy seed implantation; 19 patients received (103)Pd seeds and 10 patients received (125)I seeds. In each case, 14-French caude tip urinary catheters were placed before implantation, and axial CT slices of the pelvis were obtained before and after catheter removal for postimplant dosimetry. Dosimetric parameters were measured and compared with paired Student's t tests. Trends were assessed by linear regression with the Pearson correlation coefficient., Results: Removal of the urinary catheter significantly improved V(100) and D(90) for (103)Pd implants (mean±standard deviation (SD), 2.7%±4.2%; range, -0.4% to 15%; p=0.011 and mean±SD, 4.0%±3.4%; range, -0.1% to 13.8%; p<0.01, respectively). For (125)I implants, catheter removal improved D(90) (mean±SD, 1.5%±1.8%; range, -1.3% to 4.2%; p=0.027). For the (103)Pd group, the magnitude of change in V(100) correlated with prostate size (R(2)=0.16) and source number (R(2)=0.15)., Conclusions: Urinary catheterization can artificially reduce target coverage after prostate implant brachytherapy. The patients undergoing (103)Pd implantation with smaller (<30cm(3)) prostates and fewer (<90) sources are particularly susceptible to reduced D(90) and V(100) when a urinary catheter is present., (Copyright © 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Brachytherapy dose distributions are calculated for 15 mm ROPES eye plaque loaded with model Theragenics200 and IR06-(103)Pd seeds. The effects of stainless steel backing and Acrylic insert on dose distribution along the central axis of the eye plaque and at critical ocular structure are investigated. Monte Carlo simulation was carried out with the Version 5 of the MCNP. The dose at critical ocular structure by considering the eye composition was calculated. Results are compared with the calculated data for COMS eye plaque loaded with Theragenics200 palladium-103 seeds and model 6711 iodine-125 seed. The air kerma strength of the IR06-(103)Pd seed to deliver 85 Gy in apex of tumor in water medium was calculated to be 4.10 U/seed. Along the central axis of stainless steel plaque loaded with new (103)Pd seeds in Acrylic insert, the dose reduction relative to water is 6.9% at 5 mm (apex). Removal of the Acrylic insert from the plaque (replacing with water) did not make significantly difference in dose reduction results (~0.2%). The presence of the stainless steel backing results in dose enhancement near the plaque relative to water. Doses at points of interest are higher for ROPES eye plaque when compared to COMS eye plaque. The dosimetric parameters calculated in this work for the new palladium seed, showed that in dosimetry point of view, the IR06-(103)Pd seed is suitable for use in brachytherapy. The effect of Acrylic insert on dose distribution is negligible and the main effect on dose reduction is due to the presence of stainless steel plaque backing.

Over the past two decades, brachytherapy has played an ever expanding role in the definitive radiotherapy of prostate cancer. Brachytherapy surpasses external beam radiotherapy in its ability to deliver intense intraprostatic dose escalation. Although initially low dose rate permanent seed brachytherapy was favored for favorable risk prostate cancers, and high dose rate temporary brachytherapy for intermediate and advanced disease, both types of brachytherapy now have a place across all the risk groups of localized prostate cancer. This article will review indications and patient selection, planning and technical aspects, toxicity and efficacy for both low and high dose rate prostate brachytherapy., (Copyright © 2011. Published by Elsevier SAS.)

Purpose: In this study, the effect of prostate brachytherapy seed activity on postimplant rectal dosimetry was evaluated in Pro-Qura (Prostate Brachytherapy Quality Assurance; Seattle, WA) proctored, community-based programs., Methods and Materials: Twenty-three hundred patients (1563 iodine-125 [(125)I] and 737 palladium-103 [(103)Pd]) from 78 brachytherapists with postimplant rectal dosimetry were identified. Seed activity was stratified into three tertiles for each isotope (≤0.300, 0.301-0.326, and >0.326 mCi/seed for (125)I and ≤1.330, 1.331-1.547, and >1.547 mCi/seed for (103)Pd). Postimplant dosimetry was performed in a standardized fashion. The rectum was contoured by outlining the outer rectal wall. The volume of the rectum receiving 100% of the prescription dose (R(100)) was calculated in cubic centimeters. The prostate V(100) and D(90) volumes were also calculated., Results: The mean prostate volume was 35.8 and 32.3 cm(3) for (125)I and (103)Pd. The median time to postimplant CT was 30 days. For (125)I, the V(100) increased from 91.0% to 93.7% (p=0.012) and the D(90) increased from 105.9% to 108.7% (p<0.001) for the lowest to the highest (125)I seed activities. In contrast, no significant changes in V(100) (p=0.751) or D(90) (p=0.200) were discerned when stratified by seed activity. For both isotopes, there was no correlation between seed activity and R(100), and R(100) was highest for the intermediate seed activities. Overall, the R(100) was lower for (103)Pd vs. (125)I (0.63 vs. 0.82 cm(3), p<0.001)., Conclusions: Within the confines of seed activities used in this study, higher activity seeds did not result in a deleterious effect on rectal dose. Higher activity seeds were associated with improved prostate dosimetry for (125)I, whereas (103)Pd dosimetry was not dependent on seed activity., (Copyright © 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To re-evaluate prostate implant dosimetry using American Association of Physicists in Medicine Task Group 43 parameters and the radiobiologic approach of American Association of Physicists in Medicine Task Group 137., Methods and Materials: Among 1473 consecutive patients implanted with iodine-125 or palladium-103 sources before March 2006, there have been 55 biochemical failures. The dosimetric quality parameter, D(90), was updated according to the radionuclide and dosimetric era of the implant. For each patient, biologically equivalent dose (BED) and tumor control probability (TCP) were calculated from the updated implant D(90) plus any external beam dose using recommended indices and equations., Results: There was no significant difference in BED between biochemical failures and nonfailures, 148±27Gy and 145±24Gy, respectively (p=0.352). TCP was 0.90±0.26 for biochemical failures and 0.93±0.21 for nonfailures (p=0.414). Cox regression analysis found that neither BED nor TCP predicted for biochemical control either for the entire population or within each radionuclide-dependent dosimetric era. The only overall predictors of biochemical control were dosimetric era, Gleason score, and percent positive biopsies. Improvements in dosimetric quality over the first 300 patients were evident, but dosimetric era remained a better predictor of biochemical outcome than implant sequence number., Conclusion: In a large prostate implant population, dosimetric and derived radiobiologic parameters did not predict for failure. Apparently, too few patients had total BEDs below the level necessary for optimum biochemical control. A learning curve extended over hundreds of patients before plateauing but changes in seed characterization parameters also had a pronounced effect., (Copyright © 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

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.

Purpose: The radiobiology of prostate cancer appears to favor large fractions. Accelerated hypofractionation treatments may therefore be used to improve the therapeutic ratio, particularly when the doses to rectum and bladder are kept below the prostate dose. The 5-year experience at William Beaumont Hospital (WBH) and the California Endocurietherapy Center (CET) with accelerated-hypofractionated high-dose-rate (HDR) monotherapy in favorable prostate cancer is presented., Materials and Methods: Between 1993 and 2004, 454 patients were treated with brachytherapy of which 248 treated with HDR and 206 patients treated with low-dose-rate Palladium (LDR-Pd¹⁰³). The WBH-HDR dose was 38 Gy, in 4 fractions, twice a day. The CET-HDR dose was 42 Gy in 6 fractions in 2 separate implants 1 week apart. The WBH-LDR dose was 120 Gy., Results: Median follow-up was 4.8 years. The 5-year Phoenix biochemical control (BC) was 89%, 91%, and 88% for WBH-LDR, WBH- HDR, and CET-HDR, respectively. The majority of complications were grade 1. HDR was associated with less acute grade 1 to 3 dysuria 60% versus 39%, (P < 0.001), urinary frequency/urgency 90% to58% (P < 0.001), and rectal pain 17% to 6.5% (P < 0.001). Long-term urinary frequency/urgency 54% versus 43%, (P = 0.03) and dysuria 22% versus 15% were less with HDR. The 5-year actuarial impotence rate was 30% for LDR and 20% for HDR (P = 0.23)., Conclusions: Although the same 5-year BC rates were achieved with HDR (248 patients) and LDR (206 patients) monotherapy, HDR brachytherapy was associated with less acute and chronic genitourinary and gastrointestinal toxicities. As another accepted standard of care, accelerated hypofractionated HDR monotherapy is target specific and efficient radiobiologically than EBRT which has many smaller doses per fraction. It could be considered today as the best option in accelerated hypofractionated prostate cancer treatment.

Chagas' disease, a neglected tropical infection, affects about 18 million people, and 100 million are at risk. The only drug available, benznidazole, is effective in the acute form and in the early chronic form, but its efficacy and tolerance are inversely related to the age of the patients. Side effects are frequent in elderly patients. The search for new drugs is thus warranted. In the present study we evaluated the in vitro and in vivo effect of a cyclopalladated compound (7a) against Trypanosoma cruzi, the agent of Chagas' disease. The 7a compound inhibits trypomastigote cell invasion, decreases intracellular amastigote proliferation, and is very effective as a trypanocidal drug in vivo, even at very low dosages. It was 340-fold more cytotoxic to parasites than to mammalian cells and was more effective than benznidazole in all in vitro and in vivo experiments. The 7a cyclopalladate complex exerts an apoptosis-like death in T. cruzi trypomastigote forms and causes mitochondrion disruption seen by electron microscopy.