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Four steroidal derivatives (L 1-4 ) bearing an (N,N) metal-chelating subunit on the D-ring, in addition to the organometallic [M(arene)(N,N)Cl]Cl complexes of L 1,2 were synthesized and characterized, in which M(arene) is Rh(III)(η 5 -C 5 Me 5 ) or Ir(III)(η 5 -C 5 Me 5 ) or Ru(II)(η 6 -p-cymene). The solution chemical properties of both the estrone-based ligands and selected complexes were investigated by spectroscopic methods. At pH = 7.4, the ligands are predominantly positively charged, moderately lipophilic (logD 7.4  = +0.6 - +3.2), and exhibit low-to-medium micromolar solubility (S 7.4  = 9-543 μM) and are more hydrophilic than estrone; however, complexation improved the aqueous solubility of the obtained organometallics. The Rh(η 5 -C 5 Me 5 ) and Ru(η 6 -p-cymene) complexes of L 1 demonstrated high stability in solution (<1 % bidentate ligand dissociation at pH 7.4 for 48 h), forming a higher fraction of mixed hydroxido species [M(arene)(N,N)(OH)] + in the case of the Ru complexes. Both coordination and intermolecular interactions of the organometallic complexes with human serum albumin were observed. The ligands and their complexes were tested in human cancer cell lines to investigate their in vitro anticancer activity. Studies in Colo-205 and MCF-7 cells revealed the moderate-to-strong cytotoxicity of the ligands (IC 50  = 5-50 μM) with limited selectivity toward cancer cells over the non-cancerous CCD-19Lu fibroblast cell line. Complexation increased the cytotoxicity, especially for Rh(III)(η 5 -C 5 Me 5 ) and Ir(III)(η 5 -C 5 Me 5 ) complexes in the MCF-7 cell line compared to the ligands., 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. On behalf of all authors of the manuscript, I declare that there are no competing financial interests (all sources for funding of the work presented in the manuscript are listed in the acknowledgement), and there is no conflict of interest with the Editor or any Editorial Board member., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Platinum(II) complexes prevail as first-line treatment for many cancers but are associated with serious side effects and resistance development. Picoplatin emerged as a promising alternative to circumvent GSH-induced tumor resistance by introducing a bulky 2-picoline ligand. Although clinical studies were encouraging, picoplatin did not receive approval. Interestingly, the anticancer potential of prodrugs based on picoplatin is widely underexplored, and even less so the respective tumor-targeting approaches. We synthesized two new "hybrid" picoplatin(II) derivatives with an oxalate or cyclobutane dicarboxylate leaving group and their corresponding platinum(IV) prodrugs with an albumin-targeting maleimide moiety or a succinimide as reference. Picoplatin(II) and its derivatives indeed reacted much slower with GSH compared to the respective analogs cisplatin, carboplatin, or oxaliplatin. While PicoCarbo(IV) and PicoOxali(IV) were reduced slowly in the presence of ascorbic acid, picoplatin(IV) was extremely unstable. All three prodrugs were widely inactive in the MTT assays. The platinum(IV)-maleimide complexes rapidly bound to albumin with stable conjugates for >25 h. Albumin-binding resulted in elevated platinum plasma levels, prolonged blood circulation, and enhanced tumor accumulation of the prodrugs in mice bearing CT26 tumors. However, only maleimide-functionalized PicoCarbo(IV) and picoplatin(II) significantly inhibited tumor growth. One possible explanation is that for albumin-binding platinum(IV) prodrugs, the bulky 2-picoline moiety prevents sufficient activation/reduction to unlock their full anticancer potential.

Maleimides remain very popular conjugation moieties in the fields of bio(in)organic chemistry and biotechnology. They are particularly interesting for endogenous albumin binding in the bloodstream to exploit the enhanced permeability and retention (EPR) effect and to increase tumor accumulation of anticancer drugs. However, during drug development, insufficient aqueous solubility is frequently a limiting factor. In the present study, four new maleimide linkers were synthesized containing a water-soluble piperazine scaffold. Respective maleimide-platinum(IV)-acetato complexes demonstrated similar hydrolytic stability, albumin-binding kinetics, in vivo serum pharmacokinetics and tissue distribution compared to a reference platinum(IV)-PEG4-maleimide complex. To test the aqueous solubility, platinum(IV)-maleimide complexes containing the highly lipophilic drug ibuprofen were synthesized. Indeed, the compounds containing the new piperazine linkers displayed increased solubility (up to 370 mM) in different aqueous media, whereas the PEG4-maleimide reference was only marginally soluble. Finally, the synthetic toolbox of the new piperazine maleimides was also expanded to pure organic derivatives by conjugation to valine-citrulline- para -aminobenzyl-OH derivatives via peptide and thiourea bonds., Competing Interests: The authors declare no competing financial interest., (© 2025 The Authors. Published by American Chemical Society.)

Platinum chemotherapy is part of every second anticancer treatment regimen. However, its application is limited by severe side effects and drug resistance. The combination of platinum-based chemotherapeutics with EGFR inhibitors has shown remarkable synergism in clinical treatment. To enhance the tolerability of this combination, we designed a novel multi-action oxaliplatin-based platinum(iv) complex with an EGFR-inhibiting moiety (KP2749). KP2749 releases two independent cytotoxic agents upon reduction: oxaliplatin and the EGFR inhibitor KP2187, which was selected for its strong intrinsic fluorescence that became quenched upon complexation to metal ions. In particular, KP2749 demonstrated high stability and specific KP2187 release, with quenched fluorescent properties in its intact form, facilitating the investigation of its intracellular reduction. Notably, by exploiting its fluorescence, we demonstrated that intact KP2749 itself exhibited EGFR-inhibitory properties. Furthermore, subsequent experiments indicated that our complex was able to overcome resistance to oxaliplatin and EGFR inhibitors in vitro and in xenograft models in vivo . These effects were not only based on EGFR inhibition and DNA damage, but also improved cellular drug uptake. Finally, in silico docking analysis confirmed that the intact KP2749 complex had EGFR-binding properties, which were different from free KP2187. Consequently, these data suggested that the coordination of EGFR inhibitors to metal cores (like platinum) allow the fine-tuning of their EGFR-targeting properties. In conclusion, this study not only presents a new potential anticancer drug but also offers a novel fluorescent tool to study the intracellular drug release kinetics of platinum(iv) complexes., Competing Interests: There are no conflicts to declare., (This journal is © the Partner Organisations.)

We synthesized and characterized a novel, task-specific ionic liquid for metal extraction with considerably reduced leaching behavior compared to similar, phosphonium-based ionic liquids. The synthesis involves the design of the novel compound [TOPP] 2 [PAM] featuring both a highly hydrophobic cation and a functional anion. The characterization of the novel ionic liquid confirmed the formation of the desired structure and sufficient purity. The high viscosity of [TOPP] 2 [PAM] is responsible for the comparably high working temperature of 50°C. Extraction experiments demonstrated the suitability of [TOPP] 2 [PAM] for extracting Sc, Th and U from aqueous matrices, whereby extraction efficacies of 87.3% ± 9.1% (Sc), 95.8% ± 2.3% (Th) and 92.7% ± 0.3% (U) were achieved over 24 h. Furthermore, Sc could be separated to a high degree via selective extraction from Th as well as from the rare earth elements Y, La, Ce, Nd, Eu, Ho and Lu. Th was separated from La, Ce, Nd, Eu, Ho and Lu at pH 1.00. During all extraction experiments, leaching into the aqueous extraction matrix peaked at only 0.134% ± 0.011% after 24 h. The loading capacities for [TOPP] 2 [PAM] differed between the investigated metals, the highest values being achieved for U. After extraction, 82.7% ± 2.8% of the extracted Sc could be recovered from the IL using nitric acid (10%), but less of Th and U., 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 author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gradwohl, Windisch, Rosner, Heninger, Fuhrmann, Wallner, Keppler, Kandioller and Jirsa.)

Rapid and precise detection of biochemical markers is vital for accurate medical diagnosis. Gold nanoparticles (AuNPs) have emerged as promising candidates for diagnostic sensing due to their biocompatibility and distinctive physical properties. However, AuNPs functionalized with selective targeting vectors often suffer from reduced stability in complex biological environments. To address this, (N)-heterocyclic carbene (NHC) ligands have been investigated for their robust binding affinity to AuNP surfaces, enhancing stability. This study outlines an optimized top-down synthesis route for highly stable, azide-terminal PEGylated NHC (PEG-NHC) functionalized AuNPs. This process employs well-defined oleylamine-protected AuNPs and masked PEGylated NHC precursors. The activation and attachment mechanisms of the masked NHCs were elucidated through the identification of intermediate AuNPs formed during incomplete ligand exchange. The resulting PEG-NHC@AuNPs exhibit exceptional colloidal stability across various biologically relevant media, showing no significant aggregation or ripening over extended periods. These particles demonstrate superior stability compared to those synthesized via a bottom-up approach. Further functionalization of azide-terminal PEG-NHC@AuNPs was achieved through copper-catalyzed click- and bioorthogonal strain-promoted azide-alkyne cycloaddition reactions. The maintained colloidal stability and successful conjugation highlight the potential of azide-functionalized PEG-NHC@AuNPs as a versatile platform for a wide range of biomedical applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Current challenges in oncology are largely associated with the need to improve the effectiveness of cancer treatment and to reduce drug's side effects. An effective strategy to cope with these challenges is behind designing and developing drug delivery systems based on smart nanomaterials and approved anticancer drugs. The present study offers a novel and straightforward approach to efficiently load the cisplatin drug into the newly constructed liposome-based nanosystems as well a reliable technique for monitoring this process based on capillary electrophoresis hyphenated with inductively coupled plasma tandem mass spectrometry. The proposed drug-loading methodology comprises liposome formation via a simple ethanol-injection method and propels increased drug encapsulation using tailor-made freeze-thawing or lyophilization-hydration procedures. To optimize liposome generation and drug encapsulation, the effects of dilution medium and liposome composition (types of phospholipids and their percentage ratio) have been investigated in detail. It was shown that modest alterations of the composition of three-component phospholipid liposomes and parameters of the freeze-thawing procedure have a strong impact on the formation of cisplatin-liposome systems. The obtained cisplatin-liposome formulation features a remarkable degree of drug encapsulation, over 100 mg L -1 , and holds promise for further preclinical development as a potent drug-delivery platform., 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.)

BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.) [ 97/103 Ru]BOLD-100 were performed with the two ruthenium isotopes ruthenium-103 ( 103 Ru; β - , γ) and ruthenium-97 ( 97 Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a. [ 103 Ru]BOLD-100 (3 and 30 mg kg -1 ) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally, ex vivo autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg -1 ) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a. [ 103 Ru]BOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a. [ 97 Ru]BOLD-100.

In this contribution we report the synthesis, characterization and in vitro anticancer activity of novel cyclometalated 4-phenylthiazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) complexes. Formation and sufficient purity of the complexes were unambigiously confirmed by 1 H-, 13 C- and 2D-NMR techniques, X-ray diffractometry, HRMS and elemental analysis. The binding preferences of these cyclometalates to selected amino acids and to DNA models including G-quadruplex structures were analyzed. Additionally, their stability and behaviour in aqueous solutions was determined by UV-Vis spectroscopy. Their cellular accumulation, their ability of inducing apoptosis, as well as their interference in the cell cycle were studied in SW480 colon cancer cells. The anticancer potencies were investigated in three human cancer cell lines and revealed IC 50 values in the low micromolar range, in contrast to the biologically inactive ligands.

As cancer cells exhibit an increased uptake of iron, targeting the interaction with iron has become a straightforward strategy in the fight against cancer. This work comprehensively characterizes the chemical properties of 6-methyl-3-{(2 E )-2-[1-(2-pyridinyl)ethylidene]hydrazino}-5 H -[1,2,4]triazino[5,6- b ]indole (VLX600), a clinically investigated iron chelator, in solution. Its protonation processes, lipophilicity, and membrane permeability as well as its complexation with essential metal ions were investigated using UV-visible, electron paramagnetic resonance, and NMR spectroscopic and computational methods. Formation constants revealed the following order of metal binding affinity at pH 7.4: Cu(II) > Fe(II) > Zn(II). The structures of VLX600 (denoted as HL) and the coordination modes in its metal complexes [Cu(II)(LH)Cl 2 ], [Cu(II)(L)(CH 3 OH)Cl], [Zn(II)(LH)Cl 2 ], and [Fe(II)(LH) 2 ](NO 3 ) 2 were elucidated by single-crystal X-ray diffraction. Redox properties of the iron complexes characterized by cyclic voltammetry showed strong preference of VLX600 toward Fe(II) over Fe(III). In vitro cytotoxicity of VLX600 was determined in six different human cancer cell lines, with IC 50 values ranging from 0.039 to 0.51 μM. Premixing VLX600 with Fe(III), Zn(II), and Cu(II) salts in stoichiometric ratios had a rather little effect overall, thus neither potentiating nor abolishing cytotoxicity. Together, although clinically investigated as an iron chelator, this is the first comprehensive solution study of VLX600 and its interaction with physiologically essential metal ions.

While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence of drug resistance. A promising strategy to address these challenges is the use of platinum(iv) prodrugs, which remain inert until they reach the tumor tissue, thereby mitigating detrimental effects on healthy cells. Typically, platinum drugs are part of combination therapy settings. Consequently, a very elegant strategy is the development of platinum(iv) prodrugs bearing a second, clinically relevant therapeutic in axial position. In the present study, we focused on gemcitabine as an approved antimetabolite, which is highly synergistic with platinum drugs. In addition, to increase plasma half-life and facilitate tumor-specific accumulation, an albumin-binding maleimide moiety was attached. Our investigations revealed that maleimide-cisplatin(iv)-gemcitabine complexes cannot carry sufficient amounts of gemcitabine to induce a significant effect in vivo . Consequently, we designed a carboplatin(iv) analog, that can be applied at much higher doses. Remarkably, this novel analog demonstrated impressive in vivo results, characterized by significant improvements in overall survival. Notably, these encouraging results could also be transferred to an in vivo xenograft model with acquired gemcitabine resistance, indicating the high potential of this approach., Competing Interests: There are no conflicts to declare., (This journal is © the Partner Organisations.)

The first-in-class ruthenium-based chemotherapeutic agent BOLD-100 (formerly IT-139, NKP-1339, KP1339) is currently the subject of clinical evaluation for the treatment of gastric, pancreatic, colorectal and bile duct cancer. A radiolabeled version of the compound could present a helpful diagnostic tool. Thus, this study investigated the pharmacokinetics of BOLD-100 in more detail to facilitate the stratification of patients for the therapy. The synthesis of [ 103 Ru]BOLD-100, radiolabeled with carrier added (c.a.) ruthenium-103, was established and the product was characterized by HPLC and UV/Vis spectroscopy. In order to compare the radiolabeled and non-radioactive versions of BOLD-100, both complexes were fully evaluated in vitro and in vivo. The cytotoxicity of the compounds was determined in two colon carcinoma cell lines (HCT116 and CT26) and biodistribution studies were performed in Balb/c mice bearing CT26 allografts over a time period of 72 h post injection (p.i.). We report herein preclinical cytotoxicity and pharmacokinetic data for BOLD-100, which were found to be identical to those of its radiolabeled analog [ 103 Ru]BOLD-100.

The reaction of (1 R ,2 R )-(cyclohexane-1,2-diamine)dichloridoplatinum(II) with maleic acid unexpectedly resulted in the formation of an organometallic platinum(II) complex featuring a C , O -coordinating ligand. Additionally, a small series of close derivatives with increasing lipophilicity was synthesized. All complexes were fully characterized by multinuclear one- and two-dimensional ( 1 H, 13 C, 15 N, and 195 Pt) NMR spectroscopy, high resolution mass spectrometry, and in one case by X-ray diffraction. The lipophilicity and the impact on the DNA secondary structure as well as the cytotoxic properties in three human cancer cell lines (A549, SW480, and CH1/PA-1) were investigated. Unexpectedly, no clear-cut trend in cytotoxicity was observed with increasing lipophilicity. Also unexpectedly, the complexes showed only a low potential to inhibit cancer cell growth and no sign of interaction with DNA, in sharp contrast to the parent drug oxaliplatin, which seems to be caused by the low reactivity of the investigated compounds.

Platinum(IV) prodrugs are highly interesting alternatives to platinum(II) anticancer therapeutics due to their increased tumor selectivity and reduced side effects. In contrast to the established theory, we recently observed that the equatorial ligand(s) of e.g. oxaliplatin(IV) complexes can be hydrolyzed with formation of [(DACH)Pt(OH eq ) 2 (OAc ax ) 2 ]. In the work presented here, we investigated the reactivity and synthetic usability of this complex to be exploited as a precursor for the development of novel platinum(IV) complexes, not able to be synthesized by conventional protocols. Indeed, we could substitute the equatorial hydroxido ligand(s) e.g. by one or two monodentate biotin ligands (which would be oxidized under standard methods). The formed complexes turned out to be very stable with slow ligand release after reduction, ideal for long-circulating tumor-targeting strategies. Therefore, two platinum(IV) complexes with equatorial maleimides, capable of exploiting serum albumin as a natural nanocarrier, were synthesized as well. The complexes showed massively prolonged plasma half-life and distinctly improved anticancer activity in vivo compared to oxaliplatin. Taken together, the newly developed synthetic platform allows the simple and specific insertion of equatorial ligands into platinum(IV) complexes. This will enable the attachment of three different (bioactive) moieties generating targeted triple-action platinum(IV) prodrugs within one single platinum complex., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Competing Interests: Die Autoren erklären, dass keine Interessenkonflikte vorliegen.

The leading first-in-class ruthenium-complex BOLD-100 currently undergoes clinical phase-II anticancer evaluation. Recently, BOLD-100 is identified as anti-Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD-100-resistant colon and pancreatic carcinoma cells. Acute BOLD-100 treatment reduces lipid droplet contents of BOLD-100-sensitive but not -resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD-100-resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame-shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl-coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell-free BOLD-100-CoA adduct formation suggesting acetyl-CoA depletion as mechanism bridging BOLD-100-induced lipid metabolism alterations and histone acetylation-mediated gene expression deregulation. Indeed, BOLD-100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de-acetylation as central mode-of-action of BOLD-100 and metabolic programs stabilizing histone acetylation as relevant Achilles' heel of acquired BOLD-100-resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD-100 responsiveness. Summarizing, BOLD-100 is identified as epigenetically active substance acting via targeting several onco-metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD-100 resistance opens novel strategies to tackle therapy failure., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Nano-sized ion exchangers (NIEs) combine the properties of common bulk ion-exchange polymers with the unique advantages of downsizing into nanoparticulate matter. In particular, being by nature milti-charged ions exchangers, NIEs possess high reactivity and stability in suspensions. This brief review provides an introduction to the emerging landscape of various NIE materials and summarizes their actual and potential applications. Special attention is paid to the different methods of NIE fabrication and studying their ion-exchange behavior. Critically discussed are different examples of using NIEs in chemical analysis, e.g., as solid-phase extraction materials, ion chromatography separating phases, modifiers for capillary electrophoresis, etc., and in industry (fuel cells, catalysis, water softening). Also brought into focus is the potential of NIEs for controlled drug and contrast agent delivery.

In the last decades, inflammation has been recognized as being closely connected to cancer, and joint strategies encompassing chemotherapeutic and anti-inflammatory agents have been extensively studied. In this work, a series of novel cisplatin and oxaliplatin-based Pt(IV) complexes comprising non-steroidal anti-inflammatory drugs (NSAIDs) and their carboxyl ester analogues as axial moieties were synthesized. Several of the cisplatin-based Pt(IV) complexes 22-30 showed increased cytotoxicity in the human cancer cell lines CH1/PA-1, SW480 and A549 compared to the Pt(II) drug. For the most potent complex 26, comprising two aceclofenac (AFC) moieties, the formation of Pt(II)-9-methylguanine (9-MeG) adducts after activation with ascorbic acid (AsA) was proven. Additionally, a significant inhibition of cyclooxygenase (COX) activity and prostaglandin E 2 (PGE 2 ) production was observed, as well as increased cellular accumulation, depolarization of mitochondrial membranes, and strong proapoptotic potencies in SW480 cells. Overall, these systematic effects shown in vitro confer 26 as a potential anticancer agent combined with anti-inflammatory properties., 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A novel hydroxypropyl cellulose (gHPC) hydrogel with graded porosity has been fabricated, in which pore size, shape, and mechanical properties vary across the material. The graded porosity was achieved by cross-linking different parts of the hydrogel at temperatures below and above 42 °C, which was found to be the temperature of turbidity onset (lower critical solution temperature, LCST) for the HPC and divinylsulfone cross-linker mixture. Scanning electron microscopy imaging revealed a decreasing pore size along the cross-section of the HPC hydrogel from the top to the bottom layer. HPC hydrogels demonstrate graded mechanical properties whereby the top layer, Zone 1, cross-linked below LCST, can be compressed by about 50% before fracture, whereas the middle and bottom layers (Zone 2 and 3, respectively) cross-linked at 42 °C, can withstand 80% compression before failure. This work demonstrates a straightforward, yet novel, concept of exploiting a graded stimulus to incorporate a graded functionality into porous materials that can withstand mechanical stress and minor elastic deformations., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The task-specific ionic liquid trihexyltetradecylphosphonium 3-hydroxy-2-naphthoate has been described as a suitable extraction agent for numerous metals from aqueous phases, while additionally providing reduced leaching into the used matrices. Here, we investigate the extraction properties of this extractant towards rare earth elements. Of these, La, Ce, Nd, Ho und Lu were chosen as a representative mix of light and heavy elements. Single- as well as double-element extractions were carried out under varying conditions regarding pH, temperature and extraction time. The highest extraction efficacies and minimalized precipitation of the respective metals were recorded at a pH of 2.5. Satisfactory extraction efficacies (>80%) were achieved already after 6 hours for the elements Ce, Nd and Lu in single-element extraction experiments at room temperature. Increased temperatures improved the extraction efficacy for Nd from 36% at 20 °C to 80% at 30 °C after only 2 hours. Surprisingly, this effect was not observed for Ce in single-element experiments. In double-element feed solutions containing both Ce and Nd, however, the time-dependant extraction efficacy of Ce mirrored that of Nd. The pH in the aqueous extraction matrix changed during the extraction, showing a positive correlation with the extraction efficacy and revealing the extraction mechanism to be via anion exchange. The leaching was in good agreement with literature values, showed a positive correlation with extraction efficacies, and ranged for all extractions between 0.8 and 1.2%. Remarkably, increasing the temperature from 20 °C to 30 °C had no significant influence on leaching., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

The bottom-up synthesis of plasmonic NHC@CuNPs from common starting reagents, via the formation of the synthetically accessible NHC-Cu(I)-Br complex and its reduction by NH 3 ·BH 3 is reported. The resulting NHC@CuNPs have been characterized in detail by XPS, TEM and NMR spectroscopy. The stability of NHC@CuNPs was investigated under both inert and ambient conditions using UV-Vis analysis. While the NHC@CuNPs are stable under inert conditions for an extended period of time, the NPs oxidize under air to form Cu x O with concomitant release of the stabilizing NHC ligand.

Thiosemicarbazones (TSCs) are a class of biologically active compounds with promising anticancer activity. Their typical mechanism, especially of the clinically far developed representative Triapine, is chelation of iron (Fe), with the Fe-containing enzyme ribonucleotide reductase as primary intracellular target. However, for the subclass of terminally disubstituted, nanomolar-active derivatives like Dp44mT and Me2NNMe2, recent findings suggest that the chelation, stability, and reduction properties of the copper(II) (Cu) complexes are essential for their modes of action. Consequently, it is important to elucidate whether blood serum Cu(II) is a potential metal source for these TSCs. To gain more insights, the interaction of Triapine, Dp44mT or Me2NNMe2 with purified human serum albumin (HSA) as the main pool of labile Cu(II) was investigated by UV-vis and electron paramagnetic resonance measurements. Subsequently, a size-exclusion chromatography inductively coupled plasma mass spectrometry method for the differentiation of Cu species in serum was developed, especially separating the non-labile Cu enzyme ceruloplasmin from HSA. The results indicate that the TSCs specifically chelate copper from the N-terminal Cu-binding site of HSA. Furthermore, the Cu(II)-TSC complexes were shown to form ternary HSA conjugates, most likely via histidine. Noteworthy, Fe-chelation from transferrin was not overserved, even not for Triapine. In summary, the labile Cu pool of HSA is a potential source for Cu-TSC complex formation and, consequently, distinctly influences the anticancer activity and pharmacological behavior of TSCs., (© The Author(s) 2023. Published by Oxford University Press.)

Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents. Consequently, we synthesised cytotoxic platinum(IV) conjugates of cisplatin, carboplatin and oxaliplatin by coupling via amide bonds to five GCPQ polymers differing in their degree of palmitoylation and quaternisation. The conjugates were characterised by 1 H and 195 Pt NMR spectroscopy as well as inductively coupled plasma mass spectrometry (ICP-MS), the latter to determine the amount of platinum(IV) units per GCPQ polymer. Cytotoxicity was evaluated by the MTT assay in three human cancer cell lines (A549, non-small-cell lung carcinoma; CH1/PA-1, ovarian teratocarcinoma; SW480, colon adenocarcinoma). All conjugates displayed a high increase in their cytotoxic activity by factors of up to 286 times compared to their corresponding platinum(IV) complexes and mostly outperformed the respective platinum(II) counterparts by factors of up to 20 times, also taking into account the respective loading of platinum(IV) units per GCPQ polymer. Finally, a biodistribution experiment was performed with an oxaliplatin-based GCPQ conjugate in non-tumour-bearing BALB/c mice revealing an increased accumulation in lung tissue. These findings open promising opportunities for further tumouricidal activity studies especially focusing on lung tissue.

The synthesis, characterization and biological activity of tungstenocenes with varying biologically active ( O , O -), ( S , O - ) and ( N , O - ) chelates are described. Complexes were characterized by 1 H and 13 C NMR, elemental analysis, ESI-mass spectrometry, FT-IR spectroscopy and X-ray diffraction analysis. The aqueous stability was studied by UV/Vis spectroscopy and the W IV to W V process by cyclic voltammetry. The cytotoxicity was determined by the MTT assay in A549, CH1/PA-1 and SW480 cancer cells as well as in IMR-90 human fibroblasts. Extensive biological evaluation was performed in three other human cancer cell lines (HCT116, HT29 and MCF-7) in monolayer and multicellular tumor spheroid cultures to better understand the mode of action. Lead compounds showed promising in vitro anticancer activity in all cancer cell lines. Further studies yielded important insights into apoptosis induction, ROS generation, different patterns in metal distribution (detected by LA-ICP-TOF-MS), changes in KI67 (proliferation marker) expression and DNA interactions. The results based on qualitative and quantitative research designs show that complexes containing ( S , O -) chelates are more active than their ( O , O -) and ( N , O -) counterparts. The most striking results in spheroid models are the high antiproliferative capacity and the different distribution pattern of two complexes differing only in a W-S or W-O bond.

Small-molecule EGFR inhibitors have distinctly improved the overall survival especially in EGFR-mutated lung cancer. However, their use is often limited by severe adverse effects and rapid resistance development. To overcome these limitations, a hypoxia-activatable Co(III)-based prodrug (KP2334) was recently synthesized releasing the new EGFR inhibitor KP2187 in a highly tumor-specific manner only in hypoxic areas of the tumor. However, the chemical modifications in KP2187 necessary for cobalt chelation could potentially interfere with its EGFR-binding ability. Consequently, in this study, the biological activity and EGFR inhibition potential of KP2187 was compared to clinically approved EGFR inhibitors. In general, the activity as well as EGFR binding (shown in docking studies) was very similar to erlotinib and gefitinib (while other EGFR-inhibitory drugs behaved different) indicating no interference of the chelating moiety with the EGFR binding. Moreover, KP2187 significantly inhibited cancer cell proliferation as well as EGFR pathway activation in vitro and in vivo. Finally, KP2187 proved to be highly synergistic with VEGFR inhibitors such as sunitinib. This indicates that KP2187-releasing hypoxia-activated prodrug systems are promising candidates to overcome the clinically observed enhanced toxicity of EGFR-VEGFR inhibitor combination therapies., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Platinum(iv) prodrugs are a promising class of anticancer agents designed to overcome the limitations of conventional platinum(ii) therapeutics. In this work, we present oxaliplatin(iv)-based complexes, which upon reduction, release acetylsalicylic acid (aspirin), known for its antitumor activity against colon cancer and currently investigated in combination with oxaliplatin in a phase III clinical study. Comparison with a recently reported cisplatin analog (asplatin) revealed a massive increase in reduction stability for the oxaliplatin complex in mouse serum. This was in line with the cell culture data indicating the desired prodrug properties for the newly synthesized complex. For in vivo studies, a new derivative containing an albumin-binding maleimide unit was synthesized. Indeed, distinctly longer plasma half-life as well as higher tumor accumulation in comparison to asplatin and oxaliplatin were observed, also leading to significantly higher antitumor activity and overall survival of CT26 tumor-bearing mice., Competing Interests: There are no conflicts to declare., (This journal is © the Partner Organisations.)

Background: Nanotechnology offers many benefits in the globally important field of food production and human nutrition, particularly by implementing agricultural nanoproducts. Of these, edible plant fertilizers enriched with nanosized forms of essential metals, Mn and Fe, are growing in importance with the advantages of enhanced action on plant roots., Scope and Approach: This review focuses on the importance of tracking the bioaccumulation and biodistribution of these pertinent nanofertilizers. An emphasis is given to the critical analysis of the state-of-the-art analytical strategies to examine the Mn and Fe nanoparticles in edible plant systems as well as to shedding light on the vast gap in the methodologies dedicated to the speciation, in vitro simulation, and safety testing of these promising nanomaterials. Also provided are guidances for the food chemists and technologists on the lights and shadows of particular analytical approaches as a matter of authors' expertise as analytical chemists., Key Findings and Conclusions: While the use of nanotechnology in agriculture seems to be growing increasingly, there is still a lack of analytical methodologies capable of investigating novel Mn- and Fe-based nanomaterials as potential fertilizers. Only the advent of reliable analytical tools in the field could bridge the gaps in our knowledge about processes in which those materials participate in the plant systems and their effects on crop production and quality of the produced food., 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Based on their drug delivery properties and activity against tumors, we combined PAMAM dendrimers with various platinum(IV) complexes in order to provide an improved approach of anticancer treatment. Platinum(IV) complexes were linked to terminal NH 2 moieties of PAMAM dendrimers of generation 2 (G2) and 4 (G4) via amide bonds. Conjugates were characterized by 1 H and 195 Pt NMR spectroscopy, ICP-MS and in representative cases by pseudo-2D diffusion-ordered NMR spectroscopy. Additionally, the reduction behavior of conjugates in comparison to corresponding platinum(IV) complexes was investigated, showing a faster reduction of conjugates. Cytotoxicity was evaluated via the MTT assay in human cell lines (A549, CH1/PA-1, SW480), revealing IC 50 values in the low micromolar to high picomolar range. The synergistic combination of PAMAM dendrimers and platinum(IV) complexes resulted in up to 200 times increased cytotoxic activity of conjugates in consideration of the loaded platinum(IV) units compared to their platinum(IV) counterparts. The lowest IC 50 value of 780 ± 260 pM in the CH1/PA-1 cancer cell line was detected for an oxaliplatin-based G4 PAMAM dendrimer conjugate. Finally, in vivo experiments of a cisplatin-based G4 PAMAM dendrimer conjugate were performed based on the best toxicological profile. A maximum tumor growth inhibition effect of 65.6% compared to 47.6% for cisplatin was observed as well as a trend of prolonged animal survival.

A new class of anticancer prodrugs was designed by combining the cytotoxicity of platinum(IV) complexes and the drug carrier properties of glycol chitosan polymers: Unsymmetrically carboxylated platinum(IV) analogues of cisplatin, carboplatin and oxaliplatin, namely (OC-6-44)-acetatodiammine(3-carboxypropanoato)dichloridoplatinum(IV), (OC-6-44)-acetaodiammine(3-carboxypropanoato)(cyclobutane-1,1-dicarboxylato)platinum(IV) and (OC-6-44)-acetato(3-carboxypropanoato)(1R,2R-cyclohexane-1,2-diamine)oxalatoplatinum(IV) were synthesised and conjugated via amide bonding to degraded glycol chitosan (dGC) polymers with different chain lengths (5, 10, 18 kDa). The 15 conjugates were investigated with 1 H and 195 Pt NMR spectroscopy, and average amounts of platinum(IV) units per dGC polymer molecule with ICP-MS, revealing a range of 1.3-22.8 platinum(IV) units per dGC molecule. Cytotoxicity was tested with MTT assays in the cancer cell lines A549, CH1/PA-1, SW480 (human) and 4T1 (murine). IC 50 values in the low micromolar to nanomolar range were obtained, and higher antiproliferative activity (up to 72 times) was detected with dGC-platinum(IV) conjugates in comparison to platinum(IV) counterparts. The highest cytotoxicity (IC 50 of 0.036 ± 0.005 µM) was determined in CH1/PA-1 ovarian teratocarcinoma cells with a cisplatin(IV)-dGC conjugate, which is hence 33 times more potent than the corresponding platinum(IV) complex and twice more potent than cisplatin. Biodistribution studies of an oxaliplatin(IV)-dGC conjugate in non-tumour-bearing Balb/C mice showed an increased accumulation in the lung compared to the unloaded oxaliplatin(IV) analogue, arguing for further activity studies.

For a variety of cancer types, platinum compounds are still among the best treatment options. However, their application is limited by side effects and drug resistance. Consequently, multi-targeted platinum(IV) prodrugs that target specific traits of the malignant tissue are interesting new candidates. Recently, cisPt(PhB) 2 was synthesized which, upon reduction in the malignant tissue, releases phenylbutyrate (PhB), a metabolically active fatty acid analog, in addition to cisplatin. In this study, we in-depth investigated the anticancer properties of this new complex in cell culture and in mouse allograft experiments. CisPt(PhB) 2 showed a distinctly improved anticancer activity compared to cisplatin as well as to PhB alone and was able to overcome various frequently occurring drug resistance mechanisms. Furthermore, we observed that differences in the cellular fatty acid metabolism and mitochondrial activity distinctly impacted the drug's mode of action. Subsequent analyses revealed that "Warburg-like" cells, which are characterized by deficient mitochondrial function and fatty acid catabolism, are less capable of coping with cisPt(PhB) 2 leading to rapid induction of a non-apoptotic form of cell death. Summarizing, cisPt(PhB) 2 is a new orally applicable platinum(IV) prodrug with promising activity especially against cisplatin-resistant cancer cells with "Warburg-like" properties.

Cancer chemotherapeutics usually have serious side effects. Targeting the special properties of cancer and activation of the anticancer drug in the tumor microenvironment in situ may decrease the intensity of the side effects and improve the efficacy of therapy. In this study, half-sandwich Rh complexes are introduced, which may be activated at the acidic, extracellular pH of the tumor tissue. The synthesis and aqueous stability of mixed-ligand complexes with a general formula of [Rh(η 5 -Cp*)(N,N/O)(N)] 2+/+ are reported, where (N,N/O) indicates bidentate 8-quinolate, ethylenediamine and 1,10-phenanthroline and (N) represents the releasable monodentate ligand with a nitrogen donor atom. UV-visible spectrophotometry, 1 H NMR, and pH-potentiometry were used to determine the protonation constants of the monodentate ligands, the proton dissociation constants of the coordinated water molecules in the aqua complexes, and the formation constants of the mixed-ligand complexes. The obtained data were compared to those of the analogous Ru(η 6 - p -cymene) complexes. The developed mixed-ligand complexes were tested in drug-sensitive and resistant colon cancer cell lines (Colo205 and Colo320, respectively) and in four bacterial strains (Gram-positive and Gram-negative, drug-sensitive, and resistant) at different pH values (5-8). The mixed-ligand complexes with 1-methylimidazole displayed sufficient stability at pH 7.4, and their activation was found in cancer cells with decreasing pH; moreover, the mixed-ligand complexes demonstrated antimicrobial activity in Gram-positive and Gram-negative bacteria, including the resistant MRSA strain. This study proved the viability of incorporating releasable monodentate ligands into mixed-ligand half-sandwich complexes, which is supported by the biological assays.

A growing global emission of engineered nanoparticles (ENPs) into the aquatic environment has become an emerging safety concern that requires methods capable of identifying the occurrence and possibly determining the amounts of ENPs. In this study, we employed sector-field inductively coupled mass spectrometry to assess the presence of ENPs in coastal seawater samples collected from the Black Sea in regions suffering different anthropogenic impacts. Ultrafiltration through commercial 3 kDa membrane filters was shown to be feasible to separate the ENPs from the bulk seawater, and the subsequent ultrasound-mediated acidic dissolution makes the metals constituting the ENPs amenable to analysis. This procedure allowed the ENPs bearing Cu, Zn, V, Mo, and Sn to be for the first time quantitated in seashore surface water, their concentration ranging from 0.1 to 1.0 μg L -1 (as metal) and related to the presence of industry and/or urban stress. While these levels are decreased by natural dilution and possible sedimentation, the monitored ENPs remain measurable at a distance of 2 km from the coast. This can be attributed not only to local emission sources but also to some natural backgrounds.

A series of six highly lipophilic Cp-substituted molybdenocenes bearing different bioactive chelating ligands was synthesized and characterized by NMR spectroscopy, mass spectrometry and X-ray crystallography. In vitro experiments showed a greatly increased cytotoxic potency when compared to the non-Cp-substituted counterparts. In vivo experiments performed with the dichlorido precursor, (Ph 2 C-Cp) 2 MoCl 2 and the in vitro most active complex, containing the thioflavone ligand, showed an inhibition of tumour growth. Proteomic studies on the same two compounds demonstrated a significant regulation of tubulin-associated and mitochondrial inner membrane proteins for both compounds and a strong metabolic effect of the thioflavone containing complex., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

With an increasing production and use of engineered nanoparticles (ENPs), inevitably grows their release into the environment. This makes it important to determine in what quantitates they occur in aquatic systems like seawater. However, even when using the most sensitive ICP-MS technique, quantification of very low seawater concentrations of ENPs is still concept rather than the fact. To approach this goal, a unified protocol for the preparation of seawater samples for ICP-MS analysis has been developed in this study using a selection of silver, titanium dioxide and zinc oxide nanoparticles. In order to minimize the risk of particle loss, the effect of sample pH was examined and it was found out that a moderate in-field acidification (to pH 7.5) ensures particle stability prior to analysis. Ultrafiltration through commercial 3 kDa membrane filters was shown feasible to separate the ENPs from the bulk seawater sample provided that the filter unit is pre-conditioned with 0.1 M copper nitrate to avoid ionic metal adsorption. The following ultrasound-mediated dissolution in 30% HNO 3 directly in the filer unit and ultrafiltration makes the metals constituting the ENPs amenable to analysis. The latter was for the first time performed using high-resolution ICP-MS method validated according to the common EU standards. The limits of detection attained here were as low as 0.06, 0.09, and 17.5 μg L -1 for Ag, TiO 2 , and ZnO nanoparticles, respectively. Accuracy of the method was tested with uncontaminated open-sea water spiked with ENPs and recoveries were acceptable ranging from 85 to 110%., 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 © 2022 Elsevier B.V. All rights reserved.)

An article was published in the journal "Current Medicinal Chemistry," Volume 12, No. 18, 2005, pp: 2075-2094 [1]. The first author is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original article can be found online at: http://www.benthamscience.com/article/5874., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

An article was published in the journal "Anti-Cancer Agents in Medicinal Chemistry", Volume 7, No. 01, 2007, pp: 55-73 [1]. The first author is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original article can be found online at: https://www.eurekaselect.com/article/3359., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

An article was published in the journal "Current Pharmaceutical Design", Volume 9, No. 25, 2003, pp: 2078-2089 [1]. The first author is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original article can be found online at: https://www.eurekaselect.com/article/8545 We regret the error and apologize to readers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tris-(8-quinolinolato)gallium(III) (KP46, AP-002) is an orally administered investigational anticancer and bone-protective drug currently being evaluated in patients with advanced solid tumors with bone involvement. Despite the clinical efficacy of other gallium compounds in non-Hodgkin's lymphoma, effects of KP46 in hematological tumor settings have not been studied systematically before. We report here intriguing activities in various human cell lines, including such with multidrug resistance (MDR): In Nalm-6 lymphoblastic leukemia cell sublines, KP46 was capable of overcoming P-gp-related as well as P-gp-unrelated MDR. Apoptosis induction by KP46 was unaffected by bcl2-mediated vincristine-induced MDR in a BJAB lymphoma cell subline and even enhanced in a K562 leukemia subline with daunorubicin-induced MDR, which could be re-sensitized to daunorubicin by KP46. As the latter resistance is associated with lowered Harakiri (HRK) protein levels, a modulating effect of KP46 on HRK expression is suggested. This is consistent with the significant high upregulation of HRK on RNA and protein levels observed in KP46-treated parental BJAB cells according to qPCR and Western blot analysis, respectively. Furthermore, KP46 significantly reduces the protein level of X-linked inhibitor of apoptosis (XIAP) in BJAB cells, the most potent known inhibitor of apoptosis. Overall, these results indicate both a higher potential of HRK and XIAP as cellular targets for cancer therapy and a broader therapeutic potential of KP46 than hitherto envisaged., Competing Interests: Conflict of interest statement 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 © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In this work, biologically active α-lipoic acid (ALA) and its isologous 1,2-diselenolane (SeA) and cyclopentyl (CpA) analogues were investigated for their differences in redox potentials, cytotoxicity and ROS production. In addition, the corresponding Pt(IV) complexes comprising ALA (1-4), SeA (5-8) and CpA (9-12) as axial ligands were synthesized. Those Pt(IV) complexes were characterized by NMR spectroscopy, ESI-mass spectrometry and elemental analysis. The cytotoxicity study showed that 1,2-diselenolane containing Pt(IV) (1, 3 and 4) complexes are more cytotoxic than the 1,2-dithiolane analogues (5, 7, and 8) throughout all tested cell lines, intriguingly, cyclopentyl containing species (9, 11 and 12) are the most effective, in some cases even more potent than the parent drug oxaliplatin. Three representative complexes 2, 6 and 10 were further assessed for their redox potentials, reduction with AsA, lipophilicity, cellular accumulation and ROS production. It turned out that the cytotoxicity profile is an overall result of good lipophilicity, high cellular accumulation, and (partially) enhanced ROS generation.

Combining therapeutic with diagnostic agents (theranostics) can revolutionize the course of malignant diseases. Chemotherapy, hyperthermia, or radiation are used together with diagnostic methods such as magnetic resonance imaging (MRI). In contrast to conventional contrast agents (CAs), which only enable non-specific visualization of tissues and organs, the theranostic probe offers targeted diagnostic imaging and therapy simultaneously., Methods: Novel salinomycin (Sal)-based theranostic probes comprising two different paramagnetic metal ions, gadolinium(III) (Gd(III)) or manganese(II) (Mn(II)), as signal emitting motifs for MRI were synthesized and characterized by elemental analysis, infrared spectral analysis (IR), electroparamagnetic resonance (EPR), thermogravimetry (TG) differential scanning calorimetry (DSC) and electrospray ionization mass spectrometry (ESI-MS). To overcome the water insolubility of the two Sal-complexes, they were loaded into empty bacterial ghosts (BGs) cells as transport devices. The potential of the free and BGs-loaded metal complexes as theranostics was evaluated by in vitro relaxivity measurements in a high-field MR scanner and in cell culture studies., Results: Both the free Sal-complexes (Gd(III) salinomycinate (Sal-Gd(III) and Mn(II) salinomycinate (Sal-Mn(II)) and loaded into BGs demonstrated enhanced cytotoxic efficacy against three human tumor cell lines (A549, SW480, CH1/PA-1) relative to the free salinomycinic acid (Sal-H) and its sodium complex (Sal-Na) applied as controls with IC 50 in a submicromolar concentration range. Moreover, Sal-H, Sal-Gd(III), and Sal-Mn(II) were able to induce perturbations in the cell cycle of treated colorectal and breast human cancer cell lines (SW480 and MCF-7, respectively). The relaxivity ( r 1 ) values of both complexes as well as of the loaded BGs, were higher or comparable to the relaxivity values of the clinically applied contrast agents gadopentetate dimeglumine and gadoteridol., Conclusion: This research is the first assessment that demonstrates the potential of Gd(III) and Mn(II) complexes of Sal as theranostic agents for MRI. Due to the remarkable selectivity and mode of action of Sal as part of the compounds, they could revolutionize cancer therapy and allow for early diagnosis and monitoring of therapeutic follow-up.

α-Lipoic acid, known for its anti-inflammatory and antioxidant activity, represents a promising ligand for Pt(IV) prodrugs. Three new Pt(IV) lipoate complexes were synthesized and characterized by NMR spectroscopy ( 1 H, 13 C, 195 Pt), mass spectrometry and elemental analysis. Due to the low solubility of the complex containing two axial lipoate ligands, further experiments to examine the biological activity were performed with two Pt(IV) complexes containing just one axial lipoate ligand. Both complexes exhibit anticancer activity and produce reactive oxygen species (ROS) in the cell lines tested. Especially, the monosubstituted complex can be reduced by ascorbic acid and forms adducts with 9-methylguanine (9MeG), which is favorable for the formation of DNA-crosslinks in the cells., (© 2022 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe 2 and COTI-NMeCy), and the non-substituted analogue (COTI-NH 2 ) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe 2 as an interesting new drug candidate with improved anticancer activity and resistance profile.

This study explores quantitative bioimaging as enabled by laser ablation-inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS), designing standardization methods based on robotic micro-droplet dispensing. The potential of producing controlled and highly precise pL-volume droplets was exploited to establish on-tissue isotope dilution and standard addition. Both strategies eliminate matrix effects and offer high metrological order traceable to SI units. The absolute quantity was obtained for μm-sized regions of interest in tissue samples, as defined by the extension of the deposited pL-volume droplet. While the gold standard isotope dilution (ID) was restricted to the accurate quantification of a single element, i.d. platinum in different tissue samples (mouse liver, spleen and tumor tissue), multiplexed matrix-matched calibration was obtained by on-tissue standard addition by depositing a dilution series of certified multi-element standards. Here, the working range was determined by the heterogeneity of the tissue samples and the background levels of elements intrinsically present and/or artificially introduced during sample preparation. Both methods, ID and standard addition served as reference methods for validation of external calibration using gelatin-based micro-droplet standards. Given full ablation, these external standards revealed a high dynamic range together with an excellent repeatability. Where applicable, the cross-validation revealed consistent quantitative results for the three quantification approaches. The comparable sensitivity obtained for standard addition and external standardization, respectively expressed as slope of the calibration function, provided proof that gelatin-based micro-droplets could serve as matrix-matched calibrations. Therefore, gelatin micro-droplets offer a valid tool for multiplexed matrix-mimicking standardization at high-throughput., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The cytotoxicities of seven dimeric metal species of the general formula [M(arene)Cl 2 ] 2 , commonly used as precursors for complex synthesis and deemed biologically inactive, are investigated in seven commonly employed human cancer cell lines. Four of these complexes featured a ruthenium(II) core, where p-cymene, toluene, benzene and indane were used as arenes. Furthermore, the osmium(II) p-cymene dimer, as well as the Cp* dimers of rhodium(III) and its heavier analogue iridium(III) were included in this work (Cp*=1,2,3,4,5-pentamethylcyclopentadienide). While the cytotoxic potencies of the ruthenium(II) and osmium(II) dimers are very low (or not even detectable at applicable concentrations), surprising activity, especially in cells from ovarian malignancies (with one or two-digit micromolar IC 50 values), have been found for the rhodium(III) and iridium(III) representatives. This publication is aimed at all researchers using synthetic procedures based on functionalization of these dimeric starting materials to rationalize changes in biological properties, especially cytotoxicity in cancer cells., (© 2022 The Authors. Published by Wiley-VCH GmbH.)

Since their first discovery, N -heterocyclic carbenes have had a significant impact on organometallic chemistry. Due to their nature as strong σ-donor and π-acceptor ligands, they are exceptionally well suited to stabilize Au(I) and Au(III) complexes in biological environments. Over the last decade, the development of rationally designed NHCAu(I/III) complexes to specifically target DNA has led to a new "gold rush" in bioinorganic chemistry. This review aims to summarize the latest advances of NHCAu(I/III) complexes that are able to interact with DNA. Furthermore, the latest advancements on acyclic diamino carbene gold complexes with anticancer activity are presented as these typically overlooked NHC alternatives offer great additional design possibilities in the toolbox of carbene-stabilized gold complexes for targeted therapy.

Thiosemicarbazones are promising candidates for anticancer therapy and their mechanism of action is often linked to their metal chelating ability. In this study, five (thio)semicarbazones with different donor sets (NNS, NNO, ONS, ONO) were selected and their behaviour in aqueous solution, the stability of their copper(II) complexes in addition to their cytotoxicity, DNA-binding, DNA cleavage ability and inhibition of topoisomerase IIα were investigated and compared. We aimed to reveal relationships between the structural variations, the significantly different physico-chemical properties, solution speciation and biological activity. The cytotoxicity of the ligands did not show correlation with the solubility, lipophilicity and permeability; and the decreased activity of the oxygen donor containing compounds was explained by their stronger preference towards chelation of iron(III) over iron(II). Meanwhile, among the copper complexes the most lipophilic species with the highest stability and membrane permeability exhibited the highest cytotoxicity. The studied copper(II) complexes interact with DNA, and reaction with glutathione led to heavy DNA cleavage in the case of the highly stable complexes which could be reduced in a reversible reaction with moderate rate. All the tested copper complexes inhibited topoisomerase IIα, however, this property of the complexes with low stability is most probably linked to the liberated free copper(II)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clinical efficacy of oxaliplatin is frequently limited by severe adverse effects and therapy resistance. Acquired insensitivity to oxaliplatin is, at least in part, associated with elevated levels of glutathione (GSH). In this study we report on an oxaliplatin-based platinum(IV) prodrug, which releases L-buthionine-S,R-sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase, the rate-limiting enzyme in GSH biosynthesis. Two complexes bearing either acetate (BSO-OxOAc) or an albumin-binding maleimide (BSO-OxMal) as second axial ligand were synthesized and characterized. The in vitro anticancer activity of BSO-OxOAc was massively reduced in comparison to oxaliplatin, proving its prodrug nature. Nevertheless, the markedly lower intracellular oxaliplatin uptake in resistant HCT116/OxR cells was widely overcome by BSO-OxOAc resulting in distinctly reduced resistance levels. Platinum accumulation in organs of a colorectal cancer mouse model revealed higher tumor selectivity of BSO-OxMal as compared to oxaliplatin. This corresponded with increased antitumor activity, resulting in significantly enhanced overall survival. BSO-OxMal-treated tumors exhibited reduced GSH levels, proliferative activity and enhanced DNA damage (pH2AX) compared to oxaliplatin. Conversely, pH2AX staining especially in kidney cells was distinctly increased by oxaliplatin but not by BSO-OxMal. Taken together, our data provide compelling evidence for enhanced tumor specificity of the oxaliplatin(IV)/BSO prodrug., (© 2022. The Author(s).)

Solution speciation and serum protein binding of selected In(III) complexes bearing O,O and O,N donor sets were studied to provide comparative data for In(III) and analogous Ga(III) complexes. Aqueous stability of the In(III) complexes of maltol, deferiprone, 8-hydroxyquinoline (HQ) and 8-hydroxyquinoline-5-sulfonate (HQS) was characterized by a combined pH-potentiometric and UV-visible spectrophotometric approach. Formation of mono, bis and tris-ligand complexes was observed. The tris-ligand complexes of HQ (InQ 3 ) and deferiprone (InD 3 ) are present in solution in ca. 90% at 10 µM concentration at pH = 7.4, while the tris-maltolato complex (InM 3 ) displays insufficient stability under these conditions. Binding towards human serum albumin (HSA) and (apo)transferrin ((apo)Tf) of InQ 3 , InD 3 and InM 3 complexes and Ga(III) analogue of InQ 3 (GaQ 3 ) together with InCl 3 was investigated by a panel of methods: steady-state and time-resolved spectrofluorometry, UV-visible spectrophotometry and membrane ultrafiltration. Moderate binding of InQ 3 to HSA was found (log K' = 5.0-5.1). InD 3 binds to HSA to a much lower extent in comparison to InQ 3 . ApoTf is able to displace HQ, deferiprone and maltol effectively from their In(III) complexes. Protein binding of non-dissociated InQ 3 was also observed at high complex-to-apoTf ratios. Studies conducted with the InQ 3 /GaQ 3 - HSA - Tf ternary systems revealed the more pronounced Tf binding of In(III) via ligand release, while the original GaQ 3 scaffold is preferably retained upon protein interactions and significant albumin binding occurs. Significant dissociation of InQ 3 was detected in human blood serum as well., (© 2022. The Author(s).)

Using inductively coupled plasma mass spectrometry (in combination with ultrafiltration) and microemulsion electrokinetic chromatography, the drug properties of two new, potentially multi-targeting Ru(III) and Pt(IV) compounds, containing biologically active ligands, were evaluated. The ruthenium complex with bexarotene was shown to bind to albumin faster than to transferrin and exhibits much the same (to albumin) binding profile in human serum. The Pt(IV)-lonidamine complex interacts with albumin relatively slowly but possesses high stability and lipophilicity (log P 1.62), which makes it possible the cellular uptake in a free (of proteins) form. Although both examined compounds display a moderate solubility (below 10 -4  M), this stands compatible with their nanomolar cytotoxic activities. The Ru(III) compound, whose active moiety is a complexed anion, is deemed promising to be loaded on nanoscale anion-exchangers with the aim of controlled delivery., (© 2022. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)