The combination of photodynamic therapy and radiotherapy has given rise to a modality called radiodynamic therapy (RDT), based on reactive oxygen species-producing radiosensitizers. The production of singlet oxygen, O2(1Δg), by octahedral molybdenum (Mo6) clusters upon X-ray irradiation allows for simplification of the architecture of radiosensitizing systems. In this context, we prepared a radiosensitizing system using copper-free click chemistry between a Mo6 cluster bearing azido ligands and the homo-bifunctional linker bis-dPEG11-DBCO. The resulting compound formed nanoparticles, which featured production of O2(1Δg) and efficient cellular uptake, leading to remarkable photo- and radiotoxic effects against the prostatic adenocarcinoma TRAMP-C2 cell line. Spheroids of TRAMP-C2 cells were also used for evaluation of toxicity and phototoxicity. In vivo experiments on a mouse model demonstrated that subcutaneous injection of the nanoparticles is a safe administration mode at a dose of up to 0.08 g kg-1. The reported results confirm the relevancy of Mo6-based radiosensitizing nanosystems for RDT.
The emergence of multidrug-resistant microbial pathogens poses a significant threat, severely limiting the options for effective antibiotic therapy. This challenge can be overcome through the photoinactivation of pathogenic bacteria using materials generating reactive oxygen species upon exposure to visible light. These species target vital components of living cells, significantly reducing the likelihood of resistance development by the targeted pathogens. In our research, we have developed a nanocomposite material consisting of an aqueous colloidal suspension of graphene oxide sheets adorned with nanoaggregates of octahedral molybdenum cluster complexes. The negative charge of the graphene oxide and the positive charge of the nanoaggregates promoted their electrostatic interaction in aqueous medium and close cohesion between the colloids. Upon illumination with blue light, the colloidal system exerted a potent antibacterial effect against planktonic cultures of Staphylococcus aureus largely surpassing the individual contributions of the components. The underlying mechanism behind this phenomenon lies in the photoinduced electron transfer from the nanoaggregates of the cluster complexes to the graphene oxide sheets, which triggers the generation of reactive oxygen species. Thus, leveraging the unique properties of graphene oxide and light-harvesting octahedral molybdenum cluster complexes can open more effective and resilient antibacterial strategies.
- MeSH
- antibakteriální látky farmakologie MeSH
- lidé MeSH
- molybden farmakologie MeSH
- reaktivní formy kyslíku MeSH
- stafylokokové infekce * MeSH
- Staphylococcus aureus * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibakteriální látky MeSH
- graphene oxide MeSH Prohlížeč
- molybden MeSH
- reaktivní formy kyslíku MeSH
Within the cell, the trace element molybdenum (Mo) is only biologically active when complexed either within the nitrogenase-specific FeMo cofactor or within the molybdenum cofactor (Moco). Moco consists of an organic part, called molybdopterin (MPT) and an inorganic part, that is, the Mo-center. The enzyme which catalyzes the Mo-center formation is the molybdenum insertase (Mo-insertase). Mo-insertases consist of two functional domains called G- and E-domain. The G-domain catalyzes the formation of adenylated MPT (MPT-AMP), which is the substrate for the E-domain, that catalyzes the actual molybdate insertion reaction. Though the functions of E- and G-domain have been elucidated to great structural and mechanistic detail, their combined function is poorly characterized. In this work, we describe a structural model of the eukaryotic Mo-insertase Cnx1 complex that was generated based on cross-linking mass spectrometry combined with computational modeling. We revealed Cnx1 to form an asymmetric hexameric complex which allows the E- and G-domain active sites to align in a catalytic productive orientation toward each other.
- Klíčová slova
- biosynthesis complex, molybdenum cofactor, molybdenum insertase,
- MeSH
- Arabidopsis * chemie MeSH
- kalnexin chemie metabolismus MeSH
- koenzymy chemie MeSH
- metaloproteiny * chemie MeSH
- molybden metabolismus MeSH
- proteiny huseníčku * chemie MeSH
- pteridiny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- kalnexin MeSH
- koenzymy MeSH
- metaloproteiny * MeSH
- molybden MeSH
- proteiny huseníčku * MeSH
- pteridiny MeSH
Due to their high abundance, polymeric character, and chemical tunability, polysaccharides are perfect candidates for the stabilization of photoactive nanoscale objects, which are of great interest in modern science but can be unstable in aqueous media. In this work, we have demonstrated the relevance of oxidized dextran polysaccharide, obtained via a simple reaction with H2O2, towards the stabilization of photoactive octahedral molybdenum and tungsten iodide cluster complexes [M6I8}(DMSO)6](NO3)4 in aqueous and culture media. The cluster-containing materials were obtained by co-precipitation of the starting reagents in DMSO solution. According to the data obtained, the amount and ratio of functional carbonyl and carboxylic groups as well as the molecular weight of oxidized dextran strongly affect the extent of stabilization, i.e., high loading of aldehyde groups and high molecular weight increase the stability, while acidic groups have some negative impact on the stability. The most stable material based on the tungsten cluster complex exhibited low dark and moderate photoinduced cytotoxicity, which together with high cellular uptake makes these polymers promising for the fields of bioimaging and PDT.
- Klíčová slova
- cytotoxicity, hydrolysis, luminescence, molybdenum, octahedral iodide cluster, oxidized dextran polysaccharide, photodynamic therapy, stability, tungsten,
- MeSH
- dextrany MeSH
- dimethylsulfoxid MeSH
- jodidy MeSH
- molybden * chemie MeSH
- peroxid vodíku MeSH
- wolfram * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- dextrany MeSH
- dimethylsulfoxid MeSH
- jodidy MeSH
- molybden * MeSH
- peroxid vodíku MeSH
- wolfram * MeSH
In total, twenty elements appear to be essential for the correct functioning of the human body, half of which are metals and half are non-metals. Among those metals that are currently considered to be essential for normal biological functioning are four main group elements, sodium (Na), potassium (K), magnesium (Mg), and calcium (Ca), and six d-block transition metal elements, manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn) and molybdenum (Mo). Cells have developed various metallo-regulatory mechanisms for maintaining a necessary homeostasis of metal-ions for diverse cellular processes, most importantly in the central nervous system. Since redox active transition metals (for example Fe and Cu) may participate in electron transfer reactions, their homeostasis must be carefully controlled. The catalytic behaviour of redox metals which have escaped control, e.g. via the Fenton reaction, results in the formation of reactive hydroxyl radicals, which may cause damage to DNA, proteins and membranes. Transition metals are integral parts of the active centers of numerous enzymes (e.g. Cu,Zn-SOD, Mn-SOD, Catalase) which catalyze chemical reactions at physiologically compatible rates. Either a deficiency, or an excess of essential metals may result in various disease states arising in an organism. Some typical ailments that are characterized by a disturbed homeostasis of redox active metals include neurological disorders (Alzheimer's, Parkinson's and Huntington's disorders), mental health problems, cardiovascular diseases, cancer, and diabetes. To comprehend more deeply the mechanisms by which essential metals, acting either alone or in combination, and/or through their interaction with non-essential metals (e.g. chromium) function in biological systems will require the application of a broader, more interdisciplinary approach than has mainly been used so far. It is clear that a stronger cooperation between bioinorganic chemists and biophysicists - who have already achieved great success in understanding the structure and role of metalloenzymes in living systems - with biologists, will access new avenues of research in the systems biology of metal ions. With this in mind, the present paper reviews selected chemical and biological aspects of metal ions and their possible interactions in living systems under normal and pathological conditions.
- Klíčová slova
- Disturbed homeostasis, Essential metals, Homeostasis, Human diseases, Metalloenzymes,
- MeSH
- chrom MeSH
- draslík MeSH
- hořčík MeSH
- ionty MeSH
- katalasa MeSH
- kobalt MeSH
- lidé MeSH
- mangan * MeSH
- měď MeSH
- metaloproteiny * MeSH
- molybden MeSH
- sodík MeSH
- superoxiddismutasa MeSH
- vápník chemie MeSH
- železo MeSH
- zinek chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- chrom MeSH
- draslík MeSH
- hořčík MeSH
- ionty MeSH
- katalasa MeSH
- kobalt MeSH
- mangan * MeSH
- měď MeSH
- metaloproteiny * MeSH
- molybden MeSH
- sodík MeSH
- superoxiddismutasa MeSH
- vápník MeSH
- železo MeSH
- zinek MeSH
In this work four vanadium complexes (compounds 1, 2, 3 and 4) and one molybdenum complex (compound 5) with hydrazone ligands derived from pyridoxal were synthesized and characterized. All compounds are mononuclear species, two of them (compounds 3 and 5) are dioxide complexes and the other three (compounds 1, 2 and 4) monoxide complexes. The vanadium atom of the compound 3 is five-coordinated and all the other compounds have a six coordinated environment polyhedron. The poses for the potential intercalation of the compounds 2 and 3 with DNA were obtained by using AutoDock software. Optimizations were also performed at PM6-D3H4 semi-empirical level whereas the study of the nature of the interaction was carried out by means of the Energy Decomposition Analysis and the Non-Covalent Interaction index by using in both cases Density Functional Theory computations. The cytotoxicity in lung cancer cells (A549 cell line) of all the compounds was also evaluated. After 24 h of treatment, vanadium complexes showed high values of IC50, between 419.93 ± 22.58 and 685.88 ± 46.55 μM. After 48 h, the results showed that the compound 3 had the lowest IC50 value, 65.32 ± 9.95 μM, and the compound 2 the highest value, 375.28 ± 32.09 μM. The molybdenum complex showed the lowest IC50 value at 48 h (11.22 ± 1.34 μM). The toxicity of the compounds 3, 4 and 5 was tested in vivo, using zebrafish model, and the molybdenum complex showed higher toxic effects than the studied vanadium complexes.
- Klíčová slova
- A549 cell line, Cytotoxicity, Intercalator, Stability, Vanadium, Zebrafish model,
- MeSH
- dánio pruhované MeSH
- ligandy MeSH
- molybden * chemie farmakologie MeSH
- pyridoxal farmakologie MeSH
- vanad * chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ligandy MeSH
- molybden * MeSH
- pyridoxal MeSH
- vanad * MeSH
X-Ray-induced photodynamic therapy represents a suitable modality for the treatment of various malignancies. It is based on the production of reactive oxygen species by radiosensitizing nanoparticles activated by X-rays. Hence, it allows overcoming the depth-penetration limitations of conventional photodynamic therapy and, at the same time, reducing the dose needed to eradicate cancer in the frame of radiotherapy treatment. The direct production of singlet oxygen by octahedral molybdenum cluster complexes upon X-ray irradiation is a promising avenue in order to simplify the architecture of radiosensitizing systems. One such complex was utilized to prepare water-stable nanoparticles using the solvent displacement method. The nanoparticles displayed intense red luminescence in aqueous media, efficiently quenched by oxygen to produce singlet oxygen, resulting in a substantial photodynamic effect under blue light irradiation. A robust radiosensitizing effect of the nanoparticles was demonstrated in vitro against TRAMP-C2 murine prostatic carcinoma cells at typical therapeutic X-ray doses. Injection of a suspension of the nanoparticles to a mouse model revealed the absence of acute toxicity as evidenced by the invariance of key physiological parameters. This study paves the way for the application of octahedral molybdenum cluster-based radiosensitizers in X-ray-induced photodynamic therapy and its translation to in vivo experiments.
- MeSH
- fotochemoterapie * metody MeSH
- karcinom * MeSH
- lidé MeSH
- molybden farmakologie MeSH
- myši MeSH
- nádory prostaty * farmakoterapie MeSH
- nanočástice * MeSH
- radiosenzibilizující látky * MeSH
- rentgenové záření MeSH
- singletový kyslík MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- molybden MeSH
- radiosenzibilizující látky * MeSH
- singletový kyslík MeSH
The development of singlet oxygen photosensitizers, which target specific cellular organelles, constitutes a pertinent endeavor to optimize the efficiency of photodynamic therapy. Targeting of the cell membrane eliminates the need for endocytosis of drugs that can lead to toxicity, intracellular degradation, or drug resistance. In this context, we utilized copper-free click chemistry to prepare a singlet oxygen photosensitizing complex, made of a molybdenum-iodine nanocluster stabilized by triazolate apical ligands. In phosphate-buffered saline, the complex formed nanoaggregates with a positive surface charge due to the protonatable amine function of the apical ligands. These nanoaggregates targeted cell membranes and caused an eminent blue-light phototoxic effect against HeLa cells at nanomolar concentrations, inducing apoptotic cell death, while having no dark toxicity at physiologically relevant concentrations. The properties of this complex were compared to those of a negatively charged parent complex to highlight the dominant effect of the nature of apical ligands on biological properties of the nanocluster. These two complexes also exerted (photo)antibacterial effects on several pathogenic strains in the form of planktonic cultures and biofilms. Overall, we demonstrated that the rational design of apical ligands toward cell membrane targeting leads to enhanced photodynamic efficiency.
- MeSH
- buněčná membrána MeSH
- HeLa buňky MeSH
- jod * farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molybden * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- jod * MeSH
- ligandy MeSH
- molybden * MeSH
Cytotoxic complexes containing molybdenum are widely studied as a potential substitution for commercially used drugs that often suffer from pronounced side effects and cellular resistance. Compounds of the type [(η5 -Cp')Mo(CO)2 (N,N L)][BF4 ], where Cp is cyclopentadienyl and N,N L is a bidentate ligand, are well known for their strong anticancer activity. It is a generally accepted paradigm that the nature of the coordinated N,N L ligand has a major impact on the cytotoxicity. In this study, a series of new functionalised Cp complexes of molybdenum was synthesised from derivatised fulvenes as π-ligand precursors. Indeed, the coordination sphere's modulation by various N,N-chelating ligands afforded species active toward leukemic cell line MOLT-4 with IC50 values depending on the character of the N,N-chelator used. However, following study clearly showed that functionalisation of the Cp ring with an amine moiety considerably improved cytotoxicity. These results are of crucial importance for the future design of highly active cytotoxic drugs, as modification of cyclopentadienyl is believed to have a minor effect on biological activity.
- Klíčová slova
- MOLT-4, antitumor agents, cyclopentadienyl ligand, cytotoxicity, fulvene,
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- buněčné linie MeSH
- cyklopentany chemie farmakologie MeSH
- komplexní sloučeniny chemická syntéza chemie farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- molybden chemie farmakologie MeSH
- proliferace buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- cyklopentany MeSH
- komplexní sloučeniny MeSH
- ligandy MeSH
- molybden MeSH
X-ray-induced photodynamic therapy (X-PDT) has recently evolved into a suitable modality to fight cancer. This technique, which exploits radiosensitizers producing reactive oxygen species, allows for a reduction of the radiation dose needed to eradicate cancer in the frame of the radiotherapy treatment of deep tumors. The use of transition metal complexes able to directly produce singlet oxygen, O2(1Δg), upon X-ray irradiation constitutes a promising route towards the optimization of the radiosensitizer's architecture. In our endeavour to conceive pertinent agents for X-PDT, we designed an octahedral molybdenum cluster complex (Mo6) with iodine inner ligands, and carboxylated apical ligands bearing ethylene oxide organic functions. The sodium salt of this complex is highly soluble in aqueous media and displays red luminescence which is efficiently quenched by oxygen to produce O2(1Δg) in a high quantum yield. Furthermore, due to its high radiodensity, the complex exhibits radioluminescence in aqueous media, with the same spectral features as for photoluminescence, indicating the production of O2(1Δg) upon X-ray irradiation. The uptake of the complex by Hep-2 and MRC-5 cells is negligible during the first hours of incubation, then considerably increases in connection with the hydrolysis of the apical ligands. The complex exhibits low toxicity in vitro and induces a radiotoxic effect, noticeable against cancerous Hep-2 cells but negligible against normal MRC-5 cells, at X-ray doses that do not affect cell viability otherwise. The first evaluation of in vivo toxicity of an Mo6 complex on a mouse model evidences a moderate and delayed toxic effect on kidneys, with an intravenous LD50 value of 390 ± 30 mg kg-1, possibly connected with hydrolysis-induced aggregation of the complex. Overall, this complex displays attractive features as a singlet oxygen radiosensitizer for X-PDT, highlighting the potential of transition metal cluster complexes towards this modality.
- MeSH
- fotochemoterapie * MeSH
- fotosenzibilizující látky MeSH
- molybden MeSH
- myši MeSH
- rentgenové záření MeSH
- singletový kyslík MeSH
- voda MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fotosenzibilizující látky MeSH
- molybden MeSH
- singletový kyslík MeSH
- voda MeSH
