Publications by authors named "Mickaël Tharaud"

13 Publications

  • Page 1 of 1

Polymeric Encapsulation of a Ru(II)-Based Photosensitizer for Folate-Targeted Photodynamic Therapy of Drug Resistant Cancers.

J Med Chem 2021 Apr 5;64(8):4612-4622. Epub 2021 Apr 5.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.

The currently used photodynamic therapy (PDT) photosensitizers (PSs) are generally associated with a poor cancer cell selectivity, which is responsible for some undesirable side effects. To overcome these problems, there is an urgent need for a selective drug delivery system for PDT PSs. Herein, the encapsulation of a promising Ru(II) polypyridine complex in a polymer with terminal folate groups to form nanoparticles is presented. While the Ru(II) complex itself has a cytotoxic effect in the dark, the encapsulation is able to overcome this drawback. Upon light exposure, the nanoparticles were found to be highly phototoxic in 2D monolayer cells as well as 3D multicellular tumor spheroids upon 480 or 595 nm irradiation. Importantly, the nanoparticles demonstrated a high selectivity for cancerous cells over noncancerous cells and were found to be active in drug resistant cancer cells lines, indicating that they are able to overcome drug resistances.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02006DOI Listing
April 2021

Detection of nanoparticles by single-particle ICP-MS with complete transport efficiency through direct nebulization at few-microlitres-per-minute uptake rates.

Anal Bioanal Chem 2021 Jan 24;413(3):923-933. Epub 2020 Nov 24.

Institut de physique du globe de Paris, CNRS, Université de Paris, 75005, Paris, France.

Measurement of nanoparticle (NP) concentration and size by single-particle inductively coupled plasma mass spectrometry (spICP-MS) usually requires the use of a NP reference material to determine the loss of NPs and/or ions during their transport from the sample solution to the detection system. The determination of this loss, qualified as nebulization efficiency (η) and/or transport efficiency (η), is time-consuming, costly and lacks reliability. Nebulization of the NPs directly into the plasma (without a spray chamber) results in η = 100% and is thus a promising strategy to avoid these calibration steps. In this work, we used the μ-dDIHEN introduction system: a demountable direct injection high-efficiency nebulizer (dDIHEN) hyphenated to a flow-injection valve and a gas displacement pump. For the first time with a continuous flow nebulizer, complete transport efficiency was reached (i.e. η = 100%). Operated at a very low uptake rate (as low as 8 μL min), the μ-dDIHEN accurately and reproducibly determined average diameters of Au-, Ag- and Pt-NPs, in full agreement with their reference values. It was also successfully tested for Au-NPs in complex matrices, such as surface waters. spICP-MS analyses with the μ-dDIHEN sample introduction system only require a dissolved standard calibration to determine NP average diameter (d in nm) and number concentration (N) from the simplified set of equations: [Formula: see text] and [Formula: see text]Graphical abstract.
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http://dx.doi.org/10.1007/s00216-020-03048-yDOI Listing
January 2021

Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as a Potential Chemotherapeutic Agent: From Synthesis to Studies.

J Med Chem 2020 05 7;63(10):5568-5584. Epub 2020 May 7.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France.

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely, () (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated with the catecholate moiety. Experimental evidence (., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of was then scrutinized and , and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00431DOI Listing
May 2020

Flow and fate of silver nanoparticles in small French catchments under different land-uses: The first one-year study.

Water Res 2020 Jun 23;176:115722. Epub 2020 Mar 23.

Université de Paris, Institut de physique du globe de Paris, CNRS, F-75005, Paris, France. Electronic address:

This study focused on surface waters from three small creeks, within the Seine River watershed, which are characterized by different land-uses, namely forested, agricultural and urban. Silver nanoparticles (Ag-NPs) in these waters were detected and quantified by single-particle ICPMS during one-year of monthly sampling. Their temporal and spatial variations were investigated. Ag-NPs, in the three types of surface water, were found to range from 1.5 × 10 to 2.3 × 10 particles L and from 0.4 to 28.3 ng L at number and mass concentrations, respectively. These values are in consistent with the very few previous studies. In addition, the role of factors driving process and potential sources are discussed with correlations between Ag-NPs concentrations and biogeochemical parameters, like dissolved organic carbon concentration and divalent cations concentrations. For the forested watershed NOM controls the stability (number and mass) of the Ag-NPs as recently observed in the field in lake water in Germany. In the case of the agricultural and urban watersheds major cations such as Ca would control the number and mass of Ag-NPs. Dilution processes are rejected as conductivity and Cl ions do not show significant correlations with Ag-NPs or other major geochemical parameters. The specific exportation rates of Ag-NPs for artificial, agricultural and forested areas were calculated based on the monthly data for the full year and are equal to 5.5 ± 3.0, 0.5 ± 0.3 and 0.2 ± 0.2 gykm, respectively. These data suggest a constant release of Ag-NPs from consumer products into freshwaters in artificial areas, for instance, from textiles, washing machines, domestic tap-water filters, outdoor paints. These first data of Ag-NPs fluxes in surface waters of France enlarge the very limited database of field measurements. Moreover, for the first time, the influence of time, land-use and aquatic geochemistry parameters on Ag-NPs in real natural water samples is reported. It is also helpful to further understand the fate and the process of Ag-NPs in natural waters, as well as to the ecotoxicity studies in real-world environment.
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http://dx.doi.org/10.1016/j.watres.2020.115722DOI Listing
June 2020

Synthesis, Characterization, Cytotoxic Activity, and Metabolic Studies of Ruthenium(II) Polypyridyl Complexes Containing Flavonoid Ligands.

Inorg Chem 2020 Apr 19;59(7):4424-4434. Epub 2020 Mar 19.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France.

Four novel monocationic Ru(II) polypyridyl complexes were synthesized with the general formula [Ru(DIP)flv]X, where DIP is 4,7-diphenyl-1,10-phenanthroline, flv stands for the flavonoid ligand (5-hydroxyflavone in [Ru(DIP)(5-OHF)](PF), genistein in [Ru(DIP)(gen)](PF), chrysin in [Ru(DIP)(chr)](OTf), and morin in [Ru(DIP)(mor)](OTf)), and X is the counterion, PF, and OTf ̅ (triflate, CFSO̅), respectively. Following the chemical characterization of the complexes by H and C NMR, mass spectrometry, and elemental analysis, their cytotoxicity was tested against several cancer cell lines. The most promising complex, [Ru(DIP)(gen)](PF), was further investigated for its biological activity. Metabolic studies revealed that this complex severely impaired mitochondrial respiration and glycolysis processes, contrary to its precursor, Ru(DIP)Cl, which showed a prominent effect only on the mitochondrial respiration. In addition, its preferential accumulation in MDA-MB-435S cells (a human melanoma cell line previously described as mammary gland/breast; derived from metastatic site: pleural effusion), which are used for the study of metastasis, explained the better activity in this cell line compared to MCF-7 (human, ductal carcinoma).
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http://dx.doi.org/10.1021/acs.inorgchem.9b03562DOI Listing
April 2020

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy.

J Am Chem Soc 2020 04 25;142(14):6578-6587. Epub 2020 Mar 25.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.
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http://dx.doi.org/10.1021/jacs.9b13620DOI Listing
April 2020

Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by Tuning the Electronic Structure of Dioxo Ligands.

J Am Chem Soc 2020 04 17;142(13):6066-6084. Epub 2020 Mar 17.

Department of Chemistry, University of Konstanz, Universitätsstrasse 10, D-78457 Konstanz, Germany.

Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely, Ru-sq ([Ru(DIP)(sq)](PF) (DIP, 4,7-diphenyl-1,10-phenanthroline; sq, semiquinonate ligand), we describe in this work a structure-activity relationship (SAR) study that involves a broader range of derivatives resulting from the coordination of different catecholate-type dioxo ligands to the same Ru(DIP) core. In more detail, we chose catechols carrying either an electron-donating group (EDG) or an electron-withdrawing group (EWG) and investigated the physicochemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep-red positively charged complexes - in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes and , on the other hand, are blue/violet neutral complexes, which carry an EWG-substituted dinegatively charged catecholate ligand. The biological investigation of complexes - led to the conclusion that the difference in their physicochemical properties has a strong impact on their biological activity. Thus, complexes - expressed much higher cytotoxicities than complexes and . Complex constitutes the most promising compound in the series and was selected for a more in depth biological investigation. Apart from its remarkably high cytotoxicity (IC = 0.07-0.7 μM in different cancerous cell lines), complex was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e., nucleus, lysosomes, mitochondria, and cytoplasm) is extremely advantageous in the search for a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its outstanding cytotoxicity, make complex a valuable candidate in the field of chemotherapy research. It is noteworthy that a preliminary biodistribution study on healthy mice demonstrated the suitability of complex for further in vivo studies.
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http://dx.doi.org/10.1021/jacs.9b12464DOI Listing
April 2020

A Maltol-Containing Ruthenium Polypyridyl Complex as a Potential Anticancer Agent.

Chemistry 2020 Apr 26;26(22):4997-5009. Epub 2020 Mar 26.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005, Paris, France.

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP) (sq)](PF ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP) (mal)](PF ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP) (mal)](PF ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP) (mal)](PF ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism.
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http://dx.doi.org/10.1002/chem.201904877DOI Listing
April 2020

A Multi-action and Multi-target Ru -Pt Conjugate Combining Cancer-Activated Chemotherapy and Photodynamic Therapy to Overcome Drug Resistant Cancers.

Angew Chem Int Ed Engl 2020 04 11;59(18):7069-7075. Epub 2020 Mar 11.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005, Paris, France.

Pt complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, Pt complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, Ru polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel Pt -Ru conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the Pt centre is reduced to Pt and the axial ligands including the Ru complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi-target and multi-action effect with (photo-)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids.
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http://dx.doi.org/10.1002/anie.201916400DOI Listing
April 2020

Single-cell determination of iron content in magnetotactic bacteria: implications for the iron biogeochemical cycle.

Environ Microbiol 2020 03 30;22(3):823-831. Epub 2019 Jun 30.

Department of Plant and Microbial Biology, University of California, Berkeley, California, 94720-3102, USA.

Magnetotactic bacteria (MTB) are ubiquitous aquatic microorganisms that mineralize dissolved iron into intracellular magnetic crystals. After cell death, these crystals are trapped into sediments that remove iron from the soluble pool. MTB may significantly impact the iron biogeochemical cycle, especially in the ocean where dissolved iron limits nitrogen fixation and primary productivity. A thorough assessment of their impact has been hampered by a lack of methodology to measure the amount of, and variability in, their intracellular iron content. We quantified the iron mass contained in single MTB cells of Magnetospirillum magneticum strain AMB-1 using a time-resolved inductively coupled plasma-mass spectrometry methodology. Bacterial iron content depends on the external iron concentration, and reaches a maximum value of ~10 ng of iron per cell. From these results, we calculated the flux of dissolved iron incorporation into environmental MTB populations and conclude that MTB may mineralize a significant fraction of dissolved iron into crystals.
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http://dx.doi.org/10.1111/1462-2920.14708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051126PMC
March 2020

Speciation and reactivity of lead and zinc in heavily and poorly contaminated soils: Stable isotope dilution, chemical extraction and model views.

Environ Pollut 2017 Jun 6;225:654-662. Epub 2017 Apr 6.

Institut de Physique du Globe de Paris, Sorbonne Paris Cité, Univ. Paris Diderot, UMR 7154, CNRS, 1 rue Jussieu, 75005 Paris, France. Electronic address:

Correct characterization of metal speciation and reactivity is a prerequisite for the risk assessment and remedial activity management of contaminated soil. To better understand the intrinsic reactivity of Pb and Zn, nine heavily and poorly contaminated soils were investigated using the combined approaches of chemical extractions, multi-element stable isotopic dilution (ID) method, and multi-surface modelling. The ID results show that 0.1-38% of total Pb and 3-45% of total Zn in the studied soils are isotopically exchangeable after a 3-day equilibration. The intercomparison between experimental and modelling results evidences that single extraction with 0.43 M HNO solubilizes part of non-isotopically exchangeable fraction of Pb and Zn in the studied soils, and cannot be used as a surrogate for ID to assess labile Pb and Zn pools in soil. Both selective sequential extraction (SSE) and modelling reveal that Mn oxides are the predominant sorption surface for Pb in the studied soils; while Zn is predicted to be mainly associated with soil organic matter in the soil with low pH and Fe/Mn oxides in the soils with high pH. Multi-surface modelling can provide a reasonable prediction of Pb and Zn adsorption onto different soil constituents for the most of the studied soils. The modelling could be a promising tool to decipher the underlying mechanism that controls metal reactivity in soil, but the submodel for Mn oxides should be incorporated and the model parameters, especially for the 2-pK diffuse layer model for Mn oxides, should be updated in the further studies.
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http://dx.doi.org/10.1016/j.envpol.2017.03.051DOI Listing
June 2017

Chemical signature of magnetotactic bacteria.

Proc Natl Acad Sci U S A 2015 Feb 26;112(6):1699-703. Epub 2015 Jan 26.

Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, Sorbonne Universités, Université Pierre et Marie Curie, UMR 7590 CNRS, Institut de Recherche pour le Développement UMR 206, Museum National d'Histoire Naturelle, 75252 Paris Cedex 05, France; and.

There are longstanding and ongoing controversies about the abiotic or biological origin of nanocrystals of magnetite. On Earth, magnetotactic bacteria perform biomineralization of intracellular magnetite nanoparticles under a controlled pathway. These bacteria are ubiquitous in modern natural environments. However, their identification in ancient geological material remains challenging. Together with physical and mineralogical properties, the chemical composition of magnetite was proposed as a promising tracer for bacterial magnetofossil identification, but this had never been explored quantitatively and systematically for many trace elements. Here, we determine the incorporation of 34 trace elements in magnetite in both cases of abiotic aqueous precipitation and of production by the magnetotactic bacterium Magnetospirillum magneticum strain AMB-1. We show that, in biomagnetite, most elements are at least 100 times less concentrated than in abiotic magnetite and we provide a quantitative pattern of this depletion. Furthermore, we propose a previously unidentified method based on strontium and calcium incorporation to identify magnetite produced by magnetotactic bacteria in the geological record.
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http://dx.doi.org/10.1073/pnas.1414112112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330721PMC
February 2015

Magnetic hyperthermia efficiency in the cellular environment for different nanoparticle designs.

Biomaterials 2014 Aug 9;35(24):6400-11. Epub 2014 May 9.

Laboratoire Matière et Systèmes Complexes, UMR 7057, CNRS and Université Paris Diderot, 75205 Paris Cedex 13, France. Electronic address:

Magnetic hyperthermia mediated by magnetic nanomaterials is one promising antitumoral nanotherapy, particularly for its ability to remotely destroy deep tumors. More and more new nanomaterials are being developed for this purpose, with improved heat-generating properties in solution. However, although the ultimate target of these treatments is the tumor cell, the heating efficiency, and the underlying mechanisms, are rarely studied in the cellular environment. Here we attempt to fill this gap by making systematic measurements of both hyperthermia and magnetism in controlled cell environments, using a wide range of nanomaterials. In particular, we report a systematic fall in the heating efficiency for nanomaterials associated with tumour cells. Real-time measurements showed that this loss of heat-generating power occurred very rapidly, within a matter of minutes. The fall in heating correlated with the magnetic characterization of the samples, demonstrating a complete inhibition of the Brownian relaxation in cellular conditions.
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http://dx.doi.org/10.1016/j.biomaterials.2014.04.036DOI Listing
August 2014