Josias Boumbéwendin

Gérard Yaméogo

Roseline Mazet

Denis Wouessidjewe

Luc Choisnard

Diane Godin-Ribuot

Jean-Luc Putaux

Rasmané Semdé

Annabelle Gèze
email: annabelle.geze@univ-grenoble-alpes.fr

Pharmacokinetic study of intravenously administered artemisinin-loaded surface-decorated amphiphilic -cyclodextrin nanoparticles

Keywords: Bioesterified γ-cyclodextrins, Artemisinin, Surface-decorated nanoparticles, Intravenous administration, Pharmacokinetic parameters, Healthy rats

Artemisinin and its derivatives are currently recommended by World Health Organization for the treatment of malaria. Severe malaria requires a parenteral administration of artemisinin-based formulations. However, the effective use of artemisinin is limited by the pharmacokinetic characteristics of the drug (low water solubility, poor bioavailability and short half-life). To overcome some of these drawbacks, artemisinin-loaded surface-decorated nanoparticles were prepared by conanoprecipitation of γ-cyclodextrin bioesterified with C 10 alkyl chains and polyethylene glycol (PEG) derivatives (polysorbate 80 and DMPE-mPEG2000). Using a single dose (1.5 mg.kg -1 or 2 mg.kg -1 ) by intravenous administration, we investigated the in vivo pharmacokinetic properties in healthy rats of two types of artemisinin-loaded nanoparticle formulations, namely, nanosphere and nanoreservoir systems versus ethanolic-aqueous solution of artemisinin as reference. Significantly enhanced pharmacokinetic parameters were obtained with artemisinin-loaded nanoparticles. In comparison to reference formulation, the geometric mean exposures in plasma (AUC 0-t ) exhibited 2.35 and 3.26-fold increases when artemisinin was loaded in nanoreservoir and nanosphere systems, respectively. Its plasma half-life increased 4.00 and 6.25-fold and its clearance decreased up to 2.5 and 4.72-fold.

Artemisinin was successfully administered intravenously by means of surface-decorated amphiphilic -cyclodextrin nanostructures and showed a longer elimination half-life with respect to an artemisinin solution in ethanol. Therefore, these systems are likely to provide significant advantages for the intravenous treatment of severe malaria.

Introduction

Malaria remains a leading cause of illness and mortality worldwide, with about 219 million cases and more than 435,000 deaths in 2017, largely in sub-Saharan Africa [1]. Artemisinin (ART) and its derivatives are powerful medicines known for their ability to swiftly reduce the number of Plasmodium parasites in the blood of patients with malaria [START_REF] Cui | Discovery, mechanisms of action and combination therapy of artemisinin[END_REF]. Artemisinin, a sesquiterpene lactone endoperoxide, is a natural compound isolated from the plant Artemisia annua [START_REF] White | Qinghaosu (artemisinin): the price of success[END_REF][START_REF] Zongru | Artemisinin anti-malarial drugs in China[END_REF][START_REF] Liu | Discovery and development of artemisinin and related compounds[END_REF][START_REF] Karunajeewa | Artemisinins: artemisinin, dihydroartemisinin, artemether and artesunate[END_REF]. It has received considerable attention in the last decade because of its strong antimalarial activity [START_REF] Cui | Discovery, mechanisms of action and combination therapy of artemisinin[END_REF][START_REF] White | Qinghaosu (artemisinin): the price of success[END_REF][START_REF] Ho | Artemisinins: pharmacological actions beyond anti-malarial[END_REF]. More recently, the antiprotozoal [START_REF] Saeed | Antischistosomal activity of artemisinin derivatives in vivo and in patients[END_REF][START_REF] Want | Therapeutic efficacy of artemisinin-loaded nanoparticles in experimental visceral leishmaniasis[END_REF], antibacterial [START_REF] Lin | Antibacterial mechanism of artemisinin / beta-cyclodextrins against methicillin-resistant Staphylococcus aureus (MRSA)[END_REF], antiviral [START_REF] Efferth | Beyond malaria: The inhibition of viruses by artemisinin-type compounds[END_REF] and anticancer [START_REF] Slezakova | Anticancer activity of artemisinin and its derivatives[END_REF][START_REF] Nosrati | Biotin-functionalized copolymeric PEG-PCL micelles for in vivo tumour-targeted delivery of artemisinin[END_REF] properties of artemisinin have also been described.

Despite its high efficacy in the treatment of several diseases, there are important matters of concern regarding ART physical and pharmacokinetic characteristics due to its low water solubility, poor bioavailability and short half-life [START_REF] White | Qinghaosu (artemisinin): the price of success[END_REF][START_REF] Zongru | Artemisinin anti-malarial drugs in China[END_REF][START_REF] Liu | Discovery and development of artemisinin and related compounds[END_REF][START_REF] Karunajeewa | Artemisinins: artemisinin, dihydroartemisinin, artemether and artesunate[END_REF]. In order to improve its pharmacokinetic properties, ART is incorporated into different drug delivery systems [START_REF] Ba | Design of drug delivery systems containing artemisinin and its derivatives[END_REF]. Among the studies, the association of ART in nanoparticles or liposomes has been considered to yield improved biological outcome of ART [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF][START_REF] Ibrahim | Artemisinin nanoformulation suitable for intravenous injection: Preparation, characterization and antimalarial activities[END_REF][START_REF] Isacchi | Artemisinin and artemisinin plus curcumin liposomal formulations: Enhanced antimalarial efficacy against Plasmodium berghei-infected mice[END_REF][START_REF] Neda | Effect of artemisinin liposome and artemisinin liposome polyethylene glycol on MCF-7 cell line[END_REF].

Nano-encapsulation of drugs is a useful technique applied in controlled and targeted delivery. There are many literature reports on the association of ART with various nanoparticle systems (lipid, polymer, inorganic or cyclodextrin-based) which resulted in improved drug stability, prolonged drug release and enhanced bioavailability [START_REF] Want | Therapeutic efficacy of artemisinin-loaded nanoparticles in experimental visceral leishmaniasis[END_REF][START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF][START_REF] Chen | Multifunctional mesoporous nanoparticles as pH-responsive Fe 2+ reservoirs and artemisinin vehicles for synergistic inhibition of tumor growth[END_REF]. Amphiphilic -cyclodextrin-based nanoparticles associating ART were previously investigated by our group in order to develop a parenteral formulation for the treatment of severe malaria [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF]. Cyclodextrin (CD) derivatives grafted with decanoic alkyl chains (CD-C 10 ) were prepared by a onestep bioesterification method previously described [START_REF] Choisnard | Physicochemical characterization of α-, β-and γ-cyclodextrins bioesterified with decanoate chains used as building blocks of colloidal nanoparticles[END_REF][START_REF] Choisnard | Novel nanoparticles of β-cyclodextrin esters obtained by self-assembling of bio-transesterified β-cyclodextrins[END_REF][START_REF] Choisnard | Miscellaneous nanoaggregates made of CD esters synthesized by an enzymatic pathway[END_REF][START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF]. Using the solvent displacement methodology, the derivatives yielded a variety of nanosphere or nanoreservoir-type systems with a size ranging from 70 to 220 nm [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF][START_REF] Choisnard | Physicochemical characterization of α-, β-and γ-cyclodextrins bioesterified with decanoate chains used as building blocks of colloidal nanoparticles[END_REF][START_REF] Choisnard | Novel nanoparticles of β-cyclodextrin esters obtained by self-assembling of bio-transesterified β-cyclodextrins[END_REF][START_REF] Choisnard | Miscellaneous nanoaggregates made of CD esters synthesized by an enzymatic pathway[END_REF][START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF]. These systems could be decorated with polyethylene glycol (PEG) derivatives such as PEG1500 stearate, DMPE-mPEG2000, PEG5000 and polysorbate 80 which can reduce opsonization and phagocytosis by the macrophage cells [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as potential artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles[END_REF][START_REF] Perret | Biodistribution and preliminary toxicity studies of nanoparticles made of biotransesterified β-cyclodextrins and PEGylated phospholipids[END_REF]. PEGylated surfacedecorated -CD-C 10 nanoparticles demonstrated non-hemolytic properties and increased blood circulation time reaching 24 h for nanospheres decorated with DMPE-mPEG2000 [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as potential artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles[END_REF]. The PEGylated β-CD-C 10 nanospheres also presented an increased circulation time after intravenous injection, particularly when nanoparticles were surface decorated by PEG5000. These nanosystems caused neither acute nor extended acute toxicity [START_REF] Perret | Biodistribution and preliminary toxicity studies of nanoparticles made of biotransesterified β-cyclodextrins and PEGylated phospholipids[END_REF] following repeated intraperitoneal injections.

Both types of and -CD-C 10 nanostructures were able to associate ART. The formulation parameters were optimized to reach stable and high ART dosage corresponding to drug levels of 0.3 and 1.6 mg.mL -1 in the colloidal suspension, for the -CD-C 10 -based sphere and reservoir-type nanosystems, respectively. They showed a sustained in vitro release profiles of drug over 240 and 96 h, respectively.

In vitro antimalarial activity was evaluated using the plasmodium-lactate dehydrogenase assay. ARTloaded nanoparticles inhibited the growth of cultured Plasmodium falciparum, both multi-resistant K1 and susceptible 3D7 strains with IC 50 values of 2.8 and 7.0 ng.mL -1 close to those of the reference ART solution [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF]. The results of these previous studies highlight promising alternative formulation for injectable use of ART. The current study investigated the in vivo pharmacokinetics of ART-loaded surface-decorated amphiphilic -CD nanodevices after intravenous single dose administration.

Materials and methods

Materials

The -CD-C 10 fatty ester (M w = 2714 g.mol -1 , total degree of substitution = 9.2) was synthesized in our laboratory by a one-step bioesterification method. Artemisinin (C 15 H 22 O 5 , 98%, M w = 282.3 g.mol -1 ) was purchased from Carl Roth (GmbH). Montane ® 80 (sorbitan mono-oleate) and Montanox ® 80 (polysorbate 80, ethoxylated sorbitan mono-oleate) of pharmaceutical grade were kindly provided by Seppic (Castres, France). Benzyl benzoate was supplied by Cooper (Melun, France).

Dimyristoylphosphatidylethanolamine-polyethylene glycol 2000 (DMPE-mPEG2000) was obtained from Corden Pharma (Eichenweg, Switzerland). Water was freshly deionized in our laboratory.

Preparation of colloidal suspensions

γ-CD-C 10 -based nanosphere and nanoreservoir suspensions were prepared using the solvent displacement technique [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF]. This method consists in injecting, under magnetic stirring (500 rpm) at 25 °C, an organic solution (10 mL) of both amphiphilic and lipophilic constituents into an aqueous phase containing Montane® 80. The organic solvent is eliminated under reduced pressure and the resulting aqueous suspension of nanoparticles were concentrated to the desired final volume in the same way [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF][START_REF] Choisnard | Physicochemical characterization of α-, β-and γ-cyclodextrins bioesterified with decanoate chains used as building blocks of colloidal nanoparticles[END_REF][START_REF] Choisnard | Novel nanoparticles of β-cyclodextrin esters obtained by self-assembling of bio-transesterified β-cyclodextrins[END_REF][START_REF] Choisnard | Miscellaneous nanoaggregates made of CD esters synthesized by an enzymatic pathway[END_REF][START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF]. The resulting colloidal suspensions were purified by gel chromatography using Sephadex® G-75 columns (Sigma Aldrich, Sweden) in order to remove free PEGylated phospholipids in the supernatant. Prior to the administration to animals, the suspensions were isotonized with a glucose solution.

Physicochemical characterization of the nanosystems

The mean size, polydispersity index (PI) and zeta potential were determined after appropriate dilution using a Zetasizer (Nano Series DTS 1060, Malvern Instruments) [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF][START_REF] Choisnard | Physicochemical characterization of α-, β-and γ-cyclodextrins bioesterified with decanoate chains used as building blocks of colloidal nanoparticles[END_REF][START_REF] Choisnard | Novel nanoparticles of β-cyclodextrin esters obtained by self-assembling of bio-transesterified β-cyclodextrins[END_REF][START_REF] Choisnard | Miscellaneous nanoaggregates made of CD esters synthesized by an enzymatic pathway[END_REF][START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF]. The nanosystems were observed by transmission electron microscopy (TEM) after negative staining of the preparations with uranyl acetate or by cryo-TEM after quench-freezing of a thin film of particle suspension in liquid ethane. Both types of preparations were observed at room and low temperature, respectively, with a FEI-Philips CM200 'Cryo' microscope operating at 80 kV. The images were recorded on Kodak SO163 films [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF][START_REF] Choisnard | Physicochemical characterization of α-, β-and γ-cyclodextrins bioesterified with decanoate chains used as building blocks of colloidal nanoparticles[END_REF][START_REF] Choisnard | Novel nanoparticles of β-cyclodextrin esters obtained by self-assembling of bio-transesterified β-cyclodextrins[END_REF][START_REF] Choisnard | Miscellaneous nanoaggregates made of CD esters synthesized by an enzymatic pathway[END_REF][START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF]. The osmolarity was also measured in triplicate with an automatic microosmometer Loser Messtechnik type 15. The density of the nanoparticles in the suspension was determined using isopycnic centrifugation of Percoll gradients in iso-osmotic sucrose as previously described (0.25 M) at a ratio of 1:9 (v/v) [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as potential artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles[END_REF]. The total concentration of ART recovered in the colloidal suspensions (Ct) and the ART concentration in ultracentrifuged supernatant (Cs) were determined, after a sample dilution with methanol, by HPLC (Varian Prostar pump; Kromasil C 18 column 250 4.6 mm, 5µm particle size from Supelco Inc.) coupled to evaporative light scattering detection (ELSD Sedex Model 55, Touzart & Matignon, France) as previously described [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF]. The drug recovery DR (%) and the drug association DA (%) were estimated as follows: DR (%) = Ct/Ci x100 where Ci is the theoretical drug concentration (initially introduced in the formulation), DA (%) = (Ct -Cs)/Ct x100. The colloidal stability of all the freshly made -CD-C 10 nanoparticle suspensions loaded with ART (nanospheres and nanoreservoirs) were systematically tested in electrolyte medium (0.09% NaCl or PBS, pH 7.4). The diluted suspensions were then subjected to moderate stirring (100 rpm) at 37 °C and their particle size and polydispersity index (PI) were determined after 48 h. The suspensions were also stored at room temperature during 24 months and their stability was evaluated in terms of appearance, particle size, polydispersity index and ART concentration.

Animal experiments

The animal experimental protocol was approved by the University of Grenoble Animal Ethics Committee. A total of 72 male 8 week-old Wistar rats (weight 280-340 g) obtained from Janvier Laboratory (Le Genest-Saint Isle, France) were used. The animals were housed under standardized conditions of food, temperature (21 ± 1 °C) and hygrometry and exposed to a regular light/dark schedule (12 h/12 h) in strict accordance with French Ministry of Agriculture regulations. All animals were kept in these conditions for one week and were divided randomly into three experimental groups, referred to as groups I, II and III.

Animals were individually weighed and anesthetized with Isoflurane 2 % (Nicholas Piramal, London, England), then placed in dorsal decubitus to insert a sterile catheter into the right carotid. Catheters were filled with heparinized physiological NaCl solution (heparin Choay ® 25 000 UI/5 mL, Léo Laboratory, France) to prevent their obstruction [START_REF] Thrivikraman | Jugular vein catheterization for repeated blood sampling in the unrestrained conscious rat[END_REF].

ART formulations were then administered to rats via the caudal vein (single administration at the rate 0.8 mL.min -1 ). Groups I and II were administrated 1.5 mg.kg -1 of ART-loaded DMPE-mPEG2000/-CD-C 10 nanospheres and 2 mg.kg -1 of ART-loaded polysorbate 80/-CD-C 10 nanoreservoirs, respectively. Group III was treated with 2 mg.kg -1 of reference formulation, i.e. ART in a glucose aqueous solution containing 10% ethanol.

After injection, blood samples (600 µL) were taken from the rat via the catheter placed in the right carotid. Blood samples were serially collected in heparinized tubes at each point (six rats per point): baseline (0 min), 5 and 15 min, 1, 2, 4, 6, 8 and 24 h, respectively after iv administration. The sample were then immediately centrifuged at 5000 rpm for 10 min at 4 °C and the supernatant plasma collected and stored at -20 °C until analysis. To optimize blood sampling, the rats of each experimental group G1, G2 and G3 were distributed in three sampling series named P1, P2 and P3.

The blood samples were taken at 0, 5, 15, 60, 120 min with the rats of the P1 sampling series, those at times 6 and 8 h with the P2 series and 24 h with the P3 series. Thus, the total amount of blood taken from each rat did not exceed 3,000 µL (i.e. 1/7 th of the total blood volume of rats).

To minimize the risks of hypovolemia, an equivalent volume (600 µL) of heparinized physiological solution (0.09 % NaCl) was administered after each blood sampling. The hematocrit of each sample was also checked to control the absence of hemodilution.

Quantification of ART in the plasma

ART was quantified in the plasma by using a HPLC-ELSD method after preliminary extraction following a procedure described by Ashton et al. with minor modifications [START_REF] Avery | Rapid determination of artemisinin and related analogues using high-performance liquid chromatography and an evaporative light scattering detector[END_REF][START_REF] Ashton | Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses[END_REF][START_REF] Lapkin | Development of HPLC analytical protocols for quantification of artemisinin in biomass and extracts[END_REF]. 600 µL of phosphate buffer (0.3 M, pH 3.5) and 60 µL of hydrogen peroxide (H 2 O 2 , 30 %) were added to 300 µL of each plasma sample to precipitate proteins. The resulting mixture was plunged into ice-bath in which it was submitted to magnetic stirring for 15 min. Exactly 2.4 mL of hexane/n-butanol (94:6 v/v) solution was then added to the solution to extract ART. After centrifugation at 5000 rpm for 10 min at 4 °C, the organic phase (2 mL) was transferred into another tube and dried with nitrogen gas. The residue obtained was reconstituted in 200 µL of methanol (HPLC mobile phase), vortexed for 2 min and filtrated by using nylon filter. Finally, an aliquot of 5 µL for each preparation was injected into the HPLC-ELSD system for ART quantification analysis.

Data analysis

The pharmacokinetic parameters of ART after intravenous administration were determined from the obtained plasma concentration-time data by using non-compartmental pharmacokinetic analyses by Macro-Excel software. The trapezoidal method was used to calculate the area under the curve (AUC) of plasma concentration as a function of time and the total area under the first moment curve up to last time point (AUC 0→t ). The area under the curve of the plasma concentrations to the first moment up to infinite time (AUC 0-∞ ) is obtained by extrapolation on the lower limits. Delta AUC represents the value of the extrapolation. The elimination rate constant (k e ) was calculated by the semi-logarithmic regression analysis from the slope of the line. The half-life (t 1/2 ) of the drug was obtained by dividing 0.693 by k e . The total clearance was calculated by dividing the dose administered by AUC 0-∞ . The volume of distribution was calculated using the equation Vd = CL/k. The maximum plasma concentration (C max ) and the time to reach this maximum (T max ) were directly determined. The plasma concentration values as a percentage of the injected dose were also calculated. All data are expressed as mean value ± standard deviation (SD). Statistical analyses were performed using one-way ANOVA test, and the level of significance was set at 5%.

Results and discussion

Physicochemical characterization of ART-loaded surface-decorated -CD-C 10 nanoparticles

ART was loaded in PEGylated surface-decorated -CD-C 10 nanoparticles via a co-nanoprecipitation process. The size distribution (mean size and polydispersity index PI), zeta potential (ζ), density and drug content of nanospheres and nanoreservoirs are reported in Table 1. The colloidal systems were characterized by a mean size of 90 nm for nanospheres and 190 nm for nanoreservoir systems, both suitable for intravenous injection. The nanoparticle density was in the range of blood density. Both nanosuspensions had sufficient and stable charge loading in ART corresponding to drug levels reaching 0.48 and 1.65 mg.mL -1 for nanospheres and nanoreservoirs, respectively. These concentrations correspond to an increase of ART dose dissolved in aqueous medium by a factor of 7.5 and 25.8, respectively. The ART amount in the colloidal suspensions correspond to drug recovery (DR) close to 95 % in both systems and drug association (DA) of 88 % for nanospheres and 96% for nanoreservoir systems. In the case of nanoreservoirs, ART is mainly located in the lipophilic inner core of nanoparticles made of benzyl benzoate due to the high solubility of the drug in this medium (83 mg.mL -1 at 25 °C) as compared to the low ART hydrosolubility (0.06 mg.mL-1 at 25 °C) [START_REF] Ba | Design of drug delivery systems containing artemisinin and its derivatives[END_REF]. In the case of nanospheres, it was assumed that there are several sites for the drug location within the nanostructures. It is also quite likely that part of the drug interacts with the cavity of -CD-C 10 . It is well known that the solvent displacement technique allows to associate significant amounts of drug with a large part that is adsorbed on the surface. No ART desorption was observed with time indicating that ART does not form stacking layers at the nanosphere surface. The formulation conditions were previously optimized [START_REF] Ba | Design of drug delivery systems containing artemisinin and its derivatives[END_REF][START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF] in order to avoid this phenomenon. Here again, the low ART water solubility is in favour of an ART loading in -CD-C 10 based nanoparticles. The physicochemical characteristics of ART-loaded surface-decorated nanoparticles were in good agreement with our previous studies [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as potential artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles[END_REF] which showed that the introduction of the PEGylated phospholipid in the formulation induced a slight increase in average diameter and a stronger negative zeta potential values (about -20 and -30 mV for DMPE-PEG2000-coated -CD-C 10 nanospheres and nanoreservoirs, respectively). The slight increase in particle size was in favor of the presence of the hydrophilic PEG corona and the apparent electric negative charge may be attributed to the presence of phosphatidyl negative charge of the phospholipid moiety.

Table 1

Physicochemical characteristics of ART-loaded surface-decorated γ-CD-C 10 nanospheres and nanoreservoirs (mean ± SD, n = 3). Figure 1 shows TEM and cryo-TEM images of negatively stained and ice-embedded nanoparticle preparations, respectively. As previously reported [START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF], the shape of dried nanoreservoirs is not well defined due to the deformation and flattening of the liquid-like particles on the carbon film (Fig. 1A).

Formulation

The ice-embedded nanoreservoirs appear as electron-dense spherical particles with a diameter ranging from 70 to 200 nm (Fig. 1C), in good agreement with the DLS data. In comparison, the γ-CD-C 10 nanospheres are slightly facetted solid particles that did not deform upon drying since their size distribution (20-100 nm in diameter) is similar in images of dry (Fig. 1B) and ice-embedded (Fig. 1D) specimens.

As seen in Figure 2, ART-loaded nanospheres and nanoreservoirs stored at ambient temperature presented a good physical stability at 24 months. The amount of entrapped drug remained stable as well during this period (0.48 and 1.64 mg.mL -1 for ART loaded nanospheres and nanoreservoirs respectively). Moreover, after dilution in electrolyte medium, the nanoparticle size and polydispersity of both nanosuspensions were unchanged after 48 h, indicating the absence of aggregation over time.

In vivo pharmacokinetic study of ART-loaded surface decorated -CD-C 10 nanostructures

The pharmacokinetic study has been conducted in order to find out whether there was any enhancement in the bioavailability of ART from ART-loaded surface-decorated γ-CD-C 10 nanoparticles. The reference solution was injected at a dose of 2 mg.kg -1 . In the case of nanoreservoirs, the animals received a 400 µL injection corresponding to a similar dose of 2 mg.kg -1 . However, in the case of nanosphere suspensions, the ART dose injected in animals was slightly lower. Indeed, the maximum injectable volume in rats (800 µL) made it possible to reach a maximum dose of 1.5 mg.kg - 1 . The amount of blood sample taken from the rat (about 14 % of the total blood volume) cannot affected the pharmacokinetic experiment. Indeed, it is recognized that no more than 20% of the total blood volume should be taken at one time or within 14 days in animal. In addition, the values of the The pharmacokinetic profiles of ART were determined using the rat plasma concentration-time curve obtained after intravenous administration of ART loaded nanospheres and nanoreservoirs. The mean plasma concentration-time profiles are presented in Figure 2 and their corresponding pharmacokinetic parameters are shown in Table 2.

From Figure 3, the ART reference solution displayed higher initial mean plasma concentration with an observed C max of 15.92 µg.mL -1 after 5 min of administration of a dose of 2 mg.kg -1 against 11.50 µg.mL -1 and 10.12 µg.mL -1 after 5 min administration of 2 mg.kg -1 of ART-loaded nanoreservoirs and 1.5 mg.kg -1 of ART-loaded nanosphere suspensions, respectively. The initial plasma concentration level of ART-loaded nanoparticles corresponds to approximately 30 and 45% of the injected dose, respectively, for nanoreservoir and nanosphere suspensions. These levels were correlated with the previous in vitro release data which showed a burst effect corresponding to 32 and 50% of dissolved drug in the tested release medium after 30 min for nanoreservoir and nanosphere suspensions respectively [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF].

The concentration of ART in all formulations showed an expected declining trend. The ART from the reference solution was rapidly eliminated from the plasma and was no longer detectable after 2 h (halflife = 0.81 ± 0.1 h). It can be mentioned that a plasma half-life of the same order (0.85-1.17 h and 0.5 h) was obtained by Dai et al. [START_REF] Dai | Comparison of in vitro/in vivo blood distribution and pharmacokinetics of artemisinin, artemether and dihydroartemisinin in rats[END_REF] and Ashton et al. [START_REF] Ashton | Quantitative in vivo and ex vivo sex difference in artemisinin metabolism in rats[END_REF] after an intravenous administration of a methanol solution (10 mg.kg -1 ) and aqueous emulsion (20 mg.kg -1 ) of ART to rats. The plasma halflife of ART after oral administration was also in the same range (0.76-2.21 h) [START_REF] Ashton | Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses[END_REF][START_REF] Dai | Comparison of in vitro/in vivo blood distribution and pharmacokinetics of artemisinin, artemether and dihydroartemisinin in rats[END_REF]. ART-loaded nanosystems displayed a marked improvement in the circulation behavior over time as compared to the ART solution. The mean plasma concentrations of the ART in nanosuspensions gradually decreased to a level corresponding to the limit of quantification of the employed HPLC method (2.8 µg.mL -1 ), after 6 h (nanoreservoirs) and 8 h (nanospheres). The mean concentrations detected in this last point correspond to approximately 10 and 13% of the administered dose, respectively.

The first pharmacokinetic goal in malaria treatment is to achieve a fast onset of action with a sufficient concentration of antimalarial at the shortest possible time to clear parasite load effectively. The IC 50 value of 7.0 ng.mL -1 was considered for antimalarial action of ART [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF]. The initial plasma concentrations of ART obtained were above the IC 50 value. Despite the decrease over time, plasma concentrations of ART (10 to 3 µg.mL -1 ) also remained above the IC 50 value, 6 and 8 h after intravenous administration of 2 mg.kg -1 of ART-loaded nanoreservoirs and 1.5 mg.kg -1 of ART-loaded nanospheres, respectively.

The plasma concentration-time profiles obtained with ART-loaded nanostructures were biphasic with a rapid distribution and a slowed elimination phases in comparison to ART reference solution. The plasma half-life of ART from nanoreservoirs and nanospheres formulations were 3.23±0.16 and 5.03±0.24 h, respectively. In comparison with ART reference solution, the plasma half-life values increased by 4.00 and 6.25-fold for γ-CD-C 10 nanoreservoirs and nanospheres, respectively. This clearly indicated that ART-loaded surface-decorated amphiphilic -CD-C 10 nanoparticles remained in the blood stream as previously observed [START_REF] Gèze | Colloidal systems made of biotransesterified cyclodextrins grafted with C10 alkyl chains[END_REF] thus allowing nanostructures to release ART in the blood in a sustained manner. The mean plasma half-life of ART from γ-CD-C 10 /DMPE-mPEG2000 nanospheres was 1.56-fold higher than that of γ-CD-C 10 /polysorbate 80 nanoreservoirs, despite the greater C max obtained with nanoreservoir suspensions.

These results make it possible to meet the main objective of associating ART to nanodevices which is to improve drug plasma half-life and its bioavailability. Isacchi et al. [START_REF] Isacchi | Conventional and long-circulating liposomes of artemisinin: preparation, characterization, and pharmacokinetic profile in mice[END_REF] observed half-life times of 0.38, 0.67 and 2.02 h after intra-peritoneal administration in mice of ART (10 mg.kg -1 ) solubilized in DMSO (10 % v/v) or associated to conventional or PEGylated liposomes, respectively. However, the half-life values obtained with PEGylated liposomal formulations (2.02 h) [START_REF] Isacchi | Conventional and long-circulating liposomes of artemisinin: preparation, characterization, and pharmacokinetic profile in mice[END_REF] were below that obtained with both γ-CD-C 10 -based nanoparticles. Similar bioavailability improvement conclusions can be drawn from Table 2, that shows the pharmacokinetic parameters associated to γ-CD-C 10 /DMPE-mPEG2000 nanospheres, γ-CD-C 10 /polysorbate 80 nanoreservoirs and reference ART solution.

The plasma clearance of ART from the reference solution, ART-loaded γ-CD-C 10 /polysorbate 80 nanoreservoirs and ART-loaded γ-CD-C 10 /DMPE-mPEG2000 nanospheres were respectively 34.88±1.33 L.h -1 , 13.79±0.77 L.h -1 and 7.40±0.37 L.h -1 showing that surface-decorated γ-CD-C 10 nanostructures were able to increase the residence time of drug in the plasma resulting in slow elimination from the blood stream. The ART clearance in both nanoparticle formulations decreased up to 2.5 and 4.72-fold, respectively. As can be seen, the ART clearance is significantly (p< 0.01) reduced with the nanospheres compared to nanoreservoirs suggesting a higher hepatic extraction of nanoreservoirs. This result is consistent with the biodistribution data which showed a better vascular remanence with γ-CD-C 10 /DMPE-mPEG2000 nanospheres [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as potential artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles[END_REF]. The data summarized in Table 2 show that pharmacokinetic parameters such as t 1/2 , AUC, CL, etc., are significantly different between -CD-C 10 nanoparticle suspensions and the ART reference solution at p < 0.05. Significantly higher geometric mean plasma exposures (AUC 0-t ) (p < 0.01) compared to reference formulation were observed with the ART-loaded surface decorated γ-CD-C 10 nanoreservoir and nanosphere particles resulting in a 2.35 and 3.26-fold increase, respectively. All pharmacokinetic parameters evidenced that both nanostructures of -CD-C 10 protect ART from rapid elimination, with respect to longer mean residence time, decreased Vd and CL values in comparison to the ART reference solution. The pharmacokinetic parameters illustrate the effectiveness of surface-decorated -CD-C 10 nanoparticles as a potential injectable delivery system for ART. The enhanced pharmacokinetic parameters (Cmax and t 1/2 ) similar to those observed with ART-loaded surface decorated γ-CD-C 10 nanoreservoirs were obtained by Manjili et al. [START_REF] Manjili | In vitro and in vivo delivery of artemisinin loaded PCL-PEG-PCL micelles and its pharmacokinetic study[END_REF] after a single dose intravenous injection in rats of 25 mg.kg -1 of ART-loaded poly (-caprolactone)-poly (ethylene glycol)-poly (caprolactone, PCL-PEG-PCL) micelles. However, in the case of ART-loaded nanospheres, t 1/2 reached 5 h, which was slightly higher than the value obtained with copolymer micelles described by Manjili et al. [START_REF] Manjili | In vitro and in vivo delivery of artemisinin loaded PCL-PEG-PCL micelles and its pharmacokinetic study[END_REF]. Moreover, the ART mean plasma exposures (AUC 0-t ) are significantly higher with both nanoreservoirs and nanospheres systems as compared to ART-loaded PCL-PEG-PCL micelles, despite an ART administered dose 10 fold higher than the one we used. This suggested a gradual drug release in the early hours from injected ART loaded -CD-C 10 nanocarriers (either nanoreservoirs or nanospheres) that allows effective drug plasma concentrations to be maintained thanks to the persistent nature of nanoparticles in the blood [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as potential artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles[END_REF]. These results indicate that there is little loss of ART after intravenous injection aptly linked to their association with -CD-C 10 nanocarriers, considering that a drug fraction remains associated to the nanocarriers. It should be noted that ARTloaded DMPE-mPEG2000/-CD-C 10 nanospheres displayed better improved pharmacokinetic profiles compared to polysorbate 80/-CD-C 10 nanoreservoirs. These results may be partly explained by the release kinetics of ART in vitro [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers. I: Formulation, lyoavailability and in vitro antimalarial activity assessment[END_REF] as well as the biodistribution features specific to each nanosystem [START_REF] Yaméogo | Self-assembled biotransesterified cyclodextrins as potential artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles[END_REF]. The overall behaviour of nanoparticles is rather conducive to effective management of severe malaria.

Besides the pharmacokinetic study, the hematocrit levels measured on each blood sample remained constant, indicating that the intravenous administration of the drug-loaded nanodevices did not cause any lysis of the red blood cells. Indeed, the hematocrit rates measured in the blood samples collected before after each injection were constant, around 34-35%. These additional data indicate that the injection of nanosuspensions was relatively well tolerated taking into account our experimental conditions.

Conclusion

The present comparative pharmacokinetic study in healthy rats shows that ART-loaded surfacedecorated -CD-C 10 nanoparticles suspensions displayed improved pharmacokinetic properties after single intravenous administration. The results showed that -CD-C 10 nanostructures are able to maintain ART plasma concentrations above the therapeutically relevant concentration for a minimum period of 6 and 8 h, for ART-loaded polysorbate 80/-CD-C 10 nanoreservoirs and ART-loaded DMPE-mPEG2000/-CD-C 10 nanospheres, respectively. However, the nanosphere-type system exhibited improved pharmacokinetic characteristics compared to those of the reservoir-type. This study is in agreement with our previous observations and highlights the potential of surface-decorated -CD-C 10 nanoparticles as intravenous ART delivery system in the perspective of therapeutic management of severe malaria. Further in vivo explorative studies will establish a good correlation and support the pharmacokinetics data.

Figure 1 .

 1 Figure 1. TEM and cryo-TEM images of negatively stained (A,B) and ice-embedded (C,D) ART-loaded polysorbate 80/-CD-C 10 nanoreservoirs (A,C) and ART-loaded DMPE-mPEG2000/γ-CD-C 10 nanospheres (B,D). Bars: 200 nm.

Figure 2 .

 2 Figure 2. Mean particle sizes of ART-loaded polysorbate 80/-CD-C 10 nanoreservoirs and ART-loaded DMPE-mPEG2000/γ-CD-C 10 nanospheres after 24 months storage at ambient temperature and after 48 h in 0.09% NaCl or PBS pH 7.4 solutions (mean ± SD, n = 3).

  dilution in PBS After 48 Hrs dilution in 0.9 % NaCl hematocrit determined at each sample give good indications concerning the physiological state of the animal.

Figure 3 .

 3 Figure 3.Mean plasma concentration-time profiles of ART after single intravenous dose (n = 8) of (A) 2 mg.kg -1 of ART-loaded polysorbate 80/-CD-C 10 nanoreservoirs and ART solution in 10% ethanol; (B) 1.5 mg.kg -1 of ART-loaded DMPE-mPEG2000/-CD-C 10 nanospheres (mean ± SD, n = 3).

Table 2 .

 2 Pharmacokinetic parameters of artemisinin after intravenous administration of ART-loaded polysorbate 80/-CD-C 10 nanoreservoirs (2 mg.kg -1 ), ART-loaded DMPE-mPEG2000/-CD-C 10 nanospheres (1.5 mg.kg -1 ) and ART solution in 10% ethanol.

	Pharmacokinetic	ART (in 10% ethanol	ART-loaded polysorbate	ART-loaded DMPE-mPEG2000/-
	parameters AUC 0-t (µg.h.mL -1 ) AUC 0-inf (µg.h.mL -1 )	solution) 12.04 ± 0.49 15.43 ± 0.52	80/-CD-C 10 nanoreservoirs 28.19 ± 1.00 41.34 ± 2.31	CD-C 10 nanospheres 39.14 ± 2.31 60.83 ± 3.11
	delta AUC	3.39 ± 0.14	13.15 ± 1.53	21.70 ± 1.93
	% de delta AUC	28.18 ± 1.49	46.66 ± 4.48	55.44 ± 5.67
	t 1/2 (h)	0.81 ± 0.10	3.23 ± 0.16	5.03 ± 0.24
	k e C max (µg.mL -1 ) CL (L.h -1 )	0.89 ± 0.01 15.92 ± 0.71 34.88 ± 1.33	0.21 ± 0.01 11.50 ± 0.31 13.79 ± 0.77	0.14 ± 0.01 10.12 ± 0.31 7.40 ± 0.37
	Vd (L)	39.16 ± 1.57	64.31 ± 1.65	53.68 ± 1.26

Acknowledgments

The authors thank Christine Brunet-Manquat, Delphine Levilly (DPM), and Emeline Lemarie (HP2) for their technical assistance, as well as the NanoBio-ICMG Platform (FR 2607, Grenoble) for granting access to the Electron Microscopy facility. We also thank the French Embassy in Burkina Faso for the financial support of J.B.G. Yaméogo. This work has also been partially supported by grants from Agence Nationale de la Recherche (grant #ANR-11-BS10-0007) and LabEx ARCANE (ANR-11-LABX-0003-01).


J P P Zhao

W Y Y Hernández

W J J Zhou

E.I. I Y Yang

M Vovk

Negar Wu

M Naghavi

V Capron

Ordomsky

W Y Hern Ández

E I Vovk

M Wu

N Naghavi

M Capron

V Ordomsky

W Y Hernández

Nanocell type

Keywords: oxidation, alcohols, Ru, quinone, nanocell

come

Introduction

The selective oxidation of alcohols to versatile intermediates for the production of chemicals such as aldehydes and ketones remains a challenging task in the industry. It is of special interest the utilization of molecular oxygen as the green oxidant in the presence of a heterogeneous catalyst, thus favoring the atom economy in contrast to the use of toxic and expensive stoichiometric oxidants [START_REF] Steven | Activation through impregnation. Permanganate-coated solid supports[END_REF][START_REF] Muzart | Chromium-Catalyzed Oxidations in Organic Synthesis[END_REF][START_REF] Perree | Manganese Porphyrin-catalysed Oxidation of Olefins to Ketones by Molecular Oxygen[END_REF][START_REF] Uyanik | Hypervalent Iodine-mediated Oxidation of Alcohols[END_REF][START_REF] Satoshi | A New and Facile Method for the Direct Preparation of α-Hydroxycarboxylic Acid Esters from α,β-Unsaturated Carboxylic Acid Esters with Molecular Oxygen and Phenylsilane[END_REF].

Different heterogeneous catalytic systems based on Pt [START_REF] Zhai | Plasmon-Driven Selective Oxidation of Aromatic Alcohols to Aldehydes in Water with Recyclable Pt/TiO2 Nanocomposites[END_REF][START_REF] Ilyas | Liquid-Phase Aerobic Oxidation of Benzyl Alcohol Catalyzed by Pt/ZrO2[END_REF][START_REF] Xie | Influence of Dioxygen on the Promotional Effect of Bi during Pt-Catalyzed Oxidation of 1,6-Hexanediol[END_REF], Pd [START_REF] Hackett | Highactivity, single-site mesoporous Pd/Al2O3 catalysts for selective aerobic oxidation of allylic alcohols[END_REF][START_REF] Parlett | Support-Enhanced Selective Aerobic Alcohol Oxidation over Pd/Mesoporous Silicas[END_REF], Au [START_REF] Zhao | An excellent Au/meso-γ-Al2O3 catalyst for the aerobic selective oxidation of alcohols[END_REF][START_REF] Tanaka | Preparation of Au/CeO2 exhibiting strong surface plasmon resonance effective for selective or chemoselective oxidation of alcohols to aldehydes or ketones in aqueous suspensions under irradiation by green light[END_REF] have been reported for oxidation of alcohols. Among metallic catalysts, Ru has shown to be quite efficient in oxidation reactions [START_REF] Nie | Efficient aerobic oxidation of 5-hydroxymethylfurfural to 2,5diformylfuran on supported Ru catalysts[END_REF][START_REF] Wang | Aerobic oxidation of secondary alcohols via ruthenium-catalysed hydrogen transfer involving a new triple catalytic system[END_REF][START_REF] Zhao | Selective oxidation of alcohols to carbonyl compounds over small size colloidal Ru nanoparticles[END_REF]. However, low selectivity to aldehydes or ketones over heterogeneous catalysts is still a challenging problem due to formation of corresponding acids and esters [START_REF] Schmidt | TPAP-Catalyzed Direct Oxidation of Primary Alcohols to Carboxylic Acids through Stabilized Aldehyde Hydrates[END_REF]. The oxidation mechanism for metallic catalysts usually follows an oxidative dehydrogenation pathway, where both abstraction of hydrogen from alcohols and oxygen reduction processes (regeneration of the active site) simultaneously occur on the metal surface [START_REF] Hernandez | Electrochemically-assisted NOx storage-reduction catalysts[END_REF]. The aldehydes can be further oxidized over the same active sites to acids with decrease of the selectivity and J o u r n a l P r e -p r o o f generation of waste products. In general, these catalysts are very efficient in the selective oxidation of activated alcohols (e.g. benzyl and allyl alcohols) but less active and selective for oxidation of aliphatic primary alcohols [START_REF] Adair | Oxidant-free oxidation: ruthenium catalysed dehydrogenation of alcohols[END_REF][START_REF] Deffernez | Bimetallic Bi-Pt, Ru-Pt and Ru-Pd and trimetallic catalysts for the selective oxidation of glyoxal into glyoxalic acid in aqueous phase[END_REF][START_REF] Mori | Hydroxyapatite-Supported Palladium Nanoclusters: A Highly Active Heterogeneous Catalyst for Selective Oxidation of Alcohols by Use of Molecular Oxygen[END_REF][START_REF] Hosokawa | Effect of the Preparation Conditions of Ru/CeO2 Catalysts for the Liquid Phase Oxidation of Benzyl Alcohol[END_REF].

Recently, it has been found that metal-free electron deficient organic compounds like TEMPO (2,2,6,6-Tetramethylpiperidinyloxy) and DDQ (2,3-Dichloro-5,6-Dicyanobenzoquinone) can be used for dehydrogenation of alcohols in stoichiometric way, producing aldehydes and ketones together with the hydrogenated form of TEMPO and DDQ [START_REF] Ryland | Practical Aerobic Oxidations of Alcohols and Amines with Homogeneous Copper/TEMPO and Related Catalyst Systems[END_REF][START_REF] Ma | Development of a General and Practical Iron Nitrate/TEMPO-Catalyzed Aerobic Oxidation of Alcohols to Aldehydes/Ketones: Catalysis with Table Salt[END_REF][START_REF] Walsh | Solar photochemical oxidations of benzylic and allylic alcohols using catalytic organo-oxidation with DDQ: Application to lignin models[END_REF][START_REF] Hu | Fe (NO3)3/2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ): An efficient catalyst system for selective oxidation of alcohols under aerobic conditions[END_REF]. However, the use of large amounts of organic oxidants and difficulties related to their separation and regeneration strongly hinders the viability of this oxidation approach. To solve this drawback, the in-situ regeneration of these type of organic oxidants has been proposed, involving their combination with additional electron transfer mediators (ETM) and the utilization of a different terminal oxidant (e.g. oxygen). For example, Hu et al. explored an aerobic metal-free alcohol oxidation with a catalytic system consisting of TEMPO/Br2/NaNO2, where the Br2/HBr redox pair oxidizes TEMPOH with subsequent regeneration by NO2 [START_REF] Liu | Transition-metal-free: A highly efficient catalytic aerobic alcohol oxidation process[END_REF]. In 1977, the DDQcatalyzed reaction has been reported for the transformation of allylic alcohols to α,βunsaturated ketones using 10 mol% DDQ in the presence of 30 mol% periodic acid under biphasic conditions at room temperature [START_REF] Scott | A Rapid and Mild Process for the Oxidation of 2, 3-Dichloro-5, 6-dicyanobenzoquinone (DDQ) from 2, 3-Dichloro-5, 6-dicyanohydroquinone (DDHQ)[END_REF]. Helquist et al. illustrated similar reactivity using Mn(OAc)3 and DDQ for oxidation of allylic alcohols and benzylic alcohols to the corresponding aldehydes and ketones at mild reaction conditions [START_REF] Cosner | Selective Oxidation of Benzylic and Allylic Alcohols Using Mn(OAc)3/Catalytic 2, 3-Dichloro-5, 6-dicyano-1, 4benzoquinone[END_REF].

Despite this selective oxidation methodology favors the regeneration of the organic oxidant, it still requires the presence of metal salts in the final liquid product. Earlier, we have proposed application of anthraquinones as a catalyst for non-metallic oxidation of alcohols, however, the reaction proceed at relatively high temperature with oxidation of activated alcohols [START_REF] Zhao | Non-metallic Aerobic Oxidation of Alcohols over Anthraquinone Based Compounds[END_REF].

Hereby, we propose the preparation and application of hybrid heterogeneous catalyst characterized by the presence of an organic shell in charge of the abstraction of hydrogen during the selective oxidation of alcohols to carbonyl compounds and a metallic core able to regenerate organic shell of the catalyst (Scheme 1). We have found that deposition of sulfonated anthraquinone over Ru nanoparticles in core-shell catalyst results in selective oxidation of alcohols to aldehydes. The alcohols are selectively oxidized (oxidatively dehydrogenated) over the non-metallic anthraquinone, whereas the production of water takes place on the metallic core, in presence of oxygen. This J o u r n a l P r e -p r o o f system mimics the behavior of an electrochemical cell with oxidizing nano-anode in the form of the shell and reducing nano-cathode in the form of the core.

Experimental Section

Reagents

The chemicals RuCl3•H2O (99.9 wt%, CAS: 14898-67-0), γ-Al2O3 (99 wt%, CAS: 1344-28-1), CTAB (99 wt%, CAS: 57-09-0), NaBH4 (96 wt%, CAS: 16940-66-2), biphenyl (99.5 wt%, CAS: 92-52-4), benzyl alcohol (99 wt%, CAS: 100-51-6), 4chlorobenzyl alcohol (98 wt%, CAS: 873-76-7), 4-methylbenzyl alcohol(98 wt%, CAS: 589-18-4), cinnamyl alcohol (98 wt%, CAS: 104-54-1), 1,2-hexanediol (98 wt%, CAS: 6920-22-5), furfuryl alcohol (98 wt%, CAS: 98-00-0), HMF (95 wt%, CAS: 67-47-0), 1-octanol (>99 wt%, CAS: 111-87-5), 2-octanol (98 wt%, CAS: 6920-22-5), cyclohexanol (99 wt%, CAS: 108-93-0), 1,4-benzoquinone (98 wt%, CAS: 106-51-4), 2-ethylanthraquinone (97 wt%, CAS: 84-51-5), 1,4-naphthoquinone (97 wt%, CAS: 130-15-4), anthraquinone-2-carboxylic acid (98 wt%, CAS: 117-78-2), disodium anthraquinone -2,6-disulfonate (95 wt%, CAS: 212-719-9) are purchased from J&K Scientific Ltd.

Synthesis of Catalysts

Reverse micellar microemulsions of CTAB/1-hexanol/water (as shown in Table S1, SI) have been prepared [15, ]. Briefly, 10 g of microemulsion B containing 0.14 g NaBH4 has been dropwise added to 10 g of microemulsion A containing 0.2 g RuCl3 during 1 h under vigorous stirring. Ru nanoparticles with uniform size distribution have been formed inside the micelles. The catalyst Ru NPs has been separated by centrifugation, washed with hot water for 5 times and dried at 60 °C in vacuum oven for 12 h.

The catalysts Ru@SQ with varied shell thickness have been prepared by deposition of SQ over Ru NPs. Briefly, different amounts of SQ have been ultrasonically dissolved in 3 mL of water and subsequently mixed with 100 mg of Ru NPs. The water has been removed from resulting slurry by rotary evaporator and consequently dried at 60 °C in a vacuum oven overnight. A series of samples Ru@SQ-X% (X = 10, 25, 50 and 80) have been prepared, where X is the theoretical weight percentage of SQ. The sample with monolayer coating Ru@SQ-monolayer has been prepared by deposition of 2 wt. % of SQ over Ru NPs.

J o u r n a l P r e -p r o o f

Catalyst Characterization

The morphologies and particle size distribution of the catalysts and elemental mapping analysis has been performed using JEOL 2100 high-resolution transmission electron microscope (HRTEM) with an accelerating voltage of 200 kV. X-ray diffraction (XRD) was used to characterize the lattice structure. XRD patterns were recorded on a Rigaku D/max-2200/PC diffractometer using Cu Kα radiation (λ = 1.5418 Å) operating at 20 kV.

X-ray photoelectron spectroscopy (XPS) spectra were acquired using a Thermo Scientific ESCALAB 250Xi X-ray Photoelectron Spectrometer incorporating a 165 mm hemispherical electron energy analyzer. The incident radiation is Monochromatic Al Kα X-rays (1486.6 eV) at 225 W (15 kV, 15 ma). The deconvolution was performed on Thermo Scientific Avantage Software.

Thermogravimetric analysis (TGA) measurements were performed using a SDT 2960 analyzer from TA instrument under air flow (50 mL/min) with a ramping rate of temperature of 10 °C/min.

In-situ FTIR spectra were recorded using a Thermo Fisher Scientific Nicolet 6700 FTIR (16 scans at a resolution of 4 cm -1 ) equipped with MCT detector, high-vacuum system and heating zone. The catalyst pellet has been pretreated at 150 o C for 1 h in vacuum at 10 -5 Torr and cooled down to room temperature. The catalyst has been treated by 20 Torr hydrogen or furfuryl alcohol vapors at 25 o C~100 o C for 20 min.

The 1 H NMR spectra were measured using a Bruker ARX 400 or ARX 100 spectrometer at 400 MHz ( 1 H) and 100 MHz ( 13 C).

Catalysis

The catalytic tests were conducted in a 30 mL autoclave. For a typical test of 1octanol oxidation, 50 mg catalysts and 3 g of 1-octanol have been added in the reactor, which was pressurized with 10 bar of O2 and heated to 100 ⁰ C for 1~48 h under continuous stirring. The reference experiments with Ru NPs, pure SQ and the mixture of Ru and SQ were carried out under the same reaction conditions. Other alcohols have been oxidized in a similar way.

The catalytic oxidation of aldehyde has been performed in the same autoclave. The catalysts containing 5 mg of Ru and 0.3 g of octanal were placed in the reactor with air J o u r n a l P r e -p r o o f as oxidant at atmospheric pressure and solvent-free conditions. The mixture was stirred at 60 °C for 20 min.

The products of the reaction were analyzed using Agilent 7820A gas chromatography (GC) equipped with a HP-5 column and biphenyl as internal standard.

Cyclic voltammetry

Cyclic voltammetry (CV) was performed with a three-electrode setup controlled by a potentiostat (Reference 3000, Gamry Instruments Inc.). The synthesized catalysts containing Ru NPs or SQ were dispersed in ethanol to form a well-dispersed ink (10 mg/ml) using Nafion 117 solution (5 wt%) as a binder. 100 μL of the ink was deposited onto a polished and pre-cleaned glassy-carbon electrode with a working area of 0.1256 cm 2 . For Ru@SQ-80%, the working electrode was prepared by coating of electrode surface by 20 μL Ru NPs and subsequently 80 μL SQ ink. Ag/Ag + was used as a reference electrode in all measurements while Pt wire as a counter electrode. CVs were carried out at 25 °C in 8 mL solution of 0.1 M LiClO4 in DMSO saturated with Ar at a constant sweep rate of 100 mV/s.

Results and Discussion

Catalytic performances

Water-in-oil microemulsions built of water, hexanol and surfactant cetyltrimethylammonium bromide (CTAB) with RuCl3 and sodium borohydride have been used for the synthesis of metal nanoparticles. Ru nanoparticles form aggregates and the size of Ru nanoparticles measured by TEM varies in the range 2-3 nm (Figure 1).

Ru@quinone catalysts with core-shell structure have been prepared using rotary evaporator for deposition of quinone over Ru nanoparticles by removal of solvent. The prepared samples are denoted as Ru@quinone-X % (X=10, 25, 50, 80), where X is the weight percentage of quinone in the samples. The catalytic activity of 1-octanol oxidation is the highest over Ru NPs with decrease of the activity after deposition of SQ (Figure 2). Increase of SQ loading leads to decrease of the catalytic activity. Almost no activity has been observed for pure SQ.

Thus, presence of Ru NPs in the core of the catalyst affects the catalytic activity in alcohol oxidation. Comparison of the catalytic activity of core-shell Ru@SQ-80% with mechanical mixture Ru+SQ-80% indicates on SQ coating as the reason of low activity (Figure 2). It is interesting to note that activity normalized by Ru is comparable in a series of core-shell Ru@SQ catalysts (Figure 2). It means that the thickness of SQ coating does not affect the catalytic activity and the rate limiting step could be in Ru-SQ interface zone. Non-coated Ru NPs provide significantly higher activity indicating on different mechanism of oxidation with and without SQ coating.

The parent Ru NPs demonstrate (Figure S1, SI) strong decrease of the selectivity to octanal with increase of the conversion of 1-octanol with formation of acid and ester as side products. Figure 3 shows comparison of the selectivities over Ru NPs with coreshell Ru@SQ catalysts at the similar conversions about 60 %. At this conversion, the selectivity to octanal is only about 20 % over Ru NPs. Pure SQ provided even lower selectivity due to intensive over-oxidation to acid and ester. It is interesting to note that the selectivity to octanal was gradually increasing with increase of the content of SQ in the core-shell catalysts from 30 % for Ru@SQ-10% to 74 % for Ru@SQ-80%. Thus, the selectivity increases up to 3 times in comparison with pure Ru NPs and SQ. The catalysts with low loading of SQ still could contain accessible Ru surface, which explains lower selectivity. High selectivity at high SQ loading could be explained by full coverage of Ru surface by SQ.

Usually the aldehyde formation during 1-octanol oxidation is accompanied by subsequent non-catalytic and catalytic oxidation, which results in the formation of acid and esters. In our previous study of alcohols oxidation over Ru NPs we have demonstrated protective role of RuOx species from adsorption and deeper oxidation of aldehydes to acids [START_REF] Zhao | Selective oxidation of alcohols to carbonyl compounds over small size colloidal Ru nanoparticles[END_REF]. Similarly, the presence of SQ coating markedly reduces the exposure of active Ru NPs, which is likely to suppress the deep catalytic oxidation reaction. In order to verify this concept, we have conducted oxidation of 1-octanol J o u r n a l P r e -p r o o f using mechanical mixture of Ru NPs with 80 % of SQ (Ru+SQ-80%). It is interesting to note that the selectivity to aldehyde was significantly lower than in the case of coreshell system and comparable with Ru NPs.

SQ is almost insoluble in 1-octanol, however, it could be soluble during the catalytic reaction in the presence of water. The catalytic stability has been studied by separation of the catalyst Ru@SQ-80% after the first cycle with subsequent test using fresh 1-octanol for different reaction time to provide comparable conversions. Figure S2, SI demonstrates decrease of the selectivity to octanal from 75 to 37 % for the second cycle at the selectivity 23 % for pure Ru NPs. It means partial dissolution of SQ during the catalytic reaction, which makes catalytic performance similar to Ru NPs. It is interesting to note that the catalytic performance of Ru@SQ-80% after two cycles could be recovered by recoating of SQ shell (Figure S2, SI). It confirms solubility issue during the catalytic reaction for this composite material, however, provides simple way to recover the catalytic performance.

Characterization of Catalysts

Powder X-ray diffraction (XRD) has been used to study the crystallinity of the catalysts. 201) and (301), respectively, of orthorhombic phase of crystalline SQ [START_REF] Zhao | Sodium sulfonate groups substituted anthraquinone as an organic cathode for potassium batteries[END_REF][START_REF] Peake | X-Ray crystal structure determination of some sodium anthraquinone sulfonate derivatives[END_REF].

The composition and thermal stability of the Ru NPs and Ru@SQ catalysts has been examined by TGA (Figure S4, SI). The curves show weight losses in two steps.

At low temperature (25~300 o C) the weight loss is the result of removal of water, 1hexanol and CTAB used for the catalyst preparation. Subsequently, the weight losses of about 45 wt%, 23 wt%, 14 wt% and 9 wt% for Ru@SQ-X% samples (X=80, 50, 25, 10), respectively, have been observed between 400 °C and 600 °C, which could be ascribed to the combustion of SQ layer. The lower weight loss in comparison with the theoretical content of SQ should be ascribed to the generation of sodium sulfate as a product of oxidation. XPS analysis of Ru nanoparticles covered by SQ (monolayer and 80%) in comparison with Ru nanoparticles and pure SQ has been performed to investigate the J o u r n a l P r e -p r o o f electronic state of the ruthenium species (Figure 4). According to the XPS analysis (Table S2, SI), the ratios of S/Ru in both Ru@SQ-monolayer and Ru@SQ-80% samples are 0.1:1.0 and 2.3:1.0, respectively, which correlates well with the difference in SQ loading. Ru 3p core level spectra show the presence of ruthenium in two oxidation states: metallic Ru 0 (Ru 3p3/2 BE 462.0-463.3 eV) and lower contribution of oxidized Ru species with lower electronic density (Ru 3p3/2 BE 464.6-465.5 eV). This assignment was made according to earlier studies of various Ru compounds including metallic Ru, RuO2 and Ru(OH)3 demonstrating different Ru 3p3/2 BEs [START_REF] Morgan | Resolving ruthenium: XPS studies of common ruthenium materials[END_REF].

After SQ deposition over the surface of Ru NPs, the metallic Ru 3p doublet shifts to lower binding energy values. Additionally, the oxidized Ru peak appears demonstrating partial oxidation of Ru. Increase of SQ deposition leads to decrease of the intensity of Ru peaks due to the attenuation of Ru signal by SQ shell. It should be noted that with the increase of SQ coating the metal Ru 3p doublet shifts to lower binding energy values from 462.7 eV to 462 eV. This shift can be associated with the effect of electron transfer from SQ to Ru leading to increase of the electronic density over Ru.

Pure SQ sample demonstrates only one O 1s peak at 531.8 eV although it is expected to have two types of oxygen in SO3 2-and C=O. Most probably it is due to the strong interaction and electron transfer between oxygen in SO3 2- [START_REF] Zhao | Sodium sulfonate groups substituted anthraquinone as an organic cathode for potassium batteries[END_REF] and oxygen in C=O [START_REF] Peake | X-Ray crystal structure determination of some sodium anthraquinone sulfonate derivatives[END_REF] groups in SQ. Ru NPs demonstrate a similar O 1s peak with 531.8 eV BE, which is associated with RuO2 or surface Ru(OH)3 [START_REF] Ananth | A dielectric barrier discharge (DBD) plasma reactor: an efficient tool to prepare novel RuO2 nanorods[END_REF]. SQ coating over Ru NPs leads to appearance of two additional peaks: the broad peak at 534.1 eV, which can be assigned to oxygen in sulfo groups [START_REF] Lim | Potentiostatically deposited polypyrrole/graphene decorated nano-manganese oxide ternary film for supercapacitors[END_REF], and well defined peak at 530.2 eV (529.8 eV after 80% SQ loading). The 530.2 eV peak we associate with the bridge Ru-O-SQ species, which appearance indicates strong interaction between SQ and Ru (Scheme 3). This peak is attenuated as well as Ru 3p doublet with the increase of SQ loading.

Structure-catalytic performances relationship

In order to understand the role of Ru in the core-shell catalyst for oxidation of alcohols, we have varied the metal core. We have used Pd and Pt nanoparticles prepared in the same way for subsequent deposition of SQ to check the effect of metal of the core on the catalytic performance during oxidation of 1-octanol. loading. Thus, one can conclude that there is no interaction between Pt or Pd and SQ in contrast to Ru nanoparticles. Thus, strong interaction of Ru with SQ could be the key factor of high selectivity during oxidation of alcohols to carbonyl compounds. The mechanism of the reaction has been further studied using FTIR and electrochemical methods.

Mechanism

According to our earlier studies, oxidation of alcohols over Ru nanoparticles proceed according to Mars-van Krevelen mechanism by interaction of surface RuOx species over Ru nanoparticles with alcohol leading to the aldehyde formation and subsequent re-oxidation of Ru nanoparticles [START_REF] Zhao | Selective oxidation of alcohols to carbonyl compounds over small size colloidal Ru nanoparticles[END_REF]. In order to verify if SQ could be involved in this mechanism of oxidation of alcohols, we have performed the 1-octanol oxidation reaction in inert atmosphere. The only product of the reaction is octanal. In addition, considering alcohols oxidation to acids as consecutive reaction with intermediate aldehydes formation, the higher selectivity to octanal could be explained by suppression of further aldehyde oxidation over core-shell catalysts. In order to support this assumption, we have performed model reaction of octanal oxidation at mild reaction conditions to avoid autoxidation (Figure 6). Blank experiments without Ru J o u r n a l P r e -p r o o f species show almost no conversion of octanal at 60 o C and air instead of oxygen. Ru NPs provide conversion of octanal 26 % to acid. Increase of the amount of coated SQ leads to suppression of octanal oxidation and correlates with the results of 1-octanol accessibility to Ru core. It proves that SQ shell protects Ru core from interaction with aldehydes and suppresses over-oxidation, which could be the reason of high selectivity.

The key question in this case is how Ru@SQ catalyst provides oxidative dehydrogenation of alcohols. In-situ FTIR has been used to study the state of SQ during interaction with alcohol. FTIR spectrum of parent SQ (Figure 7) shows the peak at 1277 cm -1 attributed to the sulfonate group [START_REF] Zhao | Sodium sulfonate groups substituted anthraquinone as an organic cathode for potassium batteries[END_REF]. The peak at 1514 cm -1 can be assigned to the stretching vibration of aromatic conjugate C=C band [START_REF] Wang | Fast and efficient oil-water separation under harsh conditions of the flexible polyimide aerogel containing benzimidazole structure[END_REF]. The strong characteristic peaks at 1695 cm -1 and 1624 cm -1 can be assigned to the stretching C=O vibrations in non-chelated and a chelated quinone carbonyl group, respectively [START_REF] Demagos | New anthraquinones and anthraquinone glycosides from Morinda lucida[END_REF].

The non-chelated quinone group disappears after core-shell structure fabrication, which could be explained by strong interaction between C=O and Ru NPs in accordance with XPS results (Figure 4). It is interesting to note that the spectrum of mechanical mixture of SQ with Ru is similar to pure SQ and confirms specific interaction of SQ with Ru only in core-shell material (Figure S8, SI).

Presence of hydrogen in IR cell leads to decrease of the intensity of the C=O group at 1624 cm -1 , which could be recovered after the heating treatment at 100 °C in vacuum.

It indicates on easy reduction of C=O to C-OH and subsequent decomposition in the absence of hydrogen.

Pure SQ and mechanical mixture of SQ with Ru does not show any interaction with hydrogen (Figure S8, SI). Hydrogenation of SQ could be initiated by hydrogen dissociation over Ru [START_REF] Rose | Nature of the dissociation sites of hydrogen molecules on Ru (001)[END_REF] with subsequent hydrogen transfer to SQ through Ru-O-SQ linkers. In order to study hydrogen transfer from alcohol molecule, we have introduced furfuryl alcohol vapors in the cell with subsequent heating from 25 to 100 °C (Figure 7). The carbonyl group characterized by the peak located at 1624 cm -1 started to decrease in intensity at 80 °C in comparison with no effect for pure SQ or mechanical mixture Ru+SQ-80% (Figure S8, SI). Thus, carbonyl group of SQ in core-shell catalyst can be involved in hydrogen transfer from alcohol with generation of aldehyde and hydrogenated carbonyl group in the shell. Subsequent transfer of hydrogen through carbonyl group of SQ to Ru and decomposition with regeneration of C=O in SQ could be proposed as mechanism of oxidation of alcohols without direct contact of metal with alcohol (Scheme 1).

J o u r n a l P r e -p r o o f

The advantage of SQ in comparison with the strong electrophilic organic scavengers like TEMPO or DDQ is its intermediate reduction potential leading to lower stability of hydrogenated form, which results in efficient hydrogen transfer and regeneration of SQ over Ru surface.

Electrochemical experiments have been used to further evaluate the state of SQ in the core-shell catalyst. Cyclic voltammograms (CVs) of the bare glassy carbon (GC) electrode, Ru NPs/GC, SQ/GC, and Ru@SQ-80%/GC electrodes in Ar-saturated DMSO solution with 0.1 M LiClO4 as electrolyte were studied in the presence/absence of 0.1 M furfuryl alcohol (FA). The cyclic voltammetry data for SQ are characterized by two anodic and cathodic waves between -1.6 V and -1 V vs Ag/Ag + corresponding to the two consecutive one-electron reversible transfer process of the oxydo-reduction of anthraquinones to hydroquinone (Figure 8, Table 1). However, when 0.1 M of furfuryl alcohol (FA) is added a 3 rd anodic wave occurs at -0.14 V for SQ-FA and at -0.21 V for Ru@SQ-80%-FA corresponding to the oxidation of FA.

At the same time, blank Ru NPs/GC and bare GC electrodes have no CVs responses (Figure S9, SI). For the Ru@SQ-80%-FA, the lowest oxydo-reduction peak around -1.62 V shifts to higher voltage -1.25 V, which shows that only one electron transfer is involved in the oxidation of FA. This leads to increase of the current density of FA oxidation at -0.21 V. Moreover, the resulting current density for FA oxidation over Ru@SQ-80% is much higher in comparison with pure SQ. The negative shift and higher current density of this peak for Ru@SQ-80% combined with the shift of the peak of SQ to higher voltages indicates increase of the catalytic activity of Ru@SQ-80% in comparison to pure SQ for the oxidation of FA. The improved electrocatalytic activity in oxidation of FA could be due to the presence of Ru in the core, which accelerates the electron transfer via improved conductivity and change of the electronic state of SQ in the core-shell catalyst observed by FTIR and XPS.

Substrate Scope

The selective oxidation of a wide range of alcohols has been studied over Ru@SQ-80% catalyst in the presence of O2. For benzyl alcohol, methyl-substituted and chlorinated benzylic alcohol conversions of 92 %, 95 % and 95 % have been achieved within 6 h, respectively (Table 2). The selectivity to the target products was higher than 95 %. Similarly, unsaturated cinnamyl alcohol was converted to cinnamaldehyde with 95 % selectivity. In the case of oxidation of furfuryl alcohol and 2,5-J o u r n a l P r e -p r o o f hydroxymethylfurfural (HMF) the selectivity about 90 % was achieved to furfural and 2,5-diformylfuran (DFF), respectively, at high conversion. Non-activated aliphatic alcohol (i.e., 1-octanol) and cyclic alcohol (i.e., cyclohexanol) over Ru@SQ-80% have been converted to carbonyl compounds with a moderate activity and excellent selectivity. Secondary 2-octanol, can be oxidized with a conversion of >90 % and selectivity of 95 % to corresponding ketone, which is comparable to the selectivity achieved using TEMPO [START_REF] Cecchetto | Efficient Mn-Cu and Mn-Co-TEMPOcatalysed oxidation of alcohols into aldehydes and ketones by oxygen under mild conditions[END_REF].

The excellent catalytic activity towards various oxygenate substrates demonstrates that the uniform organic shell around the metal nanoparticles suppressed over-oxidation of aldehydes toward acids and esters. Nanocell Ru@SQ exhibits much better catalytic behavior than conventional Ru catalysts [START_REF] Corberán | Green oxidation of fatty alcohols: Challenges and opportunities[END_REF]. Isolation of metal nanoparticles from direct contact with alcohols decreases activity, however, results in significant increase of the selectivity toward carbonyl compounds. The catalytic system can be further optimized by variation of the shell type for more efficient alcohols dehydrogenation and hydrogen transfer to combine high activity and selectivity of the catalyst.

Conclusion

In conclusion, we have demonstrated that it is possible to build nanocell with coreshell structure containing Ru nanoparticles in the core and electro-deficient anthraquinones in the shell for selective oxidation of alcohols to carbonyl compounds.

XPS analysis shows strong interaction between quinone species and Ru nanoparticles leading to transfer of the electronic density to Ru and easy activation of alcohols over the shell. In-situ mechanism study confirms transfer of hydrogen to carbonyl groups of quinone species from alcohol with subsequent transfer to the core. This concept can be used for other applications, where contact of the target product of the reaction with metal results in decrease of the selectivity.

Figure 1

 1 demonstrates TEM images of Ru nanoparticles coated by different amount of disodium anthraquinone-2,6disulfonate (SQ) in Ru@SQ catalysts. There is a clear contrast between the heavier atom of Ru in the core and the lighter SQ shell. Increase of the content of SQ phase leads to increase of the thickness of the shell from 1 to 3 nm.The catalytic performance of core-shell catalysts with different content of SQ has been compared with the reference Ru nanoparticles and pure SQ in selective oxidation J o u r n a l P r e -p r o o f of 1-octanol. Besides aldehyde as the main product of the reaction, there is an octanoic acid as the product of deeper oxidation of aldehyde and octyl octanoate as the product of further esterification (Scheme 2). 1-Octanol in the presence of acid also undergoes etherification reaction to dioctyl ether.

  Figure S3, SI demonstrates broad peaks at 38.4 °, 42.2 °, 43.8 °, 58.2 ° and 69.4 °, which correspond to (100), (002), (101), (102) and (110) planes, respectively, of the hexagonal close-packed (hcp) small size Ru metal nanoparticles. SQ does not change the patterns of Ru, however, increase of SQ content leads to appearance of new signals at 16.2°, 19.5° and 26.2° corresponding to the indices of (210), (

  Figure S5, SI demonstrates selectivity-conversion curves for Pd@SQ and Pt@SQ catalysts with different content J o u r n a l P r e -p r o o f of SQ in comparison with Pd and Pt nanoparticles. In comparison with Ru catalysts, the deposition of SQ over Pt and Pd leads either to low effect in selectivity or significant decrease of the selectivity to aldehyde with increase of the contribution of acid and ester. Pt and Pd are well-known catalysts for hydrogenation/dehydrogenation reactions in comparison with Ru, which is used for hydrogenolysis reactions. Pt and Pd nanoparticles do not demonstrate strong interaction with SQ as demonstrated by XPS analysis of the samples before and after SQ impregnation (Figure S6, SI). The reason could be in strong oxophiliticy of Ru leading to easy adsorption of oxygen on the surface with formation of Ru-O species. In order to confirm it, we have examined O 1s XPS spectra. SQ covered Pt and Pd nanoparticles in O 1s spectra do not show peak around 530 eV, which has been assigned to Me-O species (Figure S7, SI). Pd 3d and Pt 4f spectra demonstrate the metallic state of the elements with no changes after SQ

Figure 5

 5 Figure 5 demonstrates the conversion of 1-octanol depending on the content of SQ in the catalyst. The yield of octanal was gradually decreasing from 9 to 1 % with increase of the content of SQ up to 80 %. It indicates on different mechanism of alcohol oxidation in this case and absence of direct contact of 1-octanol with Ru core.

Figure 1 .Figure 2 .Figure 3 .

 123 Figure 1. TEM images of (a) Ru NPs; (b) SQ; (c~f) Ru@SQ-X% catalysts, X=10, 25, 50, 80. J o u r n a l P r e -p r o o f

Figure 4 .Figure 5 .Figure 6 .Figure 7 .Figure 8 .

 45678 Figure 4. XPS spectra of Ru NPs, Ru@SQ-monolayer and Ru@SQ-80%. (a) Ru 3p, (b) O 1s core level spectra.

Acknowledgments

J o u r n a l P r e -p r o o f J.P. Zhao thanks Solvay and CIFRE (2016-1082) for providing him a stipend for PhD study CRediT authorship contribution statement V. Ordomsky, W.Y. Hernández and M. Capron conceived the idea for this work. All authors contributed to the design of the experimental set-up and experimental procedures. J.P. Zhao and W.J. Zhou prepared the catalysts and performed catalytic tests. Y. Yang and E.I. Vovk performed XPS analysis. M. Wu and N. Naghavi performed electrochemical measurements. J.P. Zhao and V. Ordomsky wrote the draught, and all the authors worked on improving the manuscript

Declaration of interests

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. a Reaction conditions: catalyst 50.0 mg, toluene 2.0 g as solvent.

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b Reaction conditions: catalyst 50.0 mg, toluene 1.0 g + ethanol 1.0 g as solvent.

c Reaction conditions: catalyst 50.0 mg, solvent-free.

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