Dendrimer for Templating the Growth of Porous Catechol-Coordinated

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Dendrimer Templated the Growth of Porous Catechol-CoordinatedTitanium Dioxide Frameworks: Toward Hemocompatible Nanomaterials Nadia Katir, Nathalie Marcotte, Sylwia Michlewska, Maksim Ionov, Nabil El Brahmi, Mosto M. Bousmina, Jean-Pierre Majoral, Maria Bryszewska, and Abdelkrim El Kadib ACS Appl. Nano Mater., Just Accepted Manuscript • DOI: 10.1021/acsanm.9b00382 • Publication Date (Web): 18 Apr 2019 Downloaded from http://pubs.acs.org on April 19, 2019

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ACS Applied Nano Materials

Dendrimer Templated the Growth of Porous Catechol-CoordinatedTitanium Dioxide Frameworks: Toward Hemocompatible Nanomaterials. Nadia Katir,† Nathalie Marcotte,‡ Sylwia Michlewska,§ Maksim Ionov,|| Nabil El Brahmi,† Mosto Bousmina,† Jean Pierre Majoral,⊥ Maria Bryszewska,|| and Abdelkrim El Kadib.†,* †

Euromed Research Center, Engineering Division, Euro-Med University of Fes (UEMF), Route de Meknes, Rond-point de Bensouda, 30070, Fès, Morocco. ‡ Institut Charles Gerhardt Montpellier UMR 5253 CNRS/ENSCM/UM, 240 Avenue du Professeur Emile Jeanbrau, 34090 Montpellier cedex 5, France. § Laboratory of Microscopic Imaging and Specialized Biological Techniques, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland. || Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska Street, 90-236 Lodz, Poland. ⊥ Laboratoire de Chimie de Coordination (LCC), CNRS, 205 route de Narbonne, 31077 Toulouse, France. KEYWORDS. Phosphorus dendrimers; sol-gel chemistry; catechol-coordinated-framework; titanium dioxide; porous materials. ABSTRACT: Phosphorus-dendrimers and nano-sized metal oxide clusters are two dissimilar nanomaterials with promising applications in nanomedicine. Although outstanding holistic properties can be reached by the combination of organic and inorganic phases, few investigations were strikingly undertaken to associate these building-blocks in a single nanostructured, openframework hybrid material. With this aim, we designed herein five novel different generations of catechol-terminated phosphorus dendrimers (DGn: n = 1-5) and used them as structure directing agents for titanium alkoxide mineralization. The well-defined topology of the starting dendrimers, the covalent bonding occurring between its peripheral catechols and soluble titanium-oxospecies and their further sol-gel co-condensation afford bimodal micro-mesoporous catechol-coordinated-titanium dioxide nanomaterials. Their interplay with cells was assessed with a special emphasis on their haemolytic activity and cytotoxicity. Interestingly, enhanced biocompatibility was observed for these materials compared to their hybrid analogues built from ammoniumterminated and phosphonate-terminated phosphorus dendrimers. These results demonstrate the importance of catecholterminated groups for both bridging titanium dioxide clusters and for improving the materials compatibility. Overall, this study sheds light on the importance of tuning surface-interface hybrid composition and provides a blueprint for the rational-design of blood-compatible and drug-transporter materials.

INTRODUCTION

The as-referred phosphorus dendrimers are a class of heteroatom-containing nano-assembled building-blocks with well-defined substructures including their shape, core, arms and surface functionalities.1-4 They constitute outstanding tools in a wide range of interdisciplinary fields, including medicinal chemistry5-9 and materials science,10-11 in which research on dendrimers generates an extensive number of scientific reports.12 The presence of nitrogen, phosphorus and sulfur within the dendritic skeletal in different positions (the core, the branching units and the peripheries) makes these heteroatomcontaining architectures very suitable for interaction with biological systems.13 Despite their forefront position in health-care and the suspected outcome in the field,

only few ground-breaking results were hitherto reported.14-15 Other nanosized materials like metal oxide clusters, naked metal nanoparticles and metal-organic frameworks constitute also a valuable toolbox for nanomedicine.16-17 The multifaceted use of these nano-objects enabled expanding research beyond a classical drug-delivery therapy to more sophisticated treatments, including gene delivery, imagery and photodynamic therapy.1823. Nanosized silica, titanium dioxide and iron oxide are the most ubiquitous nanomaterials in this category. 24-27 Beside their shape and size, it has been shown that their surface-chemistry plays a pivotal role in interaction with blood-cells, following the formation of the so-called corona nanoparticles.28-29 In concrete terms, functionalization of the external surface of the nanomaterial provides an excellent handle to tune its properties; the newly

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created chemical interface results in a novel biological identity and, consequently, promotes a different physiological response (bio-distribution, pharmacokinetics, internalization).30-32 With this statement in mind, we envisioned that the association of phosphorus dendrimers and metal oxide species in a single nanostructure will afford hybrid “nano-bio” systems with new original properties.33-34 Thus, the holistic approach of dendrimer-metal oxide hybridization constitutes a fruitful investigation route for overcoming “the dendrimer paradox – high medical expectations but poor clinical translation”.14-15 Hitherto, porous dendrimer-metal oxide hybrid materials were seldom reported and only few of them were subjected to biological assessments. We recently initiated a research program aimed at exploring the use of surface-functional dendritic architectures in materials science.10, 35-39 The co-assembly of welldefined phosphorus dendrimers and sol-gel processable metal-oxo-species enabled access to periodic mesoporous tectonic nanostructures. These mesostructured materials are different from those classically synthesized from mesophasic surfactant-inorganic oxide composites, for which the removal of the surfactant is mandatory to create porous network.40 Moreover, the unique topology, swelling in polar medium and the presence of reactive functional groups in the peripheries of phosphorus dendrimers afforded an intimate interplay with the growing metal oxide nuclei, allowing the incorporation of the two dissimilar phases in a single hybrid nanostructure.36 Phosphonate-terminated, ammonium-terminated and acetylacetonate-terminated phosphorus dendrimers were used as structure directing agents for mineralization of soluble titanium alkoxide species to provide porous dendrimer-anatase mesocrystals.37 While the amorphous versus crystalline state of the metal oxide framework has revealed no diverging biological effect, the interfacial composition built from dendrimer terminated ammonium versus terminated phosphonate accounted for decreased hemolysis and better cytocompatibility.39 This demonstrates that both the nature of terminal dendrimer and the coating of the metal oxide surface are pivotal phenomenon in interacting with blood. As a step further toward hemocompatible materials, we considered catechol as a useful peripheral group. This choice can be rooted in the well-established biochemical roles of many catecholamine neurotransmitters (adrenaline, noradrenaline, dopamine)41 and their fascinating use as coupling-surface agents to create novel functional hybrid materials.42 Catechol conjugation to titanium dioxide surface43-45 allowed photo-sensitizing the semi-conductor under natural visible light through ligand-to-metal charge transfer,46-50 while the use of native titanium dioxide is restricted to artificial irradiation.51 Surprisingly, very few catechol-terminated dendrimers were reported although their effectiveness and superiority to their linear congeners for nanoparticle stabilization and surface-coating was convincingly

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demonstrated.52-53 Phosphorus-dendrimers seem to be particularly forgotten in the library of mussel-inspired chemistry where no catechol-terminated heteroatomcontaining dendrimer was hitherto disclosed.54 Besides, although catechol-functionalized building-blocks are ubiquitous as post-grafting surface-coupling agents, their involvement as dual structure directing agent and cocondensing functionality with soluble metal alkoxide precursors remains elusive and, to the best of our knowledge, such approach of hybrid construction was never reported. The present work reports consequently three main innovations: i) the first synthesis in high yields and further characterization of five generation (DGn : n=1-5) catechol-terminated phosphorus-dendrimers, ii) their structure-directing sol-gel co-condensation to provide porous catechol-coordinated-titanium dioxide DGn-xcat@TiO2 and iii) the interplay of these nanostructures with cells. EXPERIMENTAL SECTION General. Chemicals were purchased from Sigma-Aldrich or Strem and used without further purification. All reactions were carried out in the absence of air using standard Schlenk techniques and vacuum-line manipulation. Solvents were purified with the MBRAUN SBS-800 purification system. NMR spectra were recorded with Bruker AV 400 and HD 400 spectrometers. All spectra were measured at 25°C in the indicated deuterated solvents. References for NMR chemical shifts are H 3PO4 (85%) for 31 P NMR, and SiMe4 for 1H and 13C NMR spectroscopy. 1H, 13 C and 31P chemical shifts () are reported in ppm and coupling constants (J) are reported in Hertz (Hz). The signals in the spectra are described as s (singlet), d (doublet), t (triplet), m (multiplet) and br (broad resonances). Attribution was carried out thanks to two-dimensional experiments when necessary (COSY, HMBC, HMQC). Cross-polarization magic-angle-spinning (CP/MAS) 13C and 31P NMR spectra were acquired on a Bruker Avance 400 WB spectrometer operating at 100 MHz and 162 MHz respectively. The compounds Ph 2PC6H4OH,55 N3P(S)(NMeNH2)2,56 GnxCl,57 N3P3(NMeNH2)6,58 were prepared according to literature procedures. Nitrogen sorption isotherms at 77 K were obtained with a Micromeritics ASAP 2010 apparatus. Prior to measurement, the samples were outgassed for 8 h at 120 °C. The surface area (SBET) was determined from BET treatment in the range 0.04–0.3 p/p0 assuming a surface coverage of the nitrogen molecule estimated to be 13.5 Å. X-ray powder diffraction (XRD) patterns were recorded on a D8 Advance Bruker AXS system using CuKα radiation with a step size of 0.02° in the 2θ range from 0.45 to 87° for WAXS (geometry: Bragg- Brentano, θ/2θ mode). DRUV spectra were measured in the 200–800 nm range using spectralon as the reference on a Perkin-Elmer Lambda 1050 spectrometer equipped with an integrating sphere (Lapshere, North Sutton, USA). Scanning electronic microscopy (SEM) images were obtained using a JEOL JSM 6700F and Transmission electronic microscopy (TEM) images from a JEOL JEM 2010 at an activation voltage of


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200 kV. Zeta potential measurements (electrokinetic potential) were performed with Zetasizer Nano ZS from Malvern Instruments (UK), which uses electrophoresis and LDV (Laser Doppler Velocimetry) techniques. Applying a combination of these two techniques allowed measuring the electrophoretic mobility of the molecules in solution. Results were obtained 10 times with the zero field correction. The zeta potential value was calculated directly from the Helmholtz-Smoluchowski equation using the Malvern software.59 The measurements were performed at the concentration of 20 µg.mL-1 in phosphate buffer at pH=7.4, filtered twice through 0.22 mm filter paper. The experiments were performed at 25°C. From 9 to 12 measurements of zeta potential were collected and averaged for each sample. The particle size was determined using dynamic light scattering (DLS) experiments with a photon correlation spectrometer (Zetasizer Nano-ZS, Malvern Instruments, UK). 60 Samples were prepared at a concentration of 20 µg/mL in PBS (pH 7.4), filtered twice through 0.22 mm filter paper prior to the measurement. Samples were placed in the plastic cells DTS0012 (Malvern) and measured at 25°C. The data were analyzed using the Malvern software. Sol-gel synthesis of DGn-xCat@TiO2. Details on the synthesis and full characterization of the six catecholterminated dendrimers DGn-xCat will be found in the supplementary information. For typical procedure on solgel mineralisation of titanium alkoxide, a catecholterminated dendrimer DGn-xCat was solubilised in an ethanol:water solution (5:2 volume ratio). Then, Ti(OiPr)4 in a 1:20 molar ratio ([terminal catechol] : [Ti]) was added to the dendritic solution at room temperature. After 15 min of stirring, the resulting solution was heated at 60°C for 24 hours. After filtration and extensive washing of the precipitate with ethanol, the collected solids were dried at 60 °C for 2 hours given rise to DGn-xCat@TiO2. Cytotoxicity assay. Chinese hamster cells (B14 cell line) were purchased from Child Health Centre in Warsaw (Poland). Cells were grown as a monolayer in DMEM medium supplemented with 10% foetal bovine serum with 100 units/mL gentamycin. The cells were maintained at 37°C in an atmosphere of 5% CO 2 and 95% air with more than 95% humidity. Cells were split for subcultures every 2 days. Cell viability was measured by the MTT assay.61 The test was based on the reduction of the soluble yellow MTT tetrazolium salt to a blue, insoluble formazan produced by mitochondrial succinate dehydrogenase. The amount of formazan produced was proportional to the number of living cells. Cells were seeded at a density of 2.0 x 105/well into 96-well microtitrate plates using DMEM medium. They were treated with nanoparticles at 37°C in a 5% carbon dioxide-95% air atmosphere for 24 h, and recovered by gentle washing with PBS (pH = 7.4) twice. After incubation, 50 μl of 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) solution was added to each well, followed by 3 h of incubation. Next, MTTcontaining medium was removed, and 100 μl of DMSO was added to each well to dissolve formazan crystals.

Absorbance of the converted dye was measured at 570 nm using a microplate spectrophotometer (BioTek). Cell viability was calculated as the percent ratio of absorbance of the samples to the reference control. Haemotoxicity. Healthy donors blood was purchased from Central Blood Bank in Lodz. The blood was anticoagulated, centrifuged and washed three times with PBS at pH=7.4. Erythrocytes were used immediately after isolation. DGn-xCat or DGn-xCat@TiO2 at a concentration of 10-200 µg/mL were added to red blood cells (2% haematocrit) and incubated at 37°C for 24 h with shaking. The ratio of haemolysis was calculated as follows: H (%) = (Apb 540 nm/Awater 540 nm)×100%, where H (%) is the percentage of haemolysis of the erythrocytes; Apb 540 nm is the absorbance of the erythrocytes samples incubated with dendrimers; and Awater 540 nm is the absorbance of the sample after complete haemolysis with water (100%). RESULTS AND DISCUSSION Synthesis of catechol-terminated phosphorus dendrimer (DGn-xcat). Our strategy emanates from the rising concept of onion peel chemistry that allows diversifying the nature and the number of functional groups installed within a uniform dendrimer body.62-63 In this framework, we have succeeded to incorporate up to seven phosphorus fragments within the dendrimer skeletal, in the core, the branching units, the surface and as a counter-ion.64 This phosphorus diversity is of paramount interest for biological response where it has been demonstrated that, even the nature of the hidden internal core plays a key role during cells interaction.65 Inspired by our recent dendritic motifs,64, 66 we envisioned a trivial decoration of the surface of phosphorus dendrimers by catechol groups. Hexachlorocyclophosphazene N3P3Cl6 was chosen as a core owing to its inorganic character that brings chemical stability, hydrophobicity, versatility and well-established reactivity.67-68 It is also prone to ring opening under thermal treatment to provide polyphosphazene-based nanostructures.37 The smallest building-block in our series was prepared in twostep, by substitution of the N3P3Cl6 chlorides by methyl hydrazine moieties.58 Condensation of external amines to para-catechol-benzaldehyde led to the first catecholterminated phosphorus dendrimer, referred to as DG06 cat, in 90% yield (Scheme 1a and S1). The first generation phosphorus dendrimer featuring twelve catecholterminal groups was prepared by firstly substituting chlorides on the ring core by parahydroxytriphenylphosphine, followed by Staudinger reaction between peripheral phosphines and an equimolar equivalent of azidothio-bis-hydrazinophosphine.64 Subsequent condensation of peripheral amines with paracatechol-benzaldehyde affords quantitatively DG1-12cat (Scheme 1b). To further expand their size, more bulky dendrimers were prepared. Displacement of chloride



motifs by para-hydroxytriphenylphosphine followed by

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Staudinger reaction between the as-prepared terminal

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Scheme 1. Step-by-step construction of catechol-terminated phosphorus dendrimers ((a) DG0- cat, (b) DG1- cat, (c) DG224 48 96 192 cat, (d) DG3- cat, (e) DG4- cat and (f) DG5- cat).

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Figure 1. Trees-like structure of catechol-terminated phosphorus dendrimers (DG0- cat, DG1- cat, DG2- cat, DG3- cat and DG4- cat).


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ACS Applied Nano Materials 15.19 N3P3 =N-P=S

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phosphines and azidothio-bis-hydrazinophosphine was found to be an extremely relevant two-step modification for increasing the dendrimer generation (Scheme 1c-f). Once isolated, grafting of catechol units was found to be easy-to-run by means of Schiff-base formation between terminated methyl-hydrazine and para-catecholbenzaldehyde (Scheme 1c-f). Accordingly, four other dendrimers with increased molecular weight and number of external catechols were obtained, namely DG2-24cat, DG3-48cat, DG4-96cat and DG5-192cat as illustrated in Scheme 1c-f and figure 1. Notably, the choice of methylhydrazine as a coupling reagent instead of a simple amine was dictated by the highest stability of C=N-N, while amine-to-aldehyde condensation led to water sensitive C=N bridges.69 The presence of several different phosphorus-containing fragments within the dendrimer body provides a way to accurately confirm, by means of 31P NMR, the modification undertaken layer-by-layer for increasing generation but also to detect any possible presence of undesirable impurities.64, 69-70 This constitutes a great advantage over polymeric materials and organic dendrimers where the structure is often not well-elucidated or the purity sometimes under-estimated. For the smallest DG0-6cat, the presence of one signal in 31 P NMR at 15.19 ppm assignable to the P 3N3 core and the disappearance of the one of P3N3Cl6 at 20.01 ppm reflect the complete installation of catechol derivatives within the six branching sites (Figure 2). Hydroxyl groups of the catechols were recognized at 7.52 to 7.99 ppm in 1 H NMR and their bridged carbons (ArOH) were also identified at 146-147 ppm in 13C NMR. The other bulky dendrimers (DG2-24cat, DG3-48cat, DG4-96cat and DG5192 cat) display similar peripheral characteristics as for DG0-6cat. 31P NMR unambiguously elucidates the undertaken chemical condensation of methyl hydrazine to Para-catecholbenzaldehyde, because the signal of S=P[N(Me)-NH2]2 observed at 70 ppm down shielded to 54-58 ppm for the catechol-terminated dendrimer, thereby

ascertaining the formation of S=P[N-(Me)-N=C-Ar-(OH)2]2 (Figure 2 and S1). Moreover the formation of P=N-P=S linkages within the structure of dendrimers is corroborated by the presence in 31 P NMR of two doublets at 56.75 (P=S) and 9.37(P=N) with 2JPP = 26.7 Hz. The apparition of new signals of carbon bridged catechol ArOH at 146-147 ppm in 13C NMR and the observation of the characteristic large OH vibration bands at 3200 cm -1 on Infrared spectra further corroborate the successful installation of catechol derivatives (Figure S2a). The absence of any additional phosphorus signals ruled out the occurrence of incomplete substitution or disproportionation around reactive phosphorus layers, thereby confirming the superb symmetry reached in these biomimetic dendrimers. Notably, these sophisticated building-blocks were prepared by using well-established, high-yielding, and operationally trivial procedures, with no expensive metal or harmful solvent and generated only water and nitrogen as green waste. Synthesis of DGn-xcat@TiO2 by sol-gel co-condensation of titanium alkoxide with catechol-terminated dendrimers. Having succeeded in preparing six different generations of catechol-terminated phosphorus dendrimers DGn-xcat, we turned our attention to their cocondensation with titanium alkoxide by sol-gel chemistry. Starting from soluble Ti(OiPr)4 precursor, a red colored solid material was harvested after 24 hours at 60°C. Extensive washing was applied to remove potential unreacted dendrimers or uncondensed titanium alkoxide. Analysis of the supernatant indicates the complete condensation of titanium precursor and its temporal stability substantiates a tight incorporation of the catechol dendrimer within the walls of the metal oxide framework (scheme 2). DRIFT analysis reveals broadening peaks of DGncat@TiO2 with respect to DGn-xcat because of the restricted mobility within the hybrid. 38 Other bands face significant shifts because of the interplay occurring x



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x

Scheme 2. Illustration of the different steps involved in the sol-gel synthesis of DGn- cat@TiO2 hybrid materials.

between the dendritic and the metal oxide phase. Indeed, ʋ(C=C) that resonates at 1586 and 1608 cm-1 in DGnx cat appears at 1573 and 1638 cm-1 for DGn-xcat@TiO2 in agreement with the literature (Figure S2b). 71 The double bands at 1235-1281 cm-1 associated with C-O stretch present in DGn-xcat (catechol groups) have transformed into primarily one intense band with a slight shoulder at ∼1288 cm-1 for [email protected] Solid-state NMR studies confirmed the presence of phosphorus dendrimers and the intactness of the skeletal during the mineralisation process. The smallest DG06 cat@TiO2 displays phosphorus signal at 17 ppm, attributable to the phosphorus of the core (Figure S3), and CP 13C NMR reveals the presence of expected carbon signals (Figure S4). A significant shift from 145 to 155 ppm was observed for Ar-OH in the hybrid material as a consequence of catechol ligation to titanium center (ArO-Ti). Similarly, DGn-xcat@TiO2 materials built from first to fifth generation exhibit phosphorus signals at 11, 58 ppm of the starting dendrimer (P=N and P=S) and a systematic shift for catecholic carbons ArOH from ~146 ppm for DGn-xcat to ~153 ppm in DGn-xcat@TiO2 (Figure 3 and Figure S4). Similar shift was previously reported in the literature73 and is consistent with the electronic modification occurring on carbon bridged catechol ArOH upon coordination to Lewis acidic titanium center. Different scenarios of catechol-to-titanium can take place, among them: monodentate, chelate bidentate and bridge bidentate. The nonsplitting chemical shift change for two phenolic carbon (ArOH) ruled out the occurrence of monodentate bonding as the latter will result in asymmetric geometry configuration. The chemical shift fits well with

the experimental results supported by DFT calculation for the chelate bidentate geometry. 73-74 This is not surprising since the chelate bidentate ligation is the most stable form for catechol-coordinated mononuclear titanium (IV) complexes.71 10.54 PPh 2

C6H3, C6H4 and C6H5 128.51 and 131.58

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Figure 3. P CP MAS and 24 cat@TiO2

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A deep understanding of the textural properties of DGnx cat@TiO2 was gained from nitrogen sorption analysis and electronic microscopy (SEM and TEM). Nitrogen sorption isotherms display an increased adsorbed volume at low pressure typical of microporous materials with a small hysteresis loop in a desorption branch indicating the presence of mesopores. The specific surface areas range from 280 to ~500 m2.g-1 and seem to decrease with increasing the dendrimer generation, except for DG3-48cat@TiO2 (Fig. 4g, table 1). SEM analysis reveals the presence of a condensed network built from connected microspheres that extend along the framework where void porosity can be clearly observed (Figure 4a-f). The bimodal porosity revealed in nitrogen sorption isotherms can be tentatively attributed to the simultanous presence of individual microspheres that form micropores, while their intergranular connectivity


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provides large mesopores. The observation of such nanoa

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Figure 4. Scanning electron microscopy pictures of (a,b) DG0- cat@TiO2, (c) DG2- cat@TiO2, (d) DG3- cat@TiO2, (e) DG4 cat@TiO2 and 192 x x (f) DG5- cat@TiO2. Nitrogen adsorption-desorption isotherm profile of DGn- cat@TiO2. (h) UV-visible spectroscopy of DGn- cat@TiO2.

elementary building-blocks and the absence of bulky crystals or dense and nonporous network indicates that DGn-xcat behave as a mold with many three-dimensional anchoring catechol sites for templating the nucleation of soluble metaloxo-alkoxide bursts formed during the early stage of the solgel polymerization and their further maturation. Simultanously, the sterical hindrince associated to the unique topology of these dendrimers provide a way to restrict the growth of the mineral phase into the nanometer regime. Phosphorus dendrimer displays consequently a double role where it acts simultaneously as a co-condensing modifier and a structure directing agent for titanium alkoxide mineralisation. At this stage, two merits should be highlighted: First, the co-condensation method affords herein porous materials, while it is commonly admitted that the post-grafting method induces significant pore clogging because of the tendency of the organic molecules to stack at the pore entrance.3a This becomes even challenging when bulky polymeric or dendritic scaffolds have to be used as surface coupling agents. Second, no special control can be excreted on the metal oxide network during the two-step post-grafting because the metal oxide matrix formed independently. The co-condensation approach, where the dendrimer plays a key role, offers oppositely more opportunities for adjusting the textural properties of the hybrid material. Table 1. Physico-chemical and textural properties of DGnx cat@TiO2.

λmaxe DHc Ed (mV) (nm) (nm) 6 DG0- cat@TiO2 497 291 224 -44.3 459 DG2-24cat@TiO2 433 142 204 -46.6 432 DG3-48cat@TiO2 280 292 99 -46.9 443 DG4-96cat@TiO2 384 296 147 -38.9 432 DG5-192cat@TiO2 337 351 129 -44.6 433 a Specific surface areas of the as-synthesized hybrid materials as determined by nitrogen sorption analysis. bLangmuir Volume as determined by nitrogen sorption analysis, cHydrodynamic diameter measured by DLS. dMain value of zeta potential.e UV-visible spectroscopic analyses. Material

SBETa (m2.g-1)

Vadsb (cm3.g-1)

TEM analysis showed the nanometer scale of the whole tectonic network (Figure S5) and and HRTEM analysis allowed visualisation of the smallest dimension limit near to the molecular regime where the homogeneous nanoscale hybridization could be confirmed by EDS technique (Figure 5). The latter could map the location of the starting dendrimer and the as-formed titanium dioxide in different regions and brings a clear evidence on the ho-

mogeneous distribution of the two building-blocks (through distribution of phosphorus and titanium elements, belonging respectively to the dendrimer skeletal and the titanium oxide phase) along the network as the same P:Ti ratio was obtained in different locations. This indicates that the early stage of the nucleation and growth is governed by thermodynamic parameters where peripheral catechols react homogeneously with soluble titanium isopropoxide rather than on preformed titanium oxide surface, which will result in a titanium core-dendrimer shell material. In support of this assumption, instantaneous red coloration of the liquid medium was observed upon mixing the two precursors, which is typical of metal-to-ligand charge transfer occurring between catechol and titanium Lewis acidic centers.48, 75-76 The as-obtained catechol-coordinated-titanium alkoxyoxo-species constitute well-defined macromolecular nuclei for additional condensation and growth of titanium isopropoxide to provide hierarchical tectonic nanostructures. As the sol-gel process continue and considering the large excess of titanium alkoxide with respect to catecholterminated dendrimers (a molar amount of [Ti]:[catechol] ratio of [20]:[1] was used herein), soluble titanium precursors diffuse from the solution to the surface of the as-formed elementary hybrid particles and react with the remaining Ti-OH and Ti-OR sites leading to an enrichment of the clusters by titanium-oxo-alkoxy species and an expansion of their size. At an advanced stage of the sol-gel condensation, several Ti-OH and TiOR belonging to different primary building-blocks react one to each other through cross-linking to build regular microspheres with voids and mesoporous network. XRD ruled out the presence of crystalline phase (ex. anatase) and only amorphous titanium dioxide was formed. In fact, the earliest nuclei formed by chelate-binding of catechol to titanium result in either bipyramidal heptacoordinated titanium or planar pentacoordinated titanium complexes, both of them are not in favour of a gentle crystallization to octahedral TiO6 of bulk anatase or square pyramidal TiO5 in surface anatase nanoparticles. 77 This result contrasts to those reported with phosphonate-terminated dendrimers that behave as a monodendate ligand for titanium complexes, and consequently



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provide - under liquid-phase reactions - discrete crystalline anatase nanoparticles.37-38 a

c

b

100 nm e

100 nm

P

g

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Figure 5. HRTEM (a), EDX cartographic mapping (b–d) Ti (red), P (yellow) and C (mauve) of DG0- cat@TiO2, HRTEM (e), EDX 48 cartographic mapping (f–h) Ti (red), P (green) and O (blue) of DG3- cat@TiO2, HRTEM (i), EDX cartographic mapping (j–l) Ti 96 (red), and P (green) of DG4- cat@TiO2. x

DLS measurement of dispersed DGn- Cat@TiO2 aqueous solution reveals a hydrodynamic diameter (D H) ranging

from 142 to 351 nm (Table 1). Except for the smallest DG0-6Cat@TiO2, an increase of the DH was observed with the dendrimer generation, indicating that the size of the elementary burst formed by catechol-coordinatedtitanium alkoxide monomers depends on the primary dendrimer used. Irrespective of the dendrimer used, the zeta potential of DGn-xCat@TiO2 varies from -38.9 mV to 46.9 mV (Table 1), much negative than the one of DG4N(Et)2H+@TiO2 (-22.0 mV) and that of DG4-PO(OH)O@TiO2 (-28.0 mV). Notably, no leached catecholterminated phosphorus dendrimer was found upon centrifugation, indicating that the co-condensation approach, although not explored compared to the postgrafting method, provides stable catechol-coordinatedtitanium dioxide hybrid materials. Comparatively, organic-free titanium dioxide strongly aggregates after similar sonication treatment, to micro-particles with an average particle size of 1480 nm and a negative zeta potential of 20.4 mV. The starting catechol-terminated dendrimers DGn-xcat also form larger object of 675 nm, indicative of strong hydrogen bonding interactions between several dendrimer units, and a negative zeta potential of -27.4 mV. UV-visible spectroscopic spectra of DGn-xcat@TiO2 displays a broad band in the visible range with a maximum wavelength centred around 432 - 459 nm and a tail up to

600 nm, typical of charge transfer occurring in catecholsensitized titanium dioxide hybrid materials (Figure 4 and Table 1). This band is red-shifted compared to the lower wavelength value of the starting dendrimers DGn-xcat.48, 75-76 Comparatively, UV-visible spectroscopic analyses of DG4-N(Et)2H+@TiO2 and DG4-PO(OH)O-@TiO2 reveal only an absorption band in the UV region at 320 nm. 39 This result substantiates the efficient electronic communication reached in DGn-xcat@TiO2 compared to DG4N(Et)2H+@TiO2 and DG4-PO(OH)O-@TiO2 materials. Biological activity of catechol-coordinated-titanium dioxide x DGn- cat@TiO2. For biological use as drug-delivery vehicle, systemic circulation is the most convenient channel to deliv19 er the targeted drug up to the cellular level. The suitability of any selected porous material to be used as drug transporter is consequently evaluated considering its interplay 19 with blood cells. In our previous work, we have shown the importance of the interfacial composition (ammonium versus phosphonate) of dendrimer-titanium dioxide (DG4+ N(Et)2H @TiO2 and DG4-PO(OH)O @TiO2) for improving 39 blood compatibility. With these biomimetic catecholx terminated DGn- Cat@TiO2 hybrids in hand, we were interested to rank them with respect to our extensively used ammonium and phosphonate-terminated materials. We therefore assessed their haemolytic activity and cytotoxicity.

In quantitative terms, a concentration-dependent increase of haemolysis was observed whatever the material used. However, the highest value reached, obtained


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for a particularly high concentration of 200 μM and a prolonged period of 72h, did not exceed 2%, which can be considered as non-haemolytic at all. DG4-

N(Et)2H+@TiO2, on the contrary, exhibited a significant haemolytic activity, reaching up to 54%, at a concentration of 100 μM (Figure 6a-b). b 60

a 8

DG4-P(OH)O-@TiO2

DG0-6cat DG0-6cat@TiO2

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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Figure 6.(a,b) Hemolytic activity of the hybrid materials, (c,d) Cytotoxicity of the hybrid materials after 72 h incubation

This can be related to the presence of interfacial ammonium inthe hybrid material. Indeed, it was shown that haemolysis caused by cationic PAMAM dendrimers increases with the number of charges on its surface, which favor electrostatic interactions with membranes.78 This interplay disturbs the membrane morphology by wrapping the curvature and forming holes inside.79 Similar results were also observed with ammonium-terminated phosphorus dendrimers where strong interactions with both the hydrophobic part and the polar head-group of the phospholipid bilayer were found to decrease the membrane fluidity.80 The complete bloodcompatibility of these catechol-coordinated-titanium dioxides results from their negative charges that induce repelling with the negatively charged cell membranes.39 Considering that the first contact of a drug-transporter during intravenous injection is with blood cells, our preliminary results highlight the great importance of DGn-xCat@TiO2 over DG4N(Et)2H+@TiO2 and to a rather less extend to DG4-PO(OH)O@TiO2 analogues. Having elucidated the blood-compatibility of DGn-xCat@TiO2, we were interested in testing their cytotoxicity with respect to DG4-N(Et)2H+@TiO2 and DG4PO(OH)O-@TiO2 materials. Under 24 hours incubation and regardless the concentration used, cells viability over or near 80% was noticed, indicating the low toxicity effect. Exposing the cells to even a prolonged time of 72 hours settled the cells viability within 50 to 60% range, which preliminary

validates the potential use of these materials in nanomedicine (Figure 6c-d). These findings are in sharp contrast with those previously observed for DG4N(Et)2H+@TiO2, where the cell viability was reduced to 34% for a concentration of 100 μg.mL-1 and an incubation time of only 24h. Thus, the detrimental effect of cationic groups on living membrane needs to be taken in consideration for the rational choice of the dendrimer terminal groups. Besides, some other results deserve comments. First, while the toxicity of ammonium-terminated dendrimers seemed to increase with increasing its generation,81 no clear trend was observed in our case herein. The slight superiority of DG224 Cat@TiO2 (70% viability) compared to its congeners (~ 60% viability) can be tentatively explained by its smaller hydrodynamic size (140 nm compared to 290-350 nm for the others) as revealed by DLS analysis (Table 1). Second, while in the case of ammonium-terminated dendrimers, inorganic hybridisation allows for suppressing its cytotoxicity,39 a reverse trend was observed as for the starting catecholterminated dendrimer, 100% of cells were viable at all the concentrations studied. The choice of catechol as a peripheral group seems thus to be well-suitable, at least compared to ammonium-terminated ones, for a biomedical use of these hybrid materials. However, additional toxicity tests need to be performed in order to deeply rationalize the observed effect induced upon hybridisation.



CONCLUSIONS In conclusion, we report a scalable synthesis and detailed characterization of novel catechol-terminated phosphorus dendrimers DGn-xcat. These biomimetic precursors were used for the first time as structure-directing co-condensing agents for titanium alkoxide mineralization. Their chelate-bidentate geometry toward titanium center affords hierarchicallyporous catechol-coordinated-titanium dioxide DGnx cat@TiO2, which can be considered as a new variant of the well-known metal-coordinated-polymer framework. The cocondensation approach undertaken herein is privileged to the post-grafting method; the latter being not suitable for conjugation of the bulky dendrimer on metal oxide surface because of the pore clogging. We showed herein that the as-reported DGn-xcat and their DGn-xcat@TiO2 hybrid version exhibit interesting blood-compatibility and cell-viability compared to their analogues derived from ammonium-terminated and phosphorus-terminated dendrimer-bridged-titanium dioxide. By varying the nature of dendrimers (terminal groups) and of metal oxide clusters, another channel of advanced therapy can be accessed through tailorable "interface compositionbiological response”. Considering particularly the limitation of the ‘dendritic box’ concept for physical drug-entrapment, these porous –dendrimer-coordinated-metal oxide frameworks provide opportunities to circumvent some persistent drawbacks and constitute a potential prelude to the rational design of novel, biologically-relevant nanomaterials.

ASSOCIATED CONTENT Supporting Information. Synthesis and characterization of catechol-terminated phosphorus dendrimer, NMR spectra, DRIFT and TEM, HRTEM, EDX analysis of materials. AUTHOR INFORMATION

Corresponding Author Corresponding Author *E-mail: [email protected].

ACKNOWLEDGMENT UEMF is warmly acknowledged for financial support. We thank Thomas Cacciaguerra and Vincent Collière for SEM, TEM and HRTEM analyses.

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Catechol-terminated dendrimers act as structure-directing and co-condensing agents to provide porous, highly compatible heteroatom-containing catechol-coordinated-titanium dioxide framework.


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Dendrimer for Templating the Growth of Porous Catechol-Coordinated

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