Mixed Periodic Mesoporous Organosilica Nanoparticles and Core

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Mixed Periodic Mesoporous Organosilica Nanoparticles and Core− Shell Systems, Application to in Vitro Two-Photon Imaging, Therapy, and Drug Delivery Jonas Croissant,† Damien Salles,† Marie Maynadier,‡ Olivier Mongin,§ Vincent Hugues,⊥ Mireille Blanchard-Desce,*,⊥ Xavier Cattoen̈ ,†,# Michel Wong Chi Man,† Audrey Gallud,‡ Marcel Garcia,‡ Magali Gary-Bobo,*,‡ Laurence Raehm,† and Jean-Olivier Durand*,† †

Institut Charles Gerhardt Montpellier, UMR-5253 CNRS-UM2-ENSCM-UM1, case courrier 1701 Place Eugène Bataillon, F-34095 Montpellier Cedex 05, France § Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Université Rennes 1, Campus Beaulieu, F-35042 Rennes Cedex, France ⊥ Univ. Bordeaux, Institut des Sciences Moléculaires, UMR CNRS 5255, Université Bordeaux, 351 Cours de la Libération, F-33405 Talence Cedex, (France) # Institut NEEL, CNRS, and Université Grenoble Alpes, F-38042 Grenoble, France ‡ Institut des Biomolécules Max Mousseron UMR 5247 CNRS; UM 1; UM 2 - Faculté de Pharmacie, Université Montpellier, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 05, France S Supporting Information *

ABSTRACT: In this work, we describe the synthesis of new Mixed Periodic Mesoporous Organosilica Nanoparticles (MPMO NPs), combining the co-condensation of a tetra-trialkoxysilylated twophoton photosensitizer with bis-(triethoxysilyl)phenylene or ethylene. Novel gold core-MPMO shell systems are also described. The MPMO NPs are analyzed and characterized by multiple techniques, and are very efficient for anti-cancer drug delivery combined with two-photon therapy in MCF-7 breast cancer cells, leading down to 76% cancer cell death. MPMO NPs are thus very promising for nanomedicine applications.

applications in vitro and in vivo,4,9 and yolk−shell structures for catalysis applications.10 The last strategy consists of combining a silica core with perfluorocarbon (FC-4) and CTAB dual surfactant systems. Using this method, Qiao and co-workers obtained yolk−shell silica core PMO shell NPs for catalytic application through incorporation of gold, platinum, and palladium NPs via removal of the hard silica template.1 Among the next challenges in this field, the preparation of metallic core PMO shell systems, and the formation of PMO NPs incorporating large functional organic fragments appear very promising, notably for theranostic applications. We recently reported biodegradable ethylene-disulfide based PMO NPs for efficient pH-triggered drug delivery in cancer cells,11 and Jianli Shi et al. reported glutathione-responsive hollow PMO NPs for high intensity focused ultrasound,12 and hollow PMO NPs for pH-triggered drug and gene deliveries.13

1. INTRODUCTION Periodic mesoporous organosilica (PMO) hybrid organic− inorganic materials have recently reached the nanoscale and are starting to be applied in the fields of nanotechnology.1−6 PMO matrices are powerful tools constructed via sol−gel processes involving solely bis and multiorganoalkoxysilane, without silica precursor (e.g., tetraethoxysilane), in order to obtain the highest impact of the organic fragments on the properties of the hybrid material. PMO nanoparticles (PMO NPs) have been recently described from simple, low-molecular-weight organosilane precursors.7 Using cetyltrimethylammonium bromide (CTAB) as the surfactant, the group of Kuroda2 reported 20 nm diameter ethylene-based wormlike structured monodisperse PMO NPs and the group of Huo5 prepared highly ordered PMO NPs based on methane, ethane, ethylene, and benzene organic moieties. Another strategy consists of using a silica NP core as the template and to condense the bridged organosilane precursor at the surface of the silica NP to afford hollow organosilica NPs after etching the silica core.8 This strategy allowed for designing of hollow PMO NPs for biological © XXXX American Chemical Society

Received: October 31, 2014 Revised: November 21, 2014

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dx.doi.org/10.1021/cm5040276 | Chem. Mater. XXXX, XXX, XXX−XXX

Chemistry of Materials

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extraction involved a sonication step of 30 min at 50 °C; the collection was carried out in the same manner. The as-prepared material was dried for few hours under vacuum. B2 MPMO NPs. A mixture of CTAB (250 mg, 6.86 × 10−1 mmol), distilled water (120 mL), and NaOH (875 μL, 2 M) was stirred at 80 °C for 50 min at 700 rpm in a 250 mL three necks round-bottom flask. Then, 1,4-bis(triethoxysilyl)benzene (1.0 mL, 2.52 mmol) was added along with the 2PS (178 mg, 1.29 × 10−1 mmol, in 900 μL of anhydrous ethanol), and the condensation process was conducted for 2 h. Afterward, the solution was cooled to room temperature while stirring; fractions were gathered in propylene tubes and the NPs were collected by centrifugation during 15 min at 21 krpm. Extraction and the following steps were identical as those described for E2 MPMO NPs. AE PMO NPs. A mixture of water (25 mL), ethanol (10 mL), and CTAB (160 mg, 4.40 × 10−1 mmol) in a 50 mL three neck roundbottom flask was stirred at 70 °C. Then an aqueous solution of potassium tetrachloroaurate (13 mg, 3.45 × 10−2 mmol in 1 mL) was injected, and NaOH (100 μL, 2 M) was injected to induce the instantaneous nucleation of the nanoparticles. After 30 s, hydrochloric acid (18 μL, 2 M) was added to the solution to produce 8 nm monodisperse gold nanoparticles at lower pH. The nanoparticles growth was conducted for 12 min under a 600 rpm stirring, and the temperature was set at 80 °C. Afterward, 1,2-bis(triethoxysilyl)ethene (100 μL, 2.62 × 10−1 mmol) was added dropwise to grow the porous PMO shell on the gold nanocrystals. The condensation process was conducted for 1 h 30 min. Afterward, the solution was cooled to room temperature while stirring; fractions were gathered in propylene tubes and the NPs were collected by centrifugation for 15 min at 21 krpm. Extraction and the following steps were identical as those described for E2 MPMO NPs. AB PMO NPs. A mixture of water (25 mL), ethanol (10 mL), and CTAB (160 mg, 4.40 × 10−1 mmol) in a 50 mL three neck roundbottom flask was stirred at 70 °C. Then an aqueous solution of potassium tetrachloroaurate (13 mg, 3.45 × 10−2 mmol in 1 mL) was injected, and NaOH (100 μL, 2 M) was injected to induce the instantaneous nucleation of the nanoparticles. After 30 s, hydrochloric acid (18 μL, 2 M) was added to the solution to produce 8 nm monodisperse gold nanoparticles at lower pH. The nanoparticles growth was conducted for 12 min under a 600 rpm stirring, and the temperature was set at 80 °C. Afterward, 1,4-bis(triethoxysilyl)benzene (100 μL, 2.52 × 10−1 mmol) was added dropwise, followed by sodium hydroxide (50 μL, 2 M) to grow the porous PMO shell on the gold nanocrystals. The condensation process was conducted for 2 h. Afterward, the solution was cooled to room temperature while stirring; fractions were gathered in propylene tubes and collected by centrifugation for 15 min at 21 krpm. Extraction and the following steps were identical as those described for E2 MPMO NPs. AE2 MPMO NPs. A mixture of water (25 mL), ethanol (10 mL), and CTAB (160 mg, 4.40 × 10−1 mmol) in a 50 mL three neck roundbottom flask was stirred at 70 °C. Then an aqueous solution of potassium tetrachloroaurate (13 mg, 3.45 × 10−2 mmol in 1 mL) was injected, and NaOH (100 μL, 2 M) was injected to induce the instantaneous nucleation of the nanoparticles. After 30 s, hydrochloric acid (18 μL, 2 M) was added to the solution to produce 8 nm monodisperse gold nanoparticles at lower pH. The nanoparticles growth was conducted for 12 min under a 600 rpm stirring, and the temperature was set at 80 °C. Afterward, 1,4-bis(triethoxysilyl)benzene (100 μL, 2.62 × 10−1 mmol) and the 2PS (89 mg, 6.45 × 10−2 mmol, in 900 μL of anhydrous ethanol) were added dropwise, followed by sodium hydroxide (50 μL, 2 M) to grow the porous PMO shell on the gold nanocrystals. The condensation process was conducted for 2 h. Afterward, the solution was cooled to room temperature while stirring; fractions were gathered in propylene tubes and collected by centrifugation during 15 min at 21 krpm. Extraction and the following steps were identical as those described for E2MPMO NPs. AB2 MPMO NPs. A mixture of water (25 mL), ethanol (10 mL), and CTAB (160 mg, 4.40 × 10−1 mmol) in a 50 mL three neck roundbottom flask was stirred at 70 °C. Then an aqueous solution of potassium tetrachloroaurate (13 mg, 3.45 × 10−2 mmol in 1 mL) was

Herein, we report two-photon-sensitive multifunctional PMO and gold core PMO shell NPs for anticancer applications in vitro: two-photon fluorescence imaging, two-photon PDT, and synergistic drug delivery (see Scheme 1). Such properties were Scheme 1. TPE-Nanotherapy Application of PMO Nanomaterials, Such As (a) Au@MPMO and (b) DrugLoaded Au@MPMO NPs Endocytosed in Cancer Cells, Respectively, (c) TPE-PDT, (d) Autonomous Drug Delivery, and (e) TPE-PDT Combined with Synergistic Drug Delivery

attained in the material via co-condensation of bis(triethoxysilyl)ethylene, or bis(triethoxysilyl)benzene with high ratios and a previously reported two-photon photosensitizer (2PS),14 leading to the so-called mixed PMO (MPMO) NPs. Furthermore, the gold core PMO/MPMO shell nanocarriers were fabricated in a remarkably efficient onepot process.

2. EXPERIMENTAL SECTION 2.1. Materials. Tetraethoxysilane, cetyltrimethylammonium bromide (CTAB), sodium hydroxide, dimethyl sulfoxide, camptothecin, doxorubicin hydrochloride, and ammonium nitrate were purchased from Sigma-Aldrich. Absolute ethanol was purchased from Fisher Chemicals. Hydrochloric acid was purchased from Anal. R. Norma Pure. 1,2-bis(triethoxysilyl)ethylene and 1,2-bis(triethoxysilyl)benzene were purchased from ABCR. 2.2. Methods. Absorption spectra were recorded on a HewlettPackard 8453 spectrophotometer and fluorescence data were collected on a PerkinElmer LS55 fluorimeter. Dynamic light scattering analysis were performed using a Cordouan Technologies DL 135 Particle size analyzer instrument. 29Si and 13C CPMAS solid state NMR sequences were recorded with a VARIAN VNMRS300, using Q8MH8 and adamantane references, respectively. TEM images were recorded with a JEOL instrument. SEM images were recorded with a FEI instrument. Energy-dispersive spectroscopy was performed via an FEI scanning electron microscope. 2.3. Syntheses of MPMO NPs. E2 MPMO NPs. A mixture of CTAB (250 mg, 6.86 × 10−1 mmol), distilled water (120 mL), and sodium hydroxide (875 μL, 2 M) was stirred at 80 °C for 50 min at 700 rpm in a 250 mL three necks round-bottom flask. Then, 1,4bis(triethoxysilyl)ethylene (1.0 mL, 2.63 mmol) was added along with the 2PS (178 mg, 1.29 × 10−1 mmol, in 900 μL of anhydrous ethanol), and the condensation process was conducted for 2 h. Afterward, the solution was cooled to room temperature while stirring; fractions were gathered in propylene tubes and the NPs were collected by centrifugation during 15 min at 21 krpm. The sample was then extracted twice with an alcoholic solution of ammonium nitrate (6 g L−1), and washed three times with ethanol, water, and ethanol. Each B



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Scheme 2. (a) Design of E2 or B2 Mixed PMO NPs, Composed of the 2PS and Either Bis(triethoxysilyl)ethylene (E), or Bis(triethoxysilyl)benzene (B), Respectively; (b) One-Pot Synthesis of AE or AB Gold Core PMO Shell NPs, Respectively Composed of Either the E or the B Moiety; (c) One-Pot Synthesis of AE2 or AB2 Gold Core Mixed PMO Shell NPs, Composed of Either 2PS and E (AE2), or 2PS and B (AB2 NPs)

injected, and NaOH (100 μL, 2 M) was injected to induce the instantaneous nucleation of the nanoparticles. After 30 s, hydrochloric acid (18 μL, 2 M) was added to the solution to produce 8 nm monodisperse gold nanoparticles at lower pH. The nanoparticles growth was conducted for 12 min under a 600 rpm stirring, and the temperature was set at 80 °C. Afterward, 1,4-bis(triethoxysilyl)benzene (100 μL, 2.52 × 10−1 mmol) and the 2PS (89 mg, 6.45 × 10−2 mmol, in 900 μL of anhydrous ethanol) were added dropwise, followed by sodium hydroxide (50 μL, 2 M) to grow the porous PMO shell on the gold nanocrystals. The condensation process was conducted for 2 h. Afterward, the solution was cooled to room temperature while stirring; fractions were gathered in propylene tubes and collected by centrifugation during 15 min at 21 krpm. Extraction and the following steps were identical as those described for E2 MPMO NPs. 2.4. Loading of MPMO NPs with Anticancer Drugs. Camptothecin Loading in PMO NPs. A mixture of dimethyl sulfoxide (DMSO, 1 mL), camptothecin (3 mg), and PMO NPs (25 mg) was prepared in a 5 mL round-bottom flask and stirred at 40 °C for 2 days. The preparation was centrifuged at 10000 rpm in 40 mL propylene tubes, and the supernatant was removed. Then, the nanomaterial was washed once with DMSO (without sonication), and twice with deionized water, and dried under vacuum. Doxorubicin Loading in PMO NPs. A mixture of water (250 μL), doxorubicin (1 mg), and PMO NPs (10 mg) was prepared in an eppendorf tube, sonicated for 30 min, and stirred overnight at room temperature. The preparation was centrifuged at 10000 rpm in 40 mL propylene tubes, and the supernatant was removed. The nanomaterial was washed twice with water (10 mL), and dried under vacuum. The loading capacities were deduced by the titration of doxorubicin in the supernatant fractions.

3. RESULTS AND DISCUSSION 3.1. Syntheses of MPMO NPs. First, PMO nanomaterials were designed according to three strategies shown in Scheme 2. The 1,2-bis(triethoxysilyl)ethylene (E) or 1,4-bis(triethoxysilyl)benzene (B) precursors were mixed with the 2PS to lead to E2 or B2 MPMO NPs, respectively (Scheme 2a). This synthetic process involved a mixture of water/ethanol containing CTAB, and sodium hydroxide as the catalyst (see the Supporting Information). The presence of EtOH allowed to solubilize the precursors and to control the sol−gel condensation in order to obtain the NPs with desired size and morphology. Core−shell Au@PMO NPs AE and AB were prepared in only 2 h at 80 °C in one pot. Au NPs were first generated in situ,15 and then bis(triethoxysilyl)ethylene (E) or bis(triethoxysilyl)benzene (B), were condensed respectively (Scheme 2b). Again the presence of EtOH was necessary to solubilize the precursors and to control the reaction. The same procedure was used with 2PS mixed with bis(triethoxysilyl)ethylene (E) or bis(triethoxysilyl)benzene (B) to synthesize core−shell gold core@ethylene-2PS-based PMO shell (AE2) or gold core@benzene-2PS-based PMO shell (AB2) respectively, which feature gold cores and a mixed PMO shells (Scheme 2c). Besides, our syntheses of PMO NPs were performed in only 2 h, which is remarkably fast compared to the few reported methodologies (2−6 h of reaction, plus an additional 24 h of aging).5,16 3.2. Characterisations of MPMO NPs. The structures of MPMO NPs were readily visible with transmission electron C



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Figure 1. Characterization of the structure of the PMO NPs. (a−f) Schematic representations and TEM images of E2, B2, AE, AB, AE2, and AB2 NPs.

Figure 2. (a−f) N2 adsorption−desorption isotherms, (g−l) diffraction patterns at low angles, and (m−r) UV−visible spectra of E2, B2, AE, AB, AE2, and AB2 NPs, respectively.

microscopy (TEM, Figure 1). E2 and B2 MPMO NPs were respectively of 200 and 100 nm in size, and monodisperse (Figure 1a, b). Au@PMO NPs and Au@MPMO NPs were typically of a hundred nanometers in diameter, and composed of a couple of 15 nm gold nanospheres in their center (Figure 1c−f). The mesoporous organization of the nanomaterial frameworks was further confirmed by high-magnification TEM micrographs (Figure S1a−f in the Supporting Information). Scanning electron microscopy (SEM) images as well as dynamic light scattering (DLS) analyses displayed the monodispersity of the aforementioned PMO NPs (Figure S1g−l and m−r, respectively, in the Supporting Information).

Besides, the accessibility of the mesoporous structure of the MPMO NPs was demonstrated by N2-adsorption and desorption technique, with high BET surface areas ranging from 900 to 1100 m2 g−1 (Figure 2a−f). The BJH pore size distribution was generally centered at 2.5 nm, which is also confirmed with the low angle peak in the X-ray diffractograms (Figure 2g−l). Note that E2 was structured in a 2D hexagonal arrangement, as revealed by the presence of harmonics from 4− 5° (2θ, CuKα) in the X-ray diffractograms, and by the observation of parallel channels in the TEM image (see Figure S1a in the Supporting Information). Interestingly, AE and AE2 materials synthesized from the same precursor (E) and D



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Figure 3. (a−f) Two-photon confocal microscopy images (λex = 760 nm) of incubated E2, B2, AE, AB, AE2, and AB2 NPs, respectively. Scale bars 10 μm. (g) Demonstration of the synergistic effect of two-photon photodynamic therapy (PDT) and drug delivery, either with the camptothecin (CPT) or the doxorubicin (DOX) drugs, via drug-free and drug-loaded E2 and B2 NPs. (h) Demonstration of the synergistic effect of two-photon photodynamic therapy (PDT) and drug delivery, via DOX-free Au@PMO, Au@MPMO NPs, and DOX-loaded Au@MPMO NPs.

surfactant, but in the presence of gold cores exhibited a radial porosity, whereas B2, AB and AB2 possessed a worm-like porous framework (see Figure S1b−f in the Supporting Information). It was observed from the panel of characterizations than the ethylene moiety leads to better structured materials than the benzene ones. This is in agreement with the TEM images as well as the XRD measurements, which display

significantly more distinct peaks for materials obtained with E (Figure 2g, i, k) than for those with B (Figure 2h, j, l). The chemical composition of the MPMO NPs was then characterized by multiple techniques. On one hand, the solid state nuclear magnetic resonance (NMR) 29Si cross-polarization magic angle spinning (CPMAS) spectra of the PMO NPs evidenced the formation of the siloxane framework with E



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TPE (Figure 3c, d), which is probably due to the aggregation of some gold nanospheres in the core thus leading to a plasmon resonance in the NIR and a behavior typical of gold nanorods.20 Drug-free PMO NPs were then studied for TPE-PDT under the same conditions. No cancer cell killing was observed with E2 and only 15% of cancer cell death was observed with B2 (Figure 3g). However, when gold NPs were encapsulated in the MPMO matrices, AE2 and AB2 showed 40 and 27% cancer cell killing respectively after irradiation (Figure 3h). It is noteworthy that AE and AB NPs showed no cancer cell death under the same conditions, thus two-photon PDT attributable to the gold cores are not sufficient to kill cancer cells. Furthermore, two-photon photothermal effects have been shown to be negligible with gold nanorods under two-photon excitation.21 Although we did not notice an enhancement of σ2 of 2PS in the presence of gold, a synergy between gold nanocrystals and 2PS moieties was clearly operative, and produced an important enhancement of cancer cell death. We then examined E2 and B2 MPMO NPs as vectors for camptothecin (CPT) and doxorubicin (DOX) autonomous drug deliveries. The hydrophobic CPT was loaded in the pores in DMSO, remained in the aqueous medium after loading, and was released in DMSO (1.1−1.3 wt %, see Figure S7 in the Supporting Information). DOX release experiments were first carried out at pH 7 in water, with doxorubicin-loaded MPMO and Au@MPMO NPs (see Figure S8 in the Supporting Information). No release of DOX was observed in these conditions showing that important interactions between the drug and the organosilica matrix occurred.11 The release was triggered at pH 5.5 (lysosomal pH), and all nanocarriers had high loading capacities of DOX, typically of 10 wt % (see Table S5 in the Supporting Information). With nonirradiated MCF-7 cancer cells, incubated MPMO NPs showed efficient cancer cell killing with CPT and DOX, reaching up to 45% with DOXloaded MPMO NPs (Figure 3g, see white bars). Finally, the unprecedented combined action of drug delivery and TPE-PDT on cancer cells was studied for MPMO NPs loaded with DOX. Interestingly, an important synergy of these therapeutic features was noticed for MPMO, as more cell death was observed for all the irradiated cells than without irradiation, with up to 58 and 76% cancer cell killing with E2+DOX and B2+DOX respectively. Concerning core−shell MPMO NPs composed of inserted 2PS moieties inside the framework, the efficiency of the materials was further increased up to 76% cancer cell death with both AE2 and AB2. Hence, the most promising synergistic treatment is obtained with the AE2 nanocarrier because it provided both an efficient two-photon spatiotemporally controlled cell killing (40% without drug), while the TPE-enhanced DOX delivery further decreased the cell survival.

the major proportion of the T2 and T3 signals (see Figure S2 in the Supporting Information), whereas the ethylene (−145 ppm), benzene (−134 ppm), and 2PS moieties were identified via NMR 13C CPMAS spectra (see Figure S3 in the Supporting Information). UV−visible spectra also showed the 2PS absorption band (λmax ≈ 390 nm) of MPMO NPs (Figure 2m, n, q, r), as well as the benzene groups (λmax ≈ 265 nm) of B2, AB, and AB2 NPs (Figure 2n, p, r). On the other hand, the presence of gold NPs in AE, AB, AE2, and AB2 PMO and MPMO NPs was clearly identified both by UV−visible absorption spectra (see Figure 2m−r) and by the wide-angle XRD patterns (see Figure S4 in the Supporting Information), specifically through the peak at 38° corresponding to the 111 crystallographic planes, which is absent in E2 and B2 NPs (see Figure S4a, b in the Supporting Information). Besides, highresolution TEM images of the gold cores inside AE2 and AB2 confirmed the crystalline structure of such nanoparticles with the typical 0.22 nm interatomic distance in the gold NPs (see Figure S5 in the Supporting Information). Inductively coupled plasma and energy-dispersive spectrometry analyses determined 0.8 to 4.6 wt % of gold in the NPs (see Table S1 in the Supporting Information). The 2PS content of the NPs was determined by elemental analyses of nitrogen (14 atoms per 2PS moiety) and found to be of 24 and 27 weight percent (wt %) respectively for E2 and B2 NPs, as well as 42 and 46 wt % for AE2 and AB2 NPs respectively (see Table S3 in the Supporting Information). Note that, the overall preparation yields of the surfactant-free PMO and MPMO NPs were generally ranging from 40 to 60% (see Table S2 in the Supporting Information), though lower in AE2 (30−40%) and higher in B2 (80−95%). The optical and photophysical properties of the MPMO NPs were then investigated. A nonalkoxysilylated two-photon reference (2PS ref) molecule6 was used (see structures and absorption spectra of the 2PS and 2PS ref in Figure S6a in the Supporting Information). The E2 and B2 MPMO NPs had higher quantum yields than Au@MPMO NPs (see Table S4 in the Supporting Information), and higher bathochromic shifts of the 2PS bands were observed with core−shell systems, reflecting higher aggregation states17 of the 2PS during the core−shell syntheses. The two-photon absorption cross sections of the PMO nanomaterials were measured and an important decrease in the σ2 compared to 2PS ref was observed for MPMO and Au@MPMO nanosystems from 100 Göppert Mayer (GM) to less than 10 GM per fluorophore (see Figure S6 in the Supporting Information). Nevertheless, MPMO and Au@MPMO NPs were exploited for TPE imaging and therapy of MCF-7 breast cancer cells. 3.3. Application of MPMO NPs in Two-Photon Cancer Imaging and Therapy. The two-photon-sensitive PMO nanomaterials library was then tested for two-photon nanomedical applications. An in vitro study was conducted on the MCF-7 breast cancer cell line, and the laser excitation was performed with a Carl Zeiss two-photon confocal microscope.18,19 First, the cellular uptake was assessed via twophoton fluorescence imaging to track the nanocarriers. The cell walls were stained with CellMask 15 min before the imaging experiment. As displayed in Figure 3a−f, the two-photon confocal microscopy confirmed the successful cellular-uptake, through efficient fluorescent properties of all PMO NPs composed of the 2PS (Figure 3a, b, e, f). Besides, the internalization of AE and AB NPs possessing only the gold core was also detected, showing that these NPs were efficient for

4. CONCLUSION In summary, a library of PMO NPs was described for the first time for two-photon-triggered nanomedicine. MPMO and Au@MPMO NPs were designed in efficient one-pot processes of 2−3 h. The PMO nanomaterials showed remarkably high specific surface areas, which made them suitable for drug transportation. All the NPs were endocytosed by MCF-7 cancer cells, as shown by TPE fluorescence imaging at low laser power. On the basis of these results, an unprecedented dual therapeutic approach was designed using drug-loaded MPMO and Au@ MPMO NPs, which led to synergistic cancer cell killing by TPE-PDT combined with drug delivery. Autonomous DOX F



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(17) Natte, K.; Behnke, T.; Orts-Gil, G.; Wuerth, C.; Friedrich, J. F.; Oesterle, W.; Resch-Genger, U. J. Nanopart. Res. 2012, 14, 680. (18) Croissant, J.; Maynadier, M.; Gallud, A.; Peindy N’Dongo, H.; Nyalosaso, J. L.; Derrien, G.; Charnay, C.; Durand, J.-O.; Raehm, L.; Serein-Spirau, F.; Cheminet, N.; Jarrosson, T.; Mongin, O.; BlanchardDesce, M.; Gary-Bobo, M.; Garcia, M.; Lu, J.; Tamanoi, F.; Tarn, D.; Guardado-Alvarez, T. M.; Zink, J. I. Angew. Chem., Int. Ed. 2013, 52, 13813. (19) Croissant, J.; Chaix, A.; Mongin, O.; Wang, M.; Clément, S.; Raehm, L.; Durand, J.-O.; Hugues, V.; Blanchard-Desce, M.; Maynadier, M.; Gallud, A.; Gary-Bobo, M.; Garcia, M.; Lu, J.; Tamanoi, F.; Ferris, D. P.; Tarn, D.; Zink, J. I. Small 2014, 10, 1752. (20) Jiang, C.; Zhao, T.; Yuan, P.; Gao, N.; Pan, Y.; Guan, Z.; Zhou, N.; Xu, Q.-H. ACS Appl. Mater. Interfaces 2013, 5, 4972. (21) Zhao, T.; Shen, X.; Li, L.; Guan, Z.; Gao, N.; Yuan, P.; Yao, S. Q.; Xu, Q.-H.; Xu, G. Q. Nanoscale 2012, 4, 7712. (22) Pawlicki, M.; Collins, H. A.; Denning, R. G.; Anderson, H. L. Angew. Chem., Int. Ed. 2009, 48, 3244.

delivery was tailored without irradiation, and 76% of synergistic cell death was obtained via TPE-PDT and enhanced-DOX delivery. Therefore, the library of NPs herein described are highly promising for theranostic applications with an excellent spatiotemporal accuracy.22

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ASSOCIATED CONTENT

S Supporting Information *

Characterizations of the prepared nanoPMOs, high-magnification TEM, SEM, DLS, solid-state NMR, X-rays, elemental analyses, photophysical properties, drug release, two-photon experimental settings. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*Fax: +33-467-143-852. E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank ANR P2N Mechanano for funding. Technological support from the Rio Imaging Platform is gratefully acknowledged. MBD gratefully acknowledges Conseil Regional d’Aquitaine (CRA) for financial support. VH received a fellowship from CRA. D. Cot is acknowledged for the SEM imaging, and X. Dumail for his help in the synthesis of 2PS.

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REFERENCES

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Mixed Periodic Mesoporous Organosilica Nanoparticles and Core

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