Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules

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Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules for Significantly Improved Cellular Uptake Zhaogang Teng, Chunyan Wang, Yuxia Tang, Wei Li, Lei Bao, Xuehua Zhang, Xiaodan Su, Fan Zhang, Junjie Zhang, Shouju Wang, Dongyuan Zhao, and Guangming Lu J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10694 • Publication Date (Web): 27 Dec 2017 Downloaded from http://pubs.acs.org on December 27, 2017

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Journal of the American Chemical Society

Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules for Significantly Improved Cellular Uptake

Zhaogang Teng,†,‡ Chunyan Wang,† Yuxia Tang,† Wei Li,*,§ Lei Bao,⊥ Xuehua Zhang,⊥ Xiaodan Su,¶ Fan Zhang,§ Junjie Zhang,¶ Shouju Wang,† Dongyuan Zhao,*,§ and Guangming Lu*,†,‡ †

Department of Medical Imaging, Jinling Hospital, School of Medicine, Nanjing University, Nanjing,

210002 Jiangsu, P.R. China ‡

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical

Engineering, Nanjing University, Nanjing, 210093 Jiangsu, P.R. China §

Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials,

State Key Laboratory of Molecular Engineering of Polymers, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, P.R. China ⊥

Soft Matter & Interface Group, School of Engineering, RMIT University, Melbourne, VIC 3000,

Australia. ¶

Key Laboratory for Organic Electronics & Information Displays and Institute of Advanced Materials,

Nanjing University of Posts and Telecommunications, Nanjing, 210046 Jiangsu, P.R. China

Abstract: Mesoporous solids have been widely used in various biomedical areas such as drug delivery and tumor therapy. Although deformability has been recognized as a prime important characteristic influencing cellular uptake, the synthesis of deformable mesoporous solids is still a great challenge. Herein, deformable thioether-, benzene-, and ethane-bridged hollow periodic mesoporous organosilica (HPMO) nanocapsules have successfully been synthesized for the first time by a preferential etching approach. The prepared HPMO nanocapsules possess uniform diameters (240–310 nm), high surface ACS Paragon Plus Environment

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areas (up to 878 m2⋅g–1), well-defined mesopores (2.6–3.2 nm), and large pore volumes (0.33–0.75 m3⋅g–1). Most importantly, the HPMO nanocapsules simultaneously have large hollow cavities (164–270 nm), thin shell thicknesses (20–38 nm), and abundant organic moiety in the shells, which endow a lower Young's modulus (EY) of 3.95 MPa than that of solid PMO nanoparticles (251 MPa). The HPMOs with low EY are intrinsically flexible and deformable in the solution, which has been well characterized by liquid cell electron microscopy. More interestingly, it is found that the deformable HPMOs can easily enter into human breast cancer MCF-7 cells via a spherical-to-oval morphology change, resulting in a 26-fold enhancement in cellular uptake (43.1% cells internalized with nanocapsules vs. 1.65% cells with solid counterparts). The deformable HPMO nanocapsules were further loaded with anti-cancer drug doxorubicin (DOX), which show high killing effects for MCF-7 cells, demonstrating the promise for biomedical applications.

1. Introduction Mesoporous solids have inspired prominent research interests in biomedicine such as drug/gene delivery, molecular imaging and tumor therapy because of their uniform and tunable mesopores, large surface area and pore volume, and easily functionalized inner and/or outer surfaces.1-4 For different biomedical applications, a variety of mesoporous solids with different compositions (silica, carbon, and polymer),5-8 mesostructures (hexagonal, cubic, and bicontinuous),9-13 and morphologies (sphere, rod, hollow, and film)14-18 have been successfully explored. However, to the best of our knowledge, all the mesoporous solids are stiff as they interact with biological systems because their frameworks are highly cross-linked and generally hard in nature.19-21 The synthesis of "soft" or deformable mesoporous solid materials remains a major challenge. Modulating the interaction of solid nanoparticles with cells is an important prerequisite for their application in diagnosis and treatment of various diseases.22-29 The particles' size, shape and surface charge have been demonstrated as the "standard" parameters influencing cellular interaction and uptake ACS Paragon Plus Environment

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processes.30-33 Recently, nanoparticles with elastic or deformable properties, which can compress and deform upon cellular interaction, are attracting more and more attention in both theoretical and experimental biological studies.34-36 For instance, Yi et al. analyzed, based on a theoretical model, the cellular uptake process of deformable particles and found that it is different from that of stiff particles.35 Caruso and co-workers found that softer hyaluronic acid capsules possess higher cell surface binding and cellular association compared to that of stiffer counterparts.36 Decuzzi and co-workers demonstrated that soft polymeric nanodiscoidals exhibit a longer circulation half-time and enhanced tumor accumulation than those of rigid ones.37 However, to the best of our knowledge, the reported soft and deformable nanoparticles do not possess well-defined mesopores and their compositions are generally limited to soft organic materials such as polymers and liposomes. Exploring deformable mesoporous solids is of great importance and desirable not only from the fundamental aspect of endowing materials with unique properties but also because it can open new application prospects. However, the intrinsic rigid chemical bonds in mesoporous solids generally restrict their deformation. Therefore, to make it possible, the following factors may be useful and should be considered: 1) flexible organic moieties with easily changeable bond angle and bond length in the frameworks; 2) a relatively high content of non-cross-linked free groups; 3) easily deformable nanostructure such as hollow spheres with ultra-thin shell. Herein, we report the synthesis of deformable hollow periodic mesoporous organosilica (HPMO) nanocapsules by a preferential etching approach. In this case, the abundant free groups and organic moieties in the thin mesoporous framework are essential for the deformation. The liquid cell TEM shows that the in-situ formed HPMO nanocapsules with thin shells in the etching solution are intrinsically cross-wrinkled in shape, which does not need any drying process to drive the deformation. The resultant deformable HPMO have uniform mesopores (2.6–3.2 nm), large hollow cavities (164–270 nm), thin shell thicknesses (20–38 nm), and very low Young's moduli (3.95–47.7 MPa). The preferential etching approach proposed in the work is simple, versatile, and robust. The formation mechanism is that the inner parts and structurally stable Si−(O)4 tetrahedrons of the mesostructured organosilica ACS Paragon Plus Environment

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nanospheres are preferentially etched away, resulting in ultra-thin nanocapsules with high content of flexible Si−R−Si chains and non-cross-linked Si−OX groups. When reinforced by an inorganic silica coating shell, the deformable HPMO nanocapsules can transform to a well-defined hollow structure with rigid framework even after drying, further indicating that the molecular structure and thin shell thickness nature are the origins of the deformation. Moreover, the deformable HPMO nanocapsules exhibit higher cellular uptake efficiency and killing effect for cancer cells after loading anti-cancer drugs compared to that of non-deformable nanoparticles.

2. Experimental Section 2.1. Chemicals and Materials. Cetyltrimethylammonium bromide (CTAB), concentrated ammonia aqueous solution (25–28 wt%), anhydrous ethanol, tetraethoxysilane (TEOS), and NaOH were obtained from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Bis[3-(triethoxysilyl)propyl] tetrasulfide (TESPTS), 1,2-bis(triethoxysilyl)ethane (BTSE), and 1,4-bis(triethoxysilyl)benzene (BTSB) were obtained from Sigma–Aldrich (St. Louis, MO, USA). Deionized water (Millipore) with a resistivity of 18 MΩ⋅cm was used in all experiments. Cy5.5-maleimide was obtained from Seebio Biotechnology Co., Ltd. (Shanghai, China). Methoxy polyethylene glycol-maleimide (PEG-maleimide) with a molecular weight of 2000 was purchased from Shanghai Seebio Biotech, Inc. (China). Doxorubicin (DOX) in the form of hydrochloride salt and paclitaxel (PTX) were purchased from Beijing Huafeng United Technology Co. Ltd. (China). Cell counting kit-8 (CCK-8) and 4’-6-diamidino-2-phenylindole (DAPI) were obtained from Nanjing Keygen Biotech. Co., Ltd. (China). 2.2. Synthesis of Deformable HPMO Nanocapsules. Thioether-bridged deformable HPMO nanocapsules were prepared as follows: CTAB (0.16 g) was dissolved in a mixture containing water (75 mL), ethanol (30 mL), and a concentrated ammonia aqueous solution (1.0 mL, 25–28 wt%). The mixture was then heated at 35 °C in a water bath, and followed by adding mixed precursors (0.1 mL of TESPTS and 0.25 mL of TEOS) under vigorous stirring (1100 rpm). After stirring at 35 °C for 24 h, ACS Paragon Plus Environment

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thioether-bridged mesostructured organosilica nanospheres were collected by centrifugation and washed with ethanol three times. The obtained organosilica nanospheres were then etched in 31.5 mL of NaOH aqueous solution (0.48 M) at room temperature for 30 min. The obtained products were collected by three rinse/centrifugation cycles. The CTAB templates were then removed from the organosilica by three solvent extractions in a solution containing concentrated HCl (240 µL, 37%) and ethanol (120 mL) at 60 °C for 3 h. After washing with ethanol three times, the thioether-bridged HPMO nanocapsules were obtained. The benzene-bridged HPMO nanocapsules were prepared via the same processes except that the mesostructured organosilica nanospheres were synthesized using 0.05 mL of BTSB and 0.25 mL of TEOS as co-precursors and the products were etched in 264 mL of NaOH aqueous solution (0.34 M) for 20 min. The ethane-bridged HPMO nanocapsules were prepared by etching mesostructured organosilica nanospheres in 15 mL of NaOH aqueous solution (1 M) for 20 min, which were prepared by using 0.25 mL of BTSE and 0.25 mL of TEOS as co-precursors. 2.3. Inorganic Silica Reinforcement Experiment. In a typical, one milligram of thioether-bridged HPMO nanocapsules were dispersed in a mixed solution containing 5.0 mL of ethanol, 0.1 mL of water, and 0.17 mL of concentrated ammonia aqueous solution (25 wt.%). The suspension was ultrasonically dispersed for 1 h and stirred at 40 °C for 1 h. Afterward, 14 µL of TEOS was rapidly added and the reaction was allowed to proceed for 12 h at 40 °C under continuous mechanical stirring. After washing with water, the silica reinforced thioether-bridged HPMOs were obtained. 2.4. Characterization. Transmission electron microscopy (TEM) observations were performed using an HT7700 microscope (Hitachi, Tokyo, Japan) at 100 kV. Scanning electron microscopy (SEM) observations were carried out using a Hitachi S4800 microscope (Tokyo, Japan) at 5 kV. The samples for the TEM and SEM measurements were suspended ultrasonically in ethanol and supported on a carbon-coated Cu grid or silicon wafer. Microphotographs were captured using an Olympus IX71 microscope (Japan). Fourier transform infrared (FT-IR) spectra were collected using KBr pellets of the solid samples using a Nicolet NEXUS870 spectrometer (Nicolet Instruments Inc. Madison, WI, USA). 29

Si magic-angle spinning (MAS) NMR spectra were recorded at 9.47 T using a Bruker AVIII400 ACS Paragon Plus Environment

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spectrometer operating with a frequency of 79.48 MHz, a spin rate of 6.0 kHz, and a recycle delay of 120 s. Nitrogen sorption isotherms were measured at -196 °C using a Micromeritics ASAP 2020 analyzer. The samples were degassed in a vacuum at 150 °C for 10 h before the measurements. The Brunauer–Emmett–Teller (BET) method was utilized to calculate the specific surface areas using the adsorption data in relative pressures ranging from 0.03 to 0.29. The micropore surface area was calculated using the t-plot method. The pore size distributions were derived from the adsorption branches of isotherms by applying proper nonlocal density functional theory (NLDFT) methods. The total pore volumes were estimated from the adsorbed amounts at a relative pressure of 0.995. Young’s modulus of the samples was measured by atomic force microscopy (AFM) in the mode of Peak Force Quantitative Nanomechanical Mapping (PeakForce QNM, Dimension Icon AFM, Bruker, USA). A TESPA-V2 AFM cantilever (Bruker AFM probes) was used for the measurements. The spring constant of the cantilever was calibrated at 19.6 N⋅m–1 and the normal tip radius was 20 nm. The samples were dispersed in water and sonicated for 30 min. A drop of sample suspension was placed onto a freshly cleaned silicon surface and the measurements of the mechanical properties were conducted in water (18.2 MΩ⋅cm, Millipore, Merk Australia). The Young’s modulus was calculated from the slope in the linear region of the retraction curve by using the Hertzian Model.38 Twenty curves were analyzed for each sample to obtain the averaged modulus. Zeta potential and hydrodynamic size were measured using a Brookhaven ZetaPALS analyzer. Confocal images were taken using a Leica TSC SP8 confocal laser scanning microscope (Germany) with a 63× oil immersion objective (numerical aperture = 1.40). 2.5. Modification. The thioether-bridged deformable HPMO nanocapsules and conventional PMO nanospheres were modified with the fluorescent dye Cy5.5 and PEG to study their interaction with cells. In brief, 0.065 g of thioether-bridged deformable HPMO nanocapsules or PMO nanospheres were dispersed in a mixed solution containing 1.1 mL of dioxane, 0.3 mL of water, and 0.10 g of triphenylphosphine. The solution was then heated to 40 °C, and two drops of concentrated aqueous HCl solution (37 wt%) were added. After 2 h in an atmosphere of nitrogen, the disulfide bonds in the HPMO

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nanocapsules or PMO nanospheres were reduced to thiol groups. After the obtained thiol group incorporated HPMO nanocapsules or PMO nanospheres were washed with ethanol three times, they were added into a mixed solution of water (12 mL), N,N-dimethylformamide (1.2 mL), and PEG-maleimide (3.24 mg) and shaken at room temperature for 12 h. Subsequently, the products were collected by centrifugation and re-dispersed in a mixture of 12 mL of water, 1.2 mL of N,N-dimethylformamide, and 1.2 mg of Cy5.5-maleimide. After shaking at room temperature for 12 h and a thoroughly washing with water, Cy5.5- and PEG-modified HPMO nanocapsules (HPMO-Cy5.5-PEG) or Cy5.5- and PEG-modified PMO nanospheres (PMO-Cy5.5-PEG) were obtained. 2.6. Cellular Interaction Analysis. The HPMO-Cy5.5-PEG nanocapsules or PMO-Cy5.5-PEG nanospheres associated with cells were assessed via flow cytometry and TEM. For flow cytometry analysis, human breast cancer MCF-7 cells or macrophage RAW 264.7 cells obtained from American Type Culture Collection (ATCC) were seeded into six well plates and incubated overnight at 37 °C. Then, 5 × 105 HPMO-Cy5.5-PEG nanocapsules or PMO-Cy5.5-PEG nanospheres dispersed in Dulbecco's modified Eagle's medium (DMEM) were added and incubated at 37 or 4 °C. The number of particles in the DMEM medium was quantified using a Beckman CytoFLEX flow cytometry system. At specified intervals, the cells were washed with phosphate-buffered saline (PBS) three times, harvested by trypsinization, centrifuged at 900 rpm for 5 min, re-suspended in PBS, and analyzed using the Beckman CytoFLEX flow cytometry system. The percentages of cells interacting with HPMO-Cy5.5-PEG or PMO-Cy5.5-PEG were determined by the signal of Cy5.5. To carry out TEM analysis, MCF-7 cells were incubated with 100 µg mL–1 of the HPMO-Cy5.5-PEG nanocapsules or PMO-Cy5.5-PEG nanospheres in the Roswell Park Memorial Institute (RPMI) 1640 medium for 4 h. The cells were collected by centrifugation, fixed with 2.5% glutaraldehyde and 1% OsO4, dehydrated in a graded ethanol series, embedded in resin, and then sliced into 60–80 nm sections for TEM observation. ACS Paragon Plus Environment

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2.7. In Vitro Chemotherapeutic Effect. To load DOX molecules, DOX (2.0 mg mL–1) was mixed with PEG modified PMO (PMO-PEG) or PEG modified HPMO (HPMO-PEG) at a concentration of 1.0 mg mL–1, and the mixture was shaken under dark conditions over night. Afterward, the DOX-loaded PMO-PEG (denoted as PMO-PEG/DOX) or HPMO-PEG (denoted as HPMO-PEG/DOX) were collected by centrifugation and washed with water three times. The loading and washing solutions were collected to calculate the DOX payloads. Afterwards, MCF-7 human breast cancer cells were seeded into 96-well plate at a concentration of 1 × 104 cells/well and allowed to grow for 24 h. Different concentrations of PMO-PEG/DOX or HPMO-PEG/DOX in RPMI 1640 medium were then added to the culture. After incubating for 24 h, 20 µL of CCK-8 solution was added and incubated for additional 2 h. Finally, the absorbance of each sample was measured on a microplate reader (Tecan, Switzerland) at 470 nm. The cell viability (%) was calculated as (mean absorbance value of treated cells/mean absorbance value of control cells) × 100. The cellular uptake of the PMO-PEG/DOX or HPMO-PEG/DOX was observed using a confocal laser scanning microscope. In brief, 1 mL of MCF-7 cells with a concentration of 1 × 105 cells/ml were seeded into a dish and allowed to grow for 12 h. Then, 1 mL of PMO-PEG/DOX or HPMO-PEG/DOX dispersed in RPMI 1640 medium with a concentration of 0.1 mg mL–1 were incubated with the cells at 37 °C for 4 h. The cells were then washed with phosphate-buffered saline (PBS) and stained with DAPI for imaging on a confocal laser scanning microscope.

3. Results and Discussion Mesostructured organosilica nanospheres with thioether-, benzene-, or ethane-groups were prepared via a CTAB-directing sol–gel process. TEM and SEM images show that the thioether-, benzene-, and ethane-bridged organosilica both have a well-defined spherical shape and uniform diameters of 290, 235, and 280 nm, respectively (Figure 1a-c, and Figure S1). Interestingly, after being etched in 0.48 M NaOH solution for 30 min, TEM and SEM images disclose that the thioether-bridged mesostructured ACS Paragon Plus Environment

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organosilica nanospheres are completely transformed into collapsed hollow nanocapsules with a uniform cross-wrinkled morphology (Figure 1a1, a2 and S1), indicating the intrinsical flexibility and deformation of the mesoporous framework. The diameter, cavity size, and shell thickness of the thioether-bridged HPMOs are measured to be approximately 310, 250 and 30 nm, respectively. After etching with a mild NaOH solution (0.34 M) for 20 min, the benzene-bridged organosilica nanospheres can also be transformed into deformable hollow nanocapsules with a diameter of 270 nm and a bowl-like morphology (Figure 1b1, b2 and S1). In addition, ethane-bridged deformable HPMO nanocapsules with a diameter of 240 nm and a unique cross-wrinkled shape can be obtained after treating in a relatively high concentration of NaOH solution (1 M) for 20 min (Figure 1c1, c2 and S1). The cavity size and shell thickness are measured to be approximately 220 and 25 nm for the benzene-bridged HPMOs and 164 and 38 nm for the ethane-bridged HPMOs, respectively. These results clearly indicate that deformable HPMO nanocapsules with heteroelement, aromatic, or alkyl fragments can be successfully prepared.


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Figure 1. TEM images of (a) thioether-, (b) benzene-, and (c) ethane-bridged mesostructured organosilica nanospheres synthesized via a CTAB-directed sol–gel process. TEM images of (a1, a2) thioether-, (b1, b2) benzene- and (c1, c2) ethane-bridged HPMO nanocapsules prepared by etching the corresponding organosilica nanospheres in a mild NaOH solution. Insets in (a2, b2, and c2) are the structural models of the deformed HPMO nanocapsules.

To clearly elucidate the deformation origin of HPMO nanocapsules, liquid cell electron microscopy was applied to directly analyze the HPMO nanocapsules in-situ formed in the NaOH solution without any drying process, which may result in the deformation of hollow structures due to the mechanical effect during solvent evaporation.39 An ethanol suspension of the thioether-bridged HPMOs was loaded ACS Paragon Plus Environment

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into a silicon nitride microchip with a chamber height of 2 µm (Figure 2a). The liquid cell TEM image shows that the thioether-bridged HPMOs disperse very well in the ethanol (Figure 2b). High-magnification TEM images clearly reveal that the thioether-bridged HPMOs possess a cross-wrinkled nanocapsule morphology (Figure 2c, d), suggesting that the deformed HPMO nanocapsules in-situ form during the etching process in solution, even if without additional drying process. Interestingly, the deformed HPMO nanocapsules can be recovered into well-defined hollow structure by depositing inorganic silica in the nanocapsules using TEOS as precursors in an ethanol-water solution. TEM images (Figure S2) show that the resultant hybrid HPMO nanocapsules possess an intact spherical shape and a perfect cavity even after drying. The morphological transformation may originate from the changes in the bond angles and/or bond lengths of the Si−O(C), C−C, C−S, and S−S bonds at the molecular level, which is similar to the deformation of soft polymers involving the changes in bond length and bond angle.

Figure 2. (a) Microphotograph of the ethanol suspension of the thioether-bridged HPMOs loaded in a ACS Paragon Plus Environment

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silicon nitride microchip. (b-d) liquid cell TEM images of the thioether-bridged HPMO nanocapsules prepared via the preferential etching approach.

The mechanical properties of the PMO nanoparticles and HPMO nanocapsules in water were measured directly by using quantitative nanomechanical mapping atomic force microscopy (AFM). The elastic Young's modulus (EY) of the thioether-bridged PMO nanoparticles was measured to be 233.4 ± 30.5 MPa (Figure 3). In strong contrast, the EY of the thioether-bridged HPMO nanocapsules was as low as 47.7 ± 5.7 MPa, clearly indicating that the latter are significantly "softer" in solution compared to the former. Additionally, the EY values were measured to be 350.6 ± 7.8 and 250.9 ± 33.9 MPa for the benzene- and ethane-bridged PMO nanoparticles and as low as 91.3 ± 18.9 and 3.95 ± 1.63 MPa for the corresponding HPMO nanocapsules (Figure S3). Force-deformation curves further confirm that the HPMO nanocapsules show more obvious deformations under applied forces compared to the solid PMO nanoparticles (Figure S4).

Figure 3. Quantitative nanomechanical mapping of the thioether-bridged (a) PMO nanoparticles and (b) HPMO nanocapsules using PeakForce QNM AFM. Scale bars, 250 nm. (c) Young’s modulus of the thioether-bridged PMO nanoparticles and HPMO nanocapsules.

The chemical composition of the obtained HPMO nanocapsules was confirmed using FT-IR spectra and

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Si MAS NMR. The FT-IR spectra of the thioether-bridged HPMO nanocapsules exhibit C–H

bond absorbance peaks at 1451 and 1411 cm–1 and the C–S band at 691 cm–1 (Figure 4a, curve i), indicating the thioether-incorporated organosilica frameworks.40 The benzene-bridged HPMO ACS Paragon Plus Environment

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nanocapsules show absorbance peaks at approximately 1380 and 1156 cm–1 (Figure 4a, curve ii), corresponding to Si–C bond and C–H vibration from the benzene ring.41 The ethane-bridged HPMO nanocapsules display a peak at 1414 cm–1 indicative of the C–H vibration in the CH2–CH2 groups (Figure 4a, curve iii), suggesting the ethane-bridged frameworks.42 The

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Si MAS NMR spectra of the

thioether-bridged HPMO nanocapsules show signals at –55, –60, and –67 ppm, corresponding to T1 (C–Si(OSi)1(OX)2, X = H or Et), T2 (C–Si(OSi)2(OX)) and T3 (C–Si(OSi)3) species, and at –93, –103, and –110 ppm, corresponding to Q2 (Si(OSi)2(OX)2), Q3 (Si(OSi)3(OX)), and Q4 (Si(OSi)4) species, respectively (Figure 4b, curve i).42 The benzene-bridged HPMOs show six peaks at –62, –71, –79, –92, –102, and –112 ppm, corresponding to the T1, T2, T3, Q2, Q3, and Q4 species, respectively (Figure 4b, curve ii). Additionally, the ethane-bridged HPMOs show a similar six peaks at –48, –58, –67, –94, –102, and –111 ppm (Figure 4b, curve iii). Quantitative analysis demonstrates that the silicon atoms at the T sites are 71.7%, 48.0%, and 72.1%, respectively, for the thioether-, benzene- and ethane-bridged HPMO nanocapsules (Table S1). The presence of T sites clearly indicates that the frameworks incorporate organic groups. Notably, the silicon atoms at the T sites are 22.9%, 16.8%, and 55.4%, respectively, for the mother thioether-, benzene- and ethane-bridged PMO nanospheres (Figure S5 and Table S2). The Tn/(Tn+Qm) ratios of the HPMO nanocapsules are significantly higher than that of their mother PMO nanospheres, suggesting that Q silicate species are preferentially dissolved during the mild NaOH etching process. On the other hand, the percentages of the Si-OX (X = H or Et) in the frameworks of the thioether-, benzene-, and ethane-bridged HPMOs are measured to be 10.3%, 19.3%, and 14.0%, respectively. The high content of organic groups and abundant non-cross-linked Si-OX in the frameworks are beneficial to the deformability of the HPMO nanocapsules.


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Figure 4. (a) FT-IR and (b) 29Si MAS NMR spectra of (i) thioether-bridged, (ii) benzene-bridged, and (iii) ethane-bridged HPMO nanocapsules.

Nitrogen sorption isotherms of the thioether-, benzene-, and ethane-bridged HPMOs show type IV curves with sharp capillary condensation steps in the p/p0 range of 0.4–0.5 (Figure 5a), revealing typical characteristics of mesoporous materials with narrow pore-size distribution. It should be noted that the hysteresis loops of the thioether- and ethane-bridged HPMOs are much larger than that of benzenebridged ones, indicating the presence of large hollow cavity in the deformed thioether- and ethane-bridged HPMOs. In contrast, the benzene-bridged HPMOs would completely deform into bowl-like shape with inner surfaces close contact during the high-temperature degassing process before measurements. It is well agreement with the above TEM and SEM analyses. The surface areas and pore volumes of the thioether-, benzene-, and ethane-bridged HPMOs are calculated to be 878, 629, and 282 m2⋅g–1, and 0.75, 0.33, and 0.53 cm3⋅g–1, respectively. Where the micropore surface areas of the benzene-bridged HPMOs is ~ 446 m2⋅g–1 based on the t-plot method, which is much larger than that of thioether- and ethane-bridged ones (~ 0, and 28 m2⋅g–1). That is due to the mesoporous frameworks of ACS Paragon Plus Environment

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the benzene-bridged HPMOs are more easily etched away, resulting in the complete deformation. The pore size distributions calculated based on the NLDFT reveal that the thioether-, benzene-, and ethane-bridged HPMOs have uniform mesopores of 3.2, 2.6, and 2.9 nm, respectively (Figure 5b).

Figure 5. (a) Nitrogen sorption isotherms and (b) pore size distribution curves of the thioether-bridged, (ii) benzene-bridged, and (iii) ethane-bridged HPMO nanocapsules. For clarity, the isotherms curves were offset by (i) 500 and (ii) 300 cm3⋅g–1.

The formation process of the deformable HPMO nanocapsules was monitored via the structural and morphological evolution of the thioether-bridged PMO nanospheres during the preferential etching by the sodium hydroxide solution for different time periods. After etching with 0.48 M NaOH for 1 min, the organosilicas retain a spherical shape and solid interior (Figure 6a). After 3 min, the diameter of the spheres is still identical to the mother particles. However, a number of voids of 5 ~ 12 nm in size formed in the interior areas close to the outer shells, resulting in a yolk–shell structure (Figure 6b). When the etching time increased to 5 min, the voids in the interiors enlarge to approximately 10 ~ 40 nm (Figure 6c). More notably, obvious pits appear on the surfaces because the outer shells of the nanospheres are also etched and deform toward the center. Simultaneously, the inner cores of some organosilicas are nearly etched away and deformable nanocapsules with a deflated-balloon-like morphology are presented (Figure 6d). After etching for 20-30 min, the interior organosilica frameworks are completely etched away and the outer shells are cross-wrinkled (Figure 6e and Figure 1a2). After 1 h, the outer shells' ACS Paragon Plus Environment

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thickness further decreases to 20 nm, resulting in more flexible mesostructured organosilica nanocapsules with a bowl-like morphology (Figure 6f). As a control, classic mesoporous inorganic silica nanoparticles synthesized using TEOS as the only silica source and CTAB as a structure-directing agent were applied to the preferential etching process. The results show that the mesostructured silica nanoparticles are transformed to irregular fragments or completely dissolved after incubation with a 0.48 M NaOH solution for 10 or 30 min, respectively, clearly suggesting that the organosilica framework is a critical factor for the formation of the deformable nanocapsules.

Figure 6. TEM images of the thioether-bridged mesostructured organosilica spheres incubated in NaOH aqueous solution (0.48 M) for (a) 1, (b) 3, (c-d) 5, (e) 20 min, and (f) 1 h. The arrow in (b) indicates the voids. Scale bars, 50 nm.

Based on the aforementioned observations, a preferential etching is proposed for the formation of the deformable HPMO nanocapsules (Scheme 1). When the mesostructured organosilica nanospheres are dispersed in a dilute NaOH solution, their frameworks are attacked by OH− ions, and the interiors preferentially dissolve to form small voids (step 1). The preferential etching of the interiors is ascribed to the fact that the mesostructured organosilica nanospheres have more stable outer layers because the


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Si−OH groups on the surfaces are highly cross-linked via ammonia-catalysis during the CTAB-directed sol−gel process.43 As the etching proceeds, the organosilica core further dissolves to leave relatively large voids (step 2). At the same time, the inorganic silica species in the outer shells are preferentially dissolved under the attack of OH− ions leaving more organic group bridged organosilica components in the frameworks. As the structurally stable Si−(O)4 tetrahedrons are preferentially dissolved, and the flexible Si−R−Si chains and non-cross-linked free Si−OX groups dominate in the frameworks, the inner stress to maintain the spherical morphology decreases. Thus, the solvated shells start to wrinkle inward via van der Waals force inside the HPMOs. Then, the cores are gradually etched away, and the shells become thinner and more flexible because a large number of the non-cross-linked free groups are formed (step 3). With the time, the solid nanospheres are completely transformed into deformable nanocapsules with a large hollow space and thin shell, forming a well-defined cross-wrinkled morphology (step 4 and 5). Afterward, the shell thickness of the mesostructured organosilica nanocapsules further decreases and becomes "softer", thereby the upper half of the nanocapsules shrink and deform to the low half to form a bowl-like morphology (step 6). The unique deformable character of the nanocapsules should be considered contributions from: i) flexible organic moieties with easily changeable bond angle and bond length in the thin frameworks; ii) a relatively high content of non-cross-linked free groups which can make enough stress force for the deformability; iii) easily deformable hollow nanostructure with ultra-thin shells. If the framework of the deformed HPMOs is reinforced by depositing inorganic silica, the gradual growth of Si−(O)4 tetrahedrons would decrease the non-cross-linked free Si−OX groups and the content of flexible organic groups in the nanocapsules, and meanwhile thicken the shells. As a result, the inner stress increase and the deformable structure can recover into a well-defined hollow sphere with rigid frameworks due to the lowest surface energy.


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Scheme 1. Illustration of the formation mechanism of the deformable HPMO nanocapsules.

We further investigated the cellular uptake of the fluorescent dye Cy5.5 and PEG modified deformable HPMO nanocapsules and PMO nanospheres (Figure S6 and S7). Quite notably, the cellular uptake of the HPMO-Cy5.5-PEG by human breast cancer MCF-7 cells is significantly higher than that of PMO-Cy5.5-PEG (Figure 7a and Figure S8). For example, only 1.65% of MCF-7 cells associated with PMO-Cy5.5-PEG were taken up after incubation at 37 °C for 8 h. In strong contrast, up to 43.1% MCF cells associated with the deformable HPMO-Cy5.5-PEG were taken up during the same incubation condition. The cellular uptake of the PMO-Cy5.5-PEG and HPMO-Cy5.5-PEG were also compared to macrophage RAW 264.7 cells. After incubation at 37 °C for 8 h, the percentage of RAW 264.7 cells associated with PMO-Cy5.5-PEG or HPMO-Cy5.5-PEG was measured to be 30.5% and 60.9%, respectively (Figure 7b and S9), clearly demonstrating that the nanocapsules are more easily internalized compared to the undeformable counterparts. We further incubated the samples PMO-Cy5.5-PEG or HPMO-Cy5.5-PEG with MCF-7 cells and RAW 264.7 cells at 4 °C. The cellular uptake efficiency of PMO-Cy5.5-PEG decreases to 0.07% and 0.43% after incubation for 8 h (Figure 7c, 7d, S10 and S11). Additionally, the cellular uptake efficiency of the deformable HPMO-Cy5.5-PEG by MCF-7 and RAW 264.7 cells decreases to 0.18% and 4.14%, respectively. The inhibited internalization at a low temperature suggests that the cellular uptake process is energy-dependent.36 To explore the ACS Paragon Plus Environment

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reasons for the difference in cellular uptake between the PMO-Cy5.5-PEG and HPMO-Cy5.5-PEG, the zeta potential and hydrodynamic diameter were measured. The zeta potential of the PMO-Cy5.5-PEG and HPMO-Cy5.5-PEG in water was measured to be +5.4 and +5.0 mV, respectively, suggesting that they have similar surface charge. The hydrodynamic diameter of the PMO-Cy5.5-PEG and HPMO-Cy5.5-PEG dispersed in DMEM medium for 4 h was measured to be 350 and 310 nm, respectively, disclosing similar hydrodynamic diameter and excellent dispersity. These results clearly indicate that the difference in cellular uptake of the two particles is not attributed to the surface charge, hydrodynamic diameter, or particle aggregation. Then, we analyzed the cellular uptake processes using TEM observation. The results show that the HPMO-Cy5.5-PEG nanocapsules maintain a spherical shape before associating with the MCF-7 cells (Figure 8a1, b1). Interestingly, a spherical-to-oval morphology change is observed when the HPMO-Cy5.5-PEG nanocapsules enter the cytoplasm through the cellular membranes (Figure 8a2, a3, b2, b3), demonstrating that the HPMO nanocapsules can deform during internalization. The deformation of the HPMO-Cy5.5-PEG nanocapsules is believed to be easily derived by the pressure of the cellular membrane and the van der Waals force between the particle and cell membrane. Therefore, the deformable structure of the HPMO-Cy5.5-PEG majorly contributes to the higher cellular uptake than that of PMO-Cy5.5-PEG. Firstly, the morphology change can reduce the deformation of the cellular membranes and the corresponding energy during internalization. Secondly, the HPMO-Cy5.5-PEG is reasonably lighter in weight compared to the similar sized PMO-Cy5.5-PEG, which would require less energy for cellular uptake. After entering the cells, the deformable HPMO-Cy5.5-PEG recovers to a spherical shape (Figure 8a4, b4). In contrast, the PMO-Cy5.5-PEG nanoparticles maintain a spherical morphology when they come in contact with the cellular membranes during the internalization (Figure S12).


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Figure 7. Cellular uptake of HPMO-Cy5.5-PEG and PMO-Cy5.5-PEG by (a, c) human breast cancer MCF-7 cells and (b, d) macrophage RAW 264.7 cells at (a, b) 37 °C and (c, d) 4 °C measured by flow cytometry.

Figure 8. (a1-a4) TEM images and (b1-b4) schematic illustration of the uptake processes of HPMO-Cy5.5-PEG by human breast cancer MCF-7 cells at 37 °C. The arrows indicate the cellular membranes. Scale bars, 100 nm.


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Chemotherapeutic drug, DOX, was used as an example and loaded into the PMO-PEG and HPMO-PEG to treat cancer cells. The loading capacity of the PMO-PEG and HPMO-PEG for DOX is measured up to 782 and 509 µg/mg, respectively. The Young’s modulus of the PMO-PEG/DOX and HPMO-PEG/DOX is 185.7 ± 10.2 and 35.6 ± 4.1 MPa, respectively, demonstrating that the HPMO-PEG are still much "softer" than the PMO-PEG even after loading high content of DOX. Because DOX is positively charged, the zeta potential of the PMO-PEG/DOX and HPMO-PEG/DOX in water is +20.8 and +16.9 mV, respectively, which benefit cell uptake via the electrostatic interactions between cellular membrane and particles. Confocal fluorescent images show that the PMO-PEG/DOX and HPMO-PEG/DOX can be internalized by MCF-7 human breast cancer cells (Figure 9a, Figure S13). Importantly, the MCF-7 cells incubated with the HPMO-PEG/DOX show stronger DOX signal than those with PMO-PEG/DOX, indicating that the HPMO-PEG more effectively deliver DOX into cancer cells compared to PMO-PEG. Because of the higher intracellular drug concentration, the chemotherapeutic efficacy of the HPMO-PEG/DOX to MCF-7 cells is higher than that of PMO-PEG/DOX (Figure 9b).

Figure 9. (a) Fluorescent confocal micrographs of MCF-7 human breast cancer cells incubated with 100 µg mL-1 of PMO-PEG/DOX and HPMO-PEG/DOX at 37 °C for 4 h. Nuclei were stained with DAPI (blue). The fluorescent signal of DOX is shown in red. (b) In vitro cytotoxicity of the PMO-PEG/DOX or HPMO-PEG/DOX at different DOX concentrations on MCF-7 cells for 24 h.


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4. Conclusions In summary, deformable hollow periodic mesoporous organosilica nanocapsules with different organic groups (thioether, benzene or ethane moieties) have successfully been synthesized using a preferential etching approach. The resultant HPMO nanocapsules display uniform diameters (240–310 nm), high surface areas (up to 878 m2⋅g–1), uniform mesopores (2.6–3.2 nm), and large pore volumes (0.33–0.75 m3⋅g–1). Importantly, the large hollow cavity (164–270 nm), thin shell thickness (20–38 nm), abundant flexible organic groups and non-cross-linked free Si-OX incorporated mesopore frameworks make the HPMO nanocapsules deformable with a significantly lower EY (3.95–47.7 MPa) compared to that of the solid organosilica nanospheres (233–351 MPa). Notably, we first find that the HPMO nanocapsules are intrinsically flexible and deformable in solution, which mainly results from the flexible organic moieties with easily changeable bond angle and length, and a relatively high content of non-cross-linked free groups, and easily deformable nanostructure with ultra-thin shells. More interestingly, biological TEM observations show that the HPMO nanocapsules undergo spherical-to-oval deformability during the cellular uptake process. The cellular uptake of the deformable HPMO nanocapsules by human breast cancer MCF-7 cells improved 26-fold (43.1% of cells associated with the nanocapsules vs. 1.65% of cells associated with solid counterparts). DOX loaded HPMO nanocapsules show higher killing effect for cancer cells compared to that of the undeformable particles. This is the first synthesis of deformable mesoporous solid materials, which not only provides a new and important property for their applications but also extends the choices for soft materials. It is believed that the deformable HPMO nanocapsules could lead to further development of new concepts for mesoporous materials, thus providing new opportunities in nanomedicine such as drug delivery and theranostics.

ASSOCIATED CONTENT Supporting Information


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Additional SEM and TEM images, quantitative nanomechanical mapping, Young’s moduli, force-deformation curves, percentage of different silicate species, schematic illustration of the deformation, FT-IR spectra, photoluminescence emission spectra and flow cytometry results. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Authors *[email protected] *[email protected]

*[email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We greatly appreciate the financial support from the National Key Basic Research Program of the PRC (2014CB744504 and 2014CB744501), the Natural Science Foundation of Jiangsu Province (BK20160017 and BK20130863), and the National Natural Science Foundation of China (81530054 and 21603106). We thank Chenglong Xu for measurements of Young’s moduli. We thank Jun Tao for measurements of zeta potentials and hydrodynamic diameters. L.B. acknowledges the support from RMIT Vice Chancellor Postdoctoral Fellowship. Technical support from RMIT MicroNano Research Facility (MNRF).

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Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules

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