Facile Synthesis of Monodisperse Hollow Mesoporous Organosilica

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Surfaces, Interfaces, and Applications

Facile Synthesis of Monodisperse Hollow Mesoporous Organosilica/ Silica Nanospheres by an In-Situ Dissolution and Reassembly Approach Xiaodan Su, Yuxia Tang, Yanjun Li, Zhi-Fei Wang, Jun Tao, Kun Chen, Ying Liu, Jiang Wu, Dan Wang, and Zhaogang Teng ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b21906 • Publication Date (Web): 21 Feb 2019 Downloaded from http://pubs.acs.org on February 22, 2019

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ACS Applied Materials & Interfaces

Facile

Synthesis

of

Monodisperse

Hollow

Mesoporous

Organosilica/Silica Nanospheres by an In-Situ Dissolution and Reassembly Approach Xiaodan Su,†,# Yuxia Tang,‡,# Yanjun Li,‡,# Zhifei Wang,⊥ Jun Tao,† Kun Chen,† Ying Liu,‡ Jiang Wu,§ Dan Wang,¶ Zhaogang Teng*,†,‡,∆

†Key

Laboratory for Organic Electronics & Information Displays and Institute of Advanced

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

‡Department

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

Nanjing, 210002 Jiangsu, P.R. China

⊥School

of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189 Jiangsu,

P.R. China.

§Department

of Nuclear Medicine, Jinling Hospital, School of Medicine, Nanjing University,

Nanjing, 210002 Jiangsu, P.R. China

¶Department

of Gynecology & obstetrics, Affiliated Changzheng Hospital, the Second Military

Medical University, Shanghai, 200003, P.R. China 1

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 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

∆Key

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Laboratory of Food Bio-technology, School of Food and Bioengineering, Xihua University,

Chengdu, 610039 Sichuan, P.R. China

Abstract: Hollow structured mesoporous organosilicas are a research hotspot because of their molecularly organic-inorganic hybrid frameworks, large void space, permeable shells, high surface areas, uniform pores, and various applications. However, the previous reported hard-core templating method and liquid-interface assembly approach suffered from complex preparation procedures and poor uniformity for the products. In the work, we demonstrate an in-situ dissolution and reassembly method to synthesize monodisperse benzene-bridged hollow mesoporous organosilica/silica nanoparticles

(HMOSNs)

by

sequential

addition

of

tetraethoxysilane

and

1,4-

bis(triethoxysilyl)benzene in a solution containing cetyltri-methylammonium bromide (CTAB) surfactant. The formation of the HMOSNs is completed in one-pot, which is very effective and convenient. The formation mechanism of HMOSNs is ascribed to the fact the TEOS first assemble with CTAB to form mesostructured silica cores, which further dissolve and migrate to the outer layers during the deposition of mesostructued organosilica shells. The prepared benzene-bridged HMOSNs possess uniform diameter (140 nm), large pore volume (2.79 m3/g), high specific surface area (2926 m2/g), and a high doxorubicin loading content of 16.7%. The HMOSNs can deliver Dox into human 2


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breast cancer cells and reduce their excretion. Thus, the Dox loaded HMOSNs show a high killing effect against the cancer cells.

Keywords: hollow structure, mesoporous materials, organosilica, silica, self-transformation

1. Introduction

Hollow structured micro-/nanomaterials with interior space and an outer shell have attracted increasing attentions in recent years.1-3 Particularly, hollow structured mesoporous organosilicas nanoparticles have sparked a research boom from synthesis to applications due to their molecularly organic-inorganic hybrid frameworks, large void space, thin permeable shells, high surface areas, and uniform pores.4-9 More importantly, the organic moieties in the mesoporous organosilicas can be tailored and further functionalized via classical organic reactions, and the void spaces in the hollow mesoporous organosilicas provide a compartment environment for confined reactions or loading guest molecules, which make them extremely attractive in catalysis, adsorption, and nanomedicine applications.10-15 Conceptually, hollow mesoporous organosilicas can be prepared based on hard-core templating method, which involves deposition of mesostrutured organosilica shells on hard core templates (e.g. 3



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colloidal silica and polystyrene latex), and selective removal of the hard cores via calcination or dissolution.16-21 However, the method is synthetically challenging, because pre-preparation of hardcore templates and multiple step chemical reactions are required. To overcome these drawbacks, relatively simple liquid-interface assembly approach has been used to synthesize hollow mesoporous organosilicas, in which organosilica precursors directly co-assemble with structure directing agents on the surfaces of emulsions or micelles to form mesostructured shells.22-25 However, the liquid interfaces are generally thermodynamically unstable, thus the hollow mesoporous organosilicas prepared via the liquid-interface assembly approach often polydispersed in size and ill-defined in shape. Recently, our group found that mesostructured organosilica nanoparticles prepared via sol-gel possess have highly cross-linked surfaces. Based on the new knowledge, we have established a simple “interface transformation” strategy to synthesize hollow mesoporous organosilicas via directly heating the mesostructured organosilica nanoparticles in water to form hollow structures.5,26,27 However, the “interface transformation” approach still need two steps for synthesis of hollow mesoporous organosilicas, including preparation of mesostructured organosilcia nanoparticles and a following interface transformation procedure. Qiu’s group demonstrated that growth of mesostructured organosilica shell on colloidal SiO2 nanoparticles can induce the dissolution for inner SiO2 cores, forming yolk-shell structured particles.28 After hydrothermal treatment at 100 °C, hollow structured

4


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mesoporous organosilicas are successfully prepared. Yamamoto et al. further demonstrate that hollow mesoporous organosilicas can be prepared by coating oganosilica shells on mesoporous silica nanoparticles.29 And, they found the formation mechanism is that the growth of organosilica derive the mesoporous silica cores to dissolve and further migrate to the shells. However, the methods still require preparation of colloidal SiO2 or mesoporous silica cores, and an energy-consuming hydrothermal thermal treatment procedure is needed. Taken together, more convenient, robust, and energy-saving strategy is required for synthesis of uniform hollow mesoporous organosilicas. Herein, we report an in-situ dissolution and reassembly approach to prepare monodisperse hollow mesoporous organosilica/silica nanoparticles (HMOSNs), which is simply carried out by sequentially adding tetraethoxysilane (TEOS) and 1,4-bis(triethoxysilyl)benzene (BTSB) in reaction solutions containing cetyltri-methylammonium bromide (CTAB) surfactant. The TEOS first assembly with CTAB to form mesostructured silica cores, which then dissolve and migrate to the shells after coating the mesostructued organosilica, resulting in monodisperse hollow structures. The reaction is very simple, effective, and completed in one-pot, and the formation for the HMOSNs does not require any corrosive etching agents and hydrothermal treatment procedures. The prepared benzene-bridged HMOSNs possess uniform diameter, tunable shell thickness, large pore volume (2.78 m3/g), high specific surface area (2926 m2/g), and high doxorubicin (Dox) loading content. The HMOSNs can

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deliver Dox into cancer cells and reduce their excretion, and thus the Dox loaded HMOSNs effectively kill the MCF-7/ADR cells.

2. Experimental Section

2.1. Synthesis. Benzene-bridged HMOSNs were prepared as follows: 0.04 g CTAB was dissolved in a solution composed of concentrated ammonia aqueous solution (0.5 mL, 25–28 wt%), ethanol (15 mL), and water (65 mL). The solution was stirred (1100 rpm) at 35 °C, and 0.1 mL of TEOS was added. After the reaction solution was stirred for 24 h, 36.5 µL of organosilica precursor BTSB was rapidly added under stirring (1100 rpm). After 48 h, benzene-bridged mesostructured organosilica/silica with hollow structures was formed. The products were then dispersed in ethanol (120 mL) containing concentrated HCl (240 μL, 37 %) and heated at 60 °C for 3 h to remove the CTAB surfactant. After repeating the extraction three times, benzene-bridged HMOSNs were prepared. In addition, ethane-group bridged HMOSNs were prepared via the same procedures, except that the organosilica precursor BTSB was changed with 1,2-bis(triethoxysilyl)ethane (BTSE). 2.2. Cytotoxicity Assay. MCF-7 cells were incubated for 24 h (1 × 104 cells / well). The cell was added with different concentrations of benzene-bridged HMOSNs dispersed in DMEM medium and further incubated for additional 24 h. The cell cultures were removed and DMEM (200 µL) with MTT 6


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(0.1 mg) was added. After 4 h, the cultures were replaced with 150 µL of DMSO. The absorbance value of the cells was then tested using a spectrophotometer (Tecan, Switzerland). The cell viability (%) = Atreated / Acontrol × 100. Where the Atreated represents the absorbance of the cells incubated with HMOSNs, and the Acontrol is the absorbance of untreated cells. 2.3. In Vitro Chemotherapy. DOX (1.0 mg) and benzene- or ethane-bridged HMOSNs (1.0 mg) were added in phosphate-buffered saline (1 mL). After shaking over night, the DOX-loaded HMOSNs (HMOSNs/DOX) was centrifugated and washed three times with PBS. MCF-7/ADR cells were seeded (5 × 103 cells per well) and incubated for 24 h. HMOSNs/DOX in DMEM medium were added. After 24 or 48 h, the cells were washed and added with MTT (0.5 mg/mL). After 4 h, the cultures were replaced with DMSO (100 µL). The absorbance of the cells was then tested using a spectrophotometer (Tecan, Switzerland). The cell viability (%) = Atreated / Acontrol × 100. Where the Atreated represents the absorbance of the cells incubated with the HMOSNs/DOX, and the Acontrol represents the absorbance of untreated cells. To observe the uptake of the HMOSNs/DOX, MCF-7/ADR cells were seeded at 5 × 105 cells per mL. After growing for 24 h, HMOSNs/DOX (12 μg mL−1) dispersed in DMEM were added and incubated for different times. After washing with PBS, stained with diamidino-2-phenylindole (DAPI), and fixed, the cells were imaged on a microscope.

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3. Results and discussion Scanning electron microscopy (SEM) image shows that the benzene-bridged HMOSNs prepared by the in-situ dissolution and reassembly approach have a smooth outer surfaces and a diameter of 130 nm (Figure 1a, Figure S1). A crushed particle by grinding indicates the HMOSNs have hollow structure (inset in Figure 1a). Notably, the transmission electron microscopy (TEM) images reveal that the HMOSNs have a reduced contrast cavity and an uniform gray shell, clearly indicating the hollow structure (Figure 1b and 1c). In addition, we captured the cross-section TEM images of the product by embedding the HMOSNs in epoxy resin and sliced using an ultramicrotome (Figure S2). The crosssection TEM images demonstrate that the HMOSNs have an outer shell and a through hole, further demonstrating the hollow structure. The shell thickness for the outer shell and the diameter for the hollow cavity are approximately 20 and 100 nm, respectively. The TEM image reveals that the interior surface of the HMOSNs is very rough (Figure 1c), which is inconsistent with the hollow nanospheres synthesized using templating methods, indicating an in-situ dissolution occurs. High-angle annular dark-ﬁeld scanning TEM (HAADF-STEM) image also demonstrates the hollow structure (Figure 1d). The energy-dispersive X-ray (EDX) elemental mapping shows that silicon, oxygen, and carbon located in the shells (Figure 1e-1h), demonstrating the hollow structured organosilica. In addition,

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ethane-group bridged HMOSNs with a diameter of 87 nm can also be synthesized by the in-situ dissolution and reassembly strategy (Figure S3, S4), in which BTSE is used as organosilica precursors. TEM images show that the ethane-group bridged HMOSNs have well-defined hollow structure with an 11 nm outer shell.

Figure 1. (a) SEM, (b-c) TEM, (d) HAADF-STEM, and (e-h) EDX elemental images of the benzenebridged HMOSNs synthesized via the in-situ dissolution and reassembly strategy. Inset in (a) shows a partially crushed sphere. Blue, green, and red indicate Si, O, and C, respectively.

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The Fourier transform infrared (FT-IR) spectra of the benzene-bridged HMOSNs show Si–C vibration (1370 cm–1) and C–H bond at 1150 cm–1,4 suggesting the benzene-bridged organosilica frameworks (Figure 2a). The 29Si NMR spectra of the HMOSNs display signals at –78, –69, and –60 ppm, which are ascribed to the T3 (C–Si(OSi)3), T2 (C–Si(OSi)2(OX), X = H or Et) and T1 (C– Si(OSi)1(OX)2) species. The other three peaks at –108, –100, and –90 ppm, are ascribed to Q4 (Si(OSi)4), Q3 (Si(OSi)3(OX)), and Q2 (Si(OSi)2(OX)2) species, respectively (Figure 2b). The condensation degree of the HMOSNs calculated based on the

29Si

NMR results is 81.7%,

demonstrating a high condensation degree. The T and Q species are calculated to be 67% and 33%, respectively. The T1, T2, and T3 species demonstrates that the products contain organosilica. The presence of Q2, Q3, and Q4 species indicates the dissolved silica from interior cores further reassemble on the outer shells. The N2 isotherms of the HMOSNs show type IV curves (Figure 2c). In addition, a H2 hysteresis loop with a steep desorption at p/p0 of 0.46-0.52 is observed, which is attributed to that the N2 suddenly evaporates from the hollow cavities after the evaporation from surrounding mesopores, further indicating mesoporous materials with hollow voids. The surface area of the benzene-bridged HMOSNs are measured to be up to 2926 m2g–1. Their pore volume is measured to be as high as 2.78 cm3g–1. The pore size of the benzene-bridged HMOSNs is 2.6 nm (Figure 2d).

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Figure 2. (a) FT-IR spectrum, (b) 29Si NMR spectrum, (c) nitrogen sorption isotherms, and (d) pore size distribution curve of the benzene-bridged HMOSNs synthesized via the in-situ dissolution and reassembly strategy.

The formation processes for the HMOSNs were investigated after adding the organosilica precursor BTSB to the reaction solution. Figure 3 shows the morphology change of the organosilica spheres at different reaction periods. After adding BTSB for 1 h, the percentage of solid spheres are measured to be 98.6%, and the diameter for the solid spheres is 107 nm (Figure 3a). Interestingly, 40.9% spheres show a hollow structure after adding the BTSB for 2 h, which has a clear contrast between a gray central part and a dark periphery, indicating that the interior of pre-formed silica spheres is dissolved

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(Figure 3b). The diameter for the hollow spheres formed at 2 h is 114 nm. When the reaction further continued to 12 h, more cores for the spheres are dissolved and the percentage for the hollow structured spheres reaches to 92.8% (Figure 3c). This suggests that the in-situ dissolution for the silica cores is time-dependent. The diameter for the hollow spheres formed at 12 h increases to 130 nm. The increase of the diameter for the hollow spheres from 107 to 114 and then 130 nm demonstrate that the silica/organosilica species deposit on the outer surfaces during the transformation process. After 24 h, 100% solid spheres are transformed into hollow structures (Figure 3d), indicating the in-situ dissolution and reassembly approach is highly reliable.

Figure 3. TEM images of the HMOSNs synthesized via adding the organosilica precursor BTSB to the reaction solution for (a) 1, (b) 2, (c) 12, and (d) 24 h. Scale bars, 200 nm.

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The benzene-bridged HMOSNs with different diameters are synthesized via adjusting CTAB concentrations. When CTAB is increased from 0.06 to 0.08 and then 0.16 g, the diameters of the HMOSNs are decreased from 81 to 69 and 60 nm (Figure S5), respectively. These results indicate that the diameter of the HMOSNs can be modulated via adjusting the CTAB concentrations. The decrease of the diameter of the HMOSNs with the increase of the CTAB is attributed to that the co-assembly rate of the silica/organosilica with CTAB surfactant is accelerated at high CTAB concentration. Thus, the nucleation for t the mesostructured nanoparticles is fast at high CTAB concentrations and the diameters for the products are decreased. It is believed that the HMOSNs underwent an in-situ dissolution of the silica core and a reassembly processes. The Stöber solution that typically containing ethanol, water, and silica/organosilica precursors has been widely used to synthesized uniform silica based colloids and mesoporous nanoparticles. When TEOS is added in Stöber solution containing CTAB surfactant and ammonia, the ethanol helps the hydrophobic silica precursors homogeneously dissolved in the reaction solution. The TEOS is then catalytically hydrolyzed by ammonia and co-assemble with CTAB to form mesostructured silica nanoparticles in the homogeneous solution. Along with the condensation of the silica/organosilica on the oligomers, uniform mesostructured nanoparticles are obtained. This process is relatively fast, which is similar to synthesis of classical mesoporous materials via sol-gel co-

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assembly process. As the reaction proceeds, the TEOS is completely condensed on CTAB micelles, and the size of the mesostructured silica is gradually increased. After adding the organosilica precursor BTSB, the following chemical processes occur: 1) deposition of organosilia on/in the preformed mesostructured silica nanoparticles; 2) dissolution of the mesostructured silica nanoparticles; and 3) reassembly of the dissolved silica on the organosilica shells. In detail, the added organosilica precursor is catalytically hydrolyzed by ammonia and deposited on the preformed mesostructured silica nanoparticles (step 1). NMR spectrum of the HMOSNs shows that 67% silicon atoms are at T sites, which demonstrates that the organosilica deposits on the preformed mesostructured silica nanoparticles. Afterward, the coating of the organosilica induces the dissolution of the SiO2 core (step 2). This phenomenon is consistent with the report that silica colloids are dissolved when they are mixed with organosilica nanoparticles and heated in a solution.29 The dissolution of the silica nanoparticles is attributed to that the Si-O-Si bonds are easily hydrolyzed under the attack of OH- in the basic solution. Subsequently, the dissolved silica species reassemble on the outer shells (step 3), which is confirmed by the NMR spectrum of the HMOSNs (33% Q species) and the increased particle size of the hollow particles compared to that of the solid ones. From thermodynamic view, the organosilica shells with hydrophobic benzene or ethane moieties have higher interfacial energy with water. Thus, the reassembly of the dissolved silica on the organosilica layer is benefit for reducing the

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interfacial energy of the organosilica nanoparticles with water. So, the outer organosilica layers act as the reassembly centers for the dissolved silica species. With the dissolution of the mesostructured silica cores and the reassembly on the outer shells, hollow structured mesostructured organosilica/silica nanospheres are finally formed. Because the benzene-bridged HMOSNs have benzene groups incorporated frameworks and high specific area, we next use the HMOSNs to deliver chemotherapeutic drug, Dox, to treat drug consistent MCF-7/ADR cells. The biocompatibility of the benzene-bridged HMOSNs was evaluated by incubating with MCF-7 cells. After the HMOSNs incubated with the cells for 24 h, their viability is higher than 80% at the tested concentrations (Figure S6). The cytotoxicity assay indicates that the benzene-bridged HMOSNs have excellent biocompatibility. The Dox loading content in the HMOSNs was measured up to 16.7 wt% (167 µg Dox per milligram of HMOSNs). The distribution of the HMOSNs/Dox in drug consistent MCF-7/ADR cells was monitored. After incubated with the HMOSNs/Dox for 2 h, the MCF-7 cells show red fluorescence of Dox within the cytoplasm (Figure 4), suggesting the HMOSNs can deliver Dox into the cells. After longer incubation (12-24 h), strong fluorescence was found in nuclei, indicating the Dox was released from the HMOSNs and penetrated into the nuclei.

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Figure 4. Confocal laser scanning microscope (CLSM) images of drug consistent human breast cancer MCF-7/ADR cells incubated with HMOSNs/DOX (12 μg mL−1) for different times. The blue signal is from DAPI stained nuclei. The red signal is from DOX.

The uptake of HMOSNs/Dox and free Dox by drug consistent MCF-7/ADR cells was further quantitatively investigated. After incubating with free Dox or HMOSNs/Dox for 2 h, the cells incubated with free Dox show higher drug signal than that incubated with HMOSNs/Dox (Figure 5a and 5d), which is attributed to that the small molecule drug has faster diffusion ability. After 12 h, the cellular uptake of the HMOSNs/Dox is significantly increased (Figure 5b and 5d), which shows a similar content compared to free Dox. Notably, the Dox content in the MCF-7/ADR cells is decreased 16


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when they incubated with drug for 24 h (Figure 5c and 5d), suggesting the Dox is excreted by the cells. In strong contrast, when the cells incubated with the HMOSNs/Dox, Dox content continue increases and higher than that of cells incubated with free drug. Considering the fact that the HMOSNs have the ability to deliver Dox into the drug resistant cells, the cytotoxicity of the HMOSNs/DOX on the drug resistant cells was investigated. After treated using Dox and HMOSNs/Dox for 24 h, the cell viability for the MCF-7/ADR cells gradually decreases to 54.9% and 56.5% (Figure 5e), suggesting the HMOSNs/Dox and Dox have similar therapeutic efficacy at 24 h period. When the cells incubated with the HMOSNs/Dox for long time, their viability is measured to be 62.3%, 61.1%, 45.7% at Dox concentrations of 2, 4, and 10 μg mL−1 (Figure 5f), showing significantly improved chemotherapeutic efficacy than free Dox. Furthermore, we investigated the chemotherapeutic efficiency of the benzenebridged-HMOSNs/DOX and ethane-bridged-HMOSNs/DOX on MCF-7/ADR cells. Both benzenebridged-HMOSNs/DOX and ethane-bridged-HMOSNs/DOX show similar killing effect for the cells (Figure S7). The high killing effect of the HMOSNs/Dox for drug resistant cells is attributed to that the HMOSNs can reduce the excretion of Dox.

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Figure 5. (a-c) Flow cytometry and (d) mean fluorescence intensity of drug consistent human breast cancer MCF-7/ADR cells incubated with free Dox (blue) and HMOSNs/Dox (red) for 2 h (a), 12 h (b), and 24 h (c). In vitro cytotoxicity of the HMOSNs/DOX or Dox on the drug consistent MCF7/ADR cells for (e) 24 h and (f) 48 h.

4. Conclusion In summary, hollow mesoporous organosilicas/silica nanoparticles (HMOSNs) have been successfully prepared by a facile in-situ dissolution and reassembly approach, in which HMOSNs are directly formed by sequentially adding tetraethoxysilane and 1,4-bis(triethoxysilyl)benzene to reaction solution. The method is very effective, convenient, low cost, and multistep coating processes and sacriﬁcial templates are not required. The prepared benzene-bridged HMOSNs possess hollow

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structure, large specific surface area (2926 m2/g), and high drug loading content (16.7%). The HMOSNs can effectively delivery anticancer drug into drug resistant cancer cells. Furthermore, Dox loaded HMOSNs shows a higher therapeutic efficacy for the drug resistant cancer cells than free Dox. It is believed that the in-situ dissolution and reassembly approach open a new door for preparation of HMOSNs for different promising applications.

ASSOCIATED CONTENT Supporting Information Additional SEM and TEM images, and FT-IR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Authors *[email protected]

Author Contributions #X.S.,

Y.T., and Y.L. contributed equally.

Notes 19



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The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We greatly appreciate the financial support from the Natural Science Foundation of Jiangsu Province (BK20160017) and the National Natural Science Foundation of China (21603106 and 81401469).

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Yamamoto, E.; Uchida, S.; Shimojima, A.; Wada, H.; Kuroda, K. Transformation of Mesostructured Silica Nanoparticles Into Colloidal Hollow Nanoparticles in the Presence of a Bridged-Organosiloxane Shell. Chem. Mater. 2018, 30 (2), 540–548.

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Facile Synthesis of Monodisperse Hollow Mesoporous Organosilica

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