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Mechanized Silica Nanoparticles Based on Pillar[5]arenes for On-Command Cargo Release Yu-Long Sun, Ying-Wei Yang,* Dai-Xiong Chen, Guan Wang, Yue Zhou, Chun-Yu Wang, and J. Fraser Stoddart* During the past decade, because of potential applications in the fields of sensing, anti-cancer drug release, gene transfection etc., attention has been focused on mechanized silica nanoparticles (MSNPs) coated with nanovalves, capable of trapping and regulating the release of cargo molecules.[1] These MSNPs provide a robust reservoir on the nanoscale level for the storage of cargo molecules which can then be released by activating the nanovalves with a range of stimuli, including light,[2] changes in pH[3] or redox[3f,4] states, enzymes,[5] and competitive binding agents.[6] Owing to their inertness, large pore volumes, homogeneous and tunable pore diameters, high surface areas, low cytotoxicity and ease of functionalization, mesoporous silica nanoparticles are ideal vehicles for incorporating nanovalves on to their surfaces.[1,7] Moreover, mesoporous silica nanoparticles of the appropriate size exhibit good biocompatibility and can be endocytosed by cells.[8] They can be coated with nanovalves by installing stalks on their surfaces that can, in principle at least, be encircled by crown ethers,[1,3b,6] cyclophanes,[1,4a] and cucurbit[n]urils cyclodextrins (CDs)[1,2b,3i–n,9] [1,2c,3c–h] The resulting nanovalves can act as (CB[n]s). gatekeepers to regulate the trapping and release of cargo molecules. Numerous MSNPs have been designed and demonstrated to operate in organic solvents as well as in aqueous solutions.[1–6,9]

Y.-L. Sun, Prof. Y.-W. Yang, D.-X. Chen, Y. Zhou, C.-Y. Wang State Key Laboratory of Supramolecular Structure and Materials College of Chemistry, Jilin University 2699 Qianjin Street, Changchun 130012, PR China E-mail: [email protected] [email protected] Y.-L. Sun, Prof. Y.-W. Yang, Prof. J. F. Stoddart Department of Chemistry, Northwestern University 2145 Sheridan Road, Evanston, IL, 60208-3113, USA E-mail: [email protected] G. Wang Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education College of Life Science, Jilin University 2699 Qianjin Street, Changchun 130012, PR China DOI: 10.1002/smll.201300445

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The pillar[5]arenes (P[5]As)—a relatively new class of synthetic macrocyclic receptors—are paracyclophane derivatives consisting of 1,4-disubsituted hydroquinone units linked by methylene bridges in their 2,5-positions.[10] They possess, not only functionality, but also the ability to bind substrates within their cavities.[11] P[5]A and its derivatives, for example, form stable inclusion complexes with viologen and pyridinium compounds.[10a,12] Although P[5]A has been the subject of much research during the past two years,[11,13] it has still, to our knowledge, to be incorporated into MSNPs. Herein, we describe the synthesis and properties of MSNPs where a P[5]A derivative is incorporated into the nanovalves on the surface of MCM-41 NPs (Figure 1). The negatively

Figure 1. Schematic diagram of carboxylatopillar[5]arene (CP[5] A)-based MSNPs. The nanovalves on the surface of MCM-41 NPs can be operated either by pH changes or by competitive binding to regulate the release of cargo molecules, i.e., rhodamine B (RhB), calcein, and doxorubicin hydrochloride (DOX).

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On-Command Cargo Release with Si Nanoparticles

charged, electron-rich carboxylatopillar[5] arene (CP[5]A)[12b,14] has been shown to encircle stalks terminated by positively charged pyridinium units grafted on to the surfaces of MCM-41 NPs. Both changes in pH and competitive binding agents have been employed in the operation of these new MSNPs. MCM-41 NPs were synthesized (Scheme 1) using a template-directed sol-gel method with the surfactant, cetyltrimethylammonium bromide (CTAB) as the template and tetraethylorthosilicate (TEOS) as the source of the silica, followed by removal of the template by extracting the MCM-41 NPs with acidified MeOH. Examination of the MCM-41 NPs by scanning electron microscopy (SEM) revealed (Figure 2c) them to be essentially monodisperse with diameters of ca. Scheme 1. Synthetic route to the MSNPs functionalized with CP[5]A [2]pseudorotaxanes. 140 nm. In addition, dynamic light scat- i) template activation for 30 min, then adding TEOS, heating at 80 °C, 2h; ii) 3-chloropropyl tering (DLS) was used to measure the trimethoxysilane or 3-chloropropyl triethoxysilane, dry PhMe, heating under reflux, N2 average diameter of the bare MCM-41 NPs protection, 24 h; iii) pyridine, dry PhMe, heating under reflux, N2 protection, 24 h; iv) 0.5 mM in water: it was found (see Table S4 in the RhB loading; v) CP[5]A, r.t., 24 h, capping then washing with H2O. Supporting Information) to be ca. 140 nm, in agreement with the results obtained from SEM. Transmis- spectrum, two different silicon-based species can be identision electron microscopy (TEM) revealed (Figure 2b) the fied. The existence of the covalent bonds between the organic existence of ordered 2D hexagonal arrays of cylindrical nano- stalks and the surface of the MCM-41 NPs was confirmed pores on the surfaces of the MCM-41 NPs, a feature which by the presence of T2/T3 signals in the spectrum. The resowas confirmed (Figure 2a and Figure S13) from the small- nances representing siloxanes (Q4), single silanols (Q3) and angle powder X-ray diffraction (XRD) patterns displayed by germinal silanols (Q2) can also be identified with characteristic chemical shifts. The FT-IR spectrum of the functionalthe freshly obtained MCM-41 NPs. The synthesis of MCM-41 NPs functionalized with ized MCM-41 NPs shows an absorption band at 2950 cm−1 1-butylpyridinium cations is outlined in Scheme 1 and corresponding to the C–H stretching mode of an aromatic described in detail in the Experimental Section and SI. The ring thus establishing the presence of pyridinium units of successful functionalization of the MCM-41 NPs was dem- the surfaces of the MCM-41 NPs.[15] In addtion, ζ-potential onstrated (see the SI) by 29Si CP/MAS solid-state NMR and experiments indicate that pyridine-modified MCM-41 NPs FT-IR spectroscopy. In the 29Si CP/MAS solid-state NMR have positive surface charges and the remaining three samples possess negatively surface charges (see Table S1). The absolute values of the ζ-potentials of the bare MSNPs, the pyridine-modified nanoparticles and the dye-loaded, CP[5] A-capped MSNPs were found to be >20 mV, an observation which indicates that the synthesized nanoparticles maintain a certain stability in aqueous solutions. The water-soluble CP[5]A sodium salt was synthesized using a modified procedure (see the SI) based on reports in the literature from Ogoshi et al.[14] and Li et al.[12a] At neutral and basic pHs the negatively charged CP[5]A rings encircle the pyridinium stalks on the surfaces of the MCM-41 NPs forming [2]pseudorotaxanes. Neutralization of the CP[5]A sodium salts upon lowering the pH of the solution results in the weakening of the noncovalent bonding interactions between the ring and stalk components of the [2]pseudorotaxanes, leading to the unblocking of the nanopores on the surface of these MCM-41 NPs. The intensities of the peaks in the XRD (see the SI) are lower following the covalent modification of the MCM-41 NPs and decrease even more sharply Figure 2. a) Small angle XRD pattern, b) TEM image, and c) SEM image after cargo loading and capping of the pyridinium stalks with CP[5]A to afford the MSNPs. Surface areas and pore widths of bare MCM-41 NPs. small 2013, 9, No. 19, 3224–3229


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Table 1. Properties of a series of NPs calculated from XRD, BET and BJH (See the SI for detailed calculations and methods). Bare Pyridine-Modified RhB-Loaded, CP[5]AMCM-41 NPs MCM-41 NPs Capped MSNPs SBET [m2/g]

1003

751

196

Vp [mL/g]

0.83

0.65

0.14

D1 [nm]

2.82

2.65

–

D2 [nm]

2.57

2.89

–

D3 [nm]

3.31

3.46

–

Interplanar Spacing [nm]

3.62

3.56

3.56

Pore Distance [nm]

4.18

4.11

4.11

of a cuvette and water (pH 7) was slowly added in order not to disturb the MSNPs. Release of RhB from the nanopores of the MSNPs was monitored by UV-vis absorption spectroscopy. A flat baseline shows (Figure 3) that the molecules of RhB are held firmly within the nanopores of the MSNPs at neutral pH: there is no premature release. When the pH of the solution is lowered to 5, the nanovalves open and the cargo of RhB molecules is released. The lower the pH (e.g., 2), the faster is the release of the cargo. Next, the anticancer drug, doxorubicin (DOX) hydrochloride, was loaded into the nanopores of the MSNPs: a smooth release profile was observed (see SI) on lowering the pH.

were measured by nitrogen adsorption-desorption isotherms (see the SI). It transpires that the bare and functionalized MCM-41 NPs exhibit characteristic Type IV BET isotherms, consistent with the existence of cylindrical nanopores. A pronounced step is exhibited prior to loading the MCM-41 NPs with a dye and capping them with CP[5]A to give MSNPs at a relative pressure ranging from 0.2–0.7 [P/P0] because of the capillary condensation of nitrogen inside the nanopores. A narrow pore size distribution is observed in accordance with the steep condensation step. The properties of the bare MCM-41 NPs, the pyridinium-modified MCM-41 NPs and the MSNPs loaded with RhB are summarized in Table 1. The pH-dependent threading-dethreading of pseudorotaxanes regulates the release of cargos from the nanopores of the MSNPs as shown in Figure 3. Prior to investigating the release of drugs, RhB-loaded, CP[5]A-capped MSNPs were studied as a pH-responsive model. A sample of these MNSPs was placed in the corner

Figure 4. Release of calcein from CP[5]A-capped MSNPs caused by the addition of methyl viologen. The detection wavelength was 492 nm.

Figure 3. Release profiles of MSNPs operated by pH changes. CP[5] A-capped, RhB-loaded MSNPs were able to contain RhB molecules at neutral pH (line with triangles) but release them under acidic pHs (lines with squares and circles, pHs 2 and 5) and the release rate of RhB from MSNPs depends on the pH level. The detection wavelength was 556 nm.

Since the surfaces of the pyridinium-modified MCM-41 NPs are positively charged, we envisioned that the charge on cargo molecules might influence their loading and release from the MSNPs. Hence, we have investigated two different cargo molecules, namely positively charged RhB and negatively charged calcein. We expected that the calcein molecules would enter the nanopores quickly, while RhB molecules might be slowed down by the positive charge on the surfaces of the MCM-41 NPs. The loading efficiency and capacity of the positively changed RhB turned out to be more efficient than that observed for the negatively charged calcein using the concentration gradient method of loading the MCM-41 NPs. It appears that the size of the cargo molecules is more important than their charge (see the SI) since the size of the calcein molecules exceeds that of the RhB molecules. The influence of cargo size and charge on the release efficiencies was also investigated by competitive binding activation since the charge on the calcein molecules will be pH-dependent as a result of their protonation under acidic conditions. On the addition of methyl viologen salts, which have a higher binding affinity (Ka ≈ 8 × 104 M−1)[14] into a cuvette containing MSNPs loaded with either RhB or calcein, an immediate release of the cargo molecules was observed (Figure 4) as a result of the methyl viologen-induced

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dethreading of the CP[5]A rings from the pyridinium stalks (Ka = (2.5 ± 0.7) × 103 M−1, see the SI) on the surface of the MSNPs. The difference in the release of RhB and calcein is negligible, indicating that cargo size and charge have little influence on the competitive binding modes of activation of the nanovalves. In conclusion, pillar[5]arenes are currently the subject of close scruting and interest in them is rapidly moving from synthesis to application. The research reported in this paper pushes the agenda even further along this desirable path. On account of their structural diversity, pillar[n]arenes and their derivatives are attractive candidates to be employed in designing a variety of nanovalve systems, activated by different external stimulus, for on command cargo release. In the present study, MSNPs of diameter ca. 140 nm have been fabricated, based on organic stalks containing pyridinium termini which complex with CP[5]A rings under neutral and basic conditions where they are able to trap cargo molecules irrespective of their charge. Release of the cargo molecules, be they dyes or drugs, can be achieved by lowering the pH or adding a competitive binding agent for the P[5]A derivative, which, following testing of its cytotoxicity by the MTT method with three different cell lines, has been shown[16] to be biocompatible (Figure S21).

Experimental Section Materials and Methods: Starting materials and reagents were purchased from Aldrich, Aladdin, Gibico and Invitrogen and used as received. A series of phosphate buffers (PBS buffers) were prepared according to the Appendix XV of the Chinese Pharmacopeia (the Second Part, 2010 Edition). Unless otherwise stated, all reactions were performed under a nitrogen atmosphere and in dry solvents. Powder X-ray diffraction (XRD) measurements were carried out using a Rigaku SmartLab III powder diffractometer. The radiation source was copper (Kα = 1.39225 Å). Scanning electron microscope (SEM) images were collected on a JEOL JSM 6700F instrument. Au coating of the nanoparticles used for imaging was carried out by sputtering for 2 min. Transmission electron microscopy (TEM) images were collected on a Hitachi H-800 instrument, where the accelerating voltage was 200 kV. 1H NMR spectra were recorded on a Varian 300 MHz NMR spectrometer. 13C NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer. Association constant (Ka) was carried out by NMR titrations on a Bruker AVANCE III 600 MHz NMR spectrometer. Solid-state nuclear magnetic resonance (SSNMR) experiments were performed on a Varian-400M solid-state high-resolution NMR spectrometer. 29Si nuclei were observed using cross polarization (CP) from the neighboring 1H nuclei. High-resolution mass spectra (HR-MS) were recorded on a Bruker micrOTOF-Q II Mass Spectrometer. Fourier transform infrared (FT-IR) spectra were recorded on a Bruker Vertex 80V spectrometer. Dynamic light scattering (DLS) measurements were performed on a Zetasizer Nano ZS instrument. ζ-Potential measurements were tested on a Zetasizer Nano 9300 instrument. N2 Adsorption and desorption isotherms were carried out using a Micromeritics Gemini instrument. The controlled release profiles were obtained via UV-vis spectroscopy on a Shimadzu UV-2550 spectrophotometer. Human lung cancer cell A549, human small 2013, 9, No. 19, 3224–3229

cervical cancer Hela and human ovarial cancer Skov-3 were obtained from the Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, Jilin University. CP[5]A was synthesized according to our reported procedure.[12d] Preparation of Pyridine-Modified MCM-41 NPs: Bare MCM-41 NPs were synthesized according to a modified procedure based on a literature report.[3c] On this basis, bare MCM-41 NPs (100 mg) were dissolved in dry PhMe (10 mL), and 3-chloropropyl trimethoxysilane (1 mM) was added to the solution. The mixture was heated under reflux for 24 h under N2 protection. The light yellow solution was allowed to cool down and was then collected by filtration, washed thoroughly with PhMe, and dried under vacuum to give pure 3-chloropropyl-modified MCM-41 NPs. The 3-chloropropyl-modified MCM-41 NPs were characterized by XRD, FT-IR and 29Si CP/MAS SSNMR. 3-Chloropropyl-modified MCM-41 NPs were heated under reflux in a solution of pyridine in PhMe for 24 h under N2 (1 atm) to give the pyridine-modified MCM-41 NPs. The mixture was allowed to cool down, before being filtered, washed and dried under vacuum. The pyridine-modified MCM-41 NPs were characterized by XRD, FT-IR, 29Si CP/MAS SSNMR, ζ-potential, BET and BJH. Dye Loading and CP[5]A Capping: Loading of the nanopores of MSNPs with rhodamine B (RhB) or calcein was carried out by soaking the pyridine-modified MCM-41 NPs in an aqueous solution of RhB (0.5 mM) for 5 h at room temperature. An excess of the CP[5]A sodium salt was then added to the mixture. The resulting reaction mixture was stirred for 1 day at room temperature. The dye-loaded, CP[5]A-capped MSNPs were collected by centrifugation and washed thoroughly with H2O. Controlled Release Experiments: The dye-loaded, CP[5]Acapped MSNPs were placed in the bottom corner of a cuvette, and ultrapure H2O was added carefully. The UV-vis absorption spectrum of the solution was recorded as a function of time. Activation of the nanovalves was accomplished by changing the pH or by competitive binding. The method of changing pH: half the volume of the solution in the cuvette was withdrawn and then an equal volume of PBS at specific pH value was replenished to keep a constant volume. Release profiles were obtained by plotting the absorption of RhB/calcein in the solution at the absorption maximum as a function of time. The solution in the cuvette was stirred gently throughout the controlled release experiments. Cell Culture: All cells were cultured in Dulbecco-modified eagle medium (DMEM medium) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin under standard culture conditions (37 °C, in 95% humidified air containing 5% CO2). Cell Proliferation Assay: An MTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) cell proliferation assay was conducted. Five thousand cells in 200 μL media per well were placed in 96-well plates and incubated for 24 h. Cells were treated subsequently with a Me2SO control alone or with a varying dose of CP[5]A from 0 to 200 μM. After incubating the cells for 24 h, each well was incubated with 20 mL MTT agent (5 mg/mL) for another 4 h in a CO2 incubator. Thereafter, the medium containing MTT was removed, and Me2SO (150 mL) was loaded into each well to dissolve the formazan crystals. Metabolically active cells were quantified spectrophotometrically at 492 nm by detecting the reduction of yellow tetrazolium MTT to an intracellular purple formazan. The process was repeated in triplicate for all treatment concentrations.



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Supporting Information Supporting Information is available from the Wiley Online Library or from the author. [4]

Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant No. 21272093) and the Research Fund for the Doctoral Program of Higher Education of China (No. 20120061120117). This work was performed under the auspices of the King Abdulaziz City of Science and Technology (KACST) and Northwestern University (NU) Joint Center of Excellence for Integrated NanoSystems (JCEINS). We thank Drs. Turki S. Saud and Nezar H. Khdary for their support and interest in the research. We also thank Prof. Dr. Jihong Yu and Mr. Chuanlong Miao in the State Key Laboratory of Inorganic Synthesis and Preparative Chemistry at Jilin University for their technical support relating to the XRD, BET and BJH experiments.

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Received: February 10, 2013 Published online: May 8, 2013


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