ARTICLE pubs.acs.org/Langmuir
Thiolated Mucoadhesive and PEGylated Nonmucoadhesive Organosilica Nanoparticles from 3-Mercaptopropyltrimethoxysilane Galiya S. Irmukhametova,†,† Grigoriy A. Mun,† and Vitaliy V. Khutoryanskiy†,* † †
Reading School of Pharmacy, University of Reading, Whiteknights, RG6 6AD Reading, United Kingdom Department of Colloidal and Macromolecular Chemistry, al-Farabi Kazakh National University, Kazakhstan
bS Supporting Information ABSTRACT: A novel approach has been developed to synthesize thiolated sub-100 nm organosilica nanoparticles from 3-mercaptopropyltrimethoxysilane (MPTS) through its self-condensation in dimethylsulfoxide in contact with atmospheric oxygen. The formation of MPTS nanoparticles proceeds through the condensation of methoxysilane groups and simultaneous disulfide bridging caused by partial oxidation of thiol groups. These nanoparticles showed excellent colloidal stability in dilute aqueous dispersions but underwent further self-assembly into chains and necklaces at higher concentrations. They exhibited very good ability to adhere to ocular mucosal surfaces, which can find applications in drug delivery. The thiolated nanoparticles could also be easily modified through PEGylation resulting in a loss of their mucoadhesive properties.
1. INTRODUCTION Organosilica materials have received substantial attention in the past two decades with a number of reports describing their synthesis, structural features, properties, and applications. Thiolated organosilicates have been of special interest because of their ability to bind transition metals,1 possibilities for their further functionalization,2 and applications in catalysis3 or in chromatography.4 The majority of reports describing the synthesis of thiolated organosilicates have used co-condensation of 3-mercaptopropyltrimethoxysilane (MPTS) with tetraethoxysilane or tetramethoxysilane in the presence of surfactants or block-copolymers as templates to develop mesoporous structures.2,58 These reactions were typically conducted in protic solvents such as water, alcohols, or their mixtures, and co-condensation was usually induced by addition of NaOH or NH4OH resulting in formation of mesoporous materials with particle sizes greater than 500 nm.6 Only a few studies have been reported on the synthesis of sub100 nm thiolated organosilica nanoparticles. These nanoparticles may have numerous potential applications in drug delivery and diagnostics due to their ability to penetrate through certain biological barriers.9 Moller and co-workers10 have described the development of thiol-functionalized 50 and 200 nm nanoparticles by co-condensation of MPTS with tetraethyl orthosilicate in the presence of surfactants, with triethanolamine as the basic medium. They demonstrated that the use of triethanolamine not only allows control over the particle size on the nanoscale by changing its concentration but also results in materials forming very stable colloidal dispersions with narrow size distributions. In a series of publications, Nakamura and Ishimura1113 have described a one-pot synthesis of thiolated organosilica r 2011 American Chemical Society
nanoparticles from various mercaptosilane derivatives in water and waterethanol mixtures using NH4OH as a base. The 66 and 81 nm diameter nanoparticles were only obtained in water when low concentration of mercaptosilane was used (6.25 mmol/L). At higher concentrations the size of the particles was relatively large, lying within the range 1251266 nm. In the present work, we have developed a novel approach for synthesis of thiolated nanoparticles from 200 mmol/L solutions of MPTS in dimethylsulfoxide in the presence of atmospheric oxygen. These new synthetic conditions result in formation of sub-100 nm nanoparticles with excellent colloidal stability in dilute aqueous dispersions. Because of the presence of numerous thiol groups on the surface, these nanoparticles exhibited excellent mucoadhesive properties and ability to retain on freshly excised bovine cornea. However, this mucoadhesive ability is lost when the nanoparticles were PEGylated.
2. EXPERIMENTAL SECTION 2.1. Materials. 3-Mercaptopropyltrimethoxysilane (95%) was purchased from ABCR GmbH & Co. (Germany). 3-aminopropyltrimethoxysilane (APTS), methoxyethylene glycol maleimide (MePEG, g90% (NMR), MW 5000), 5-iodoacetamido fluorescein (g95% (HPLC)), 5,50 -dithiobis(2-nitrobenzoic acid) (DTNB, g98% (TLC), hydrogen peroxide (30%, puriss, stabilized), and cysteine hydrochloride were purchased from Sigma-Aldrich, Inc. and used as received. Dimethyl Received: April 15, 2011 Revised: May 31, 2011 Published: June 27, 2011 9551
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Table 1. Characteristics of Organosilica Nano- and Microparticles Prepared under Various Synthesis Conditions solvent
yield, %
diameter, nm
PDI
ξ, mV
SH groups contenta, μmol/g
0.5 mol/L NaOH
DMSO
32
55 ( 4
0.191
37 ( 8
251 ( 129
0.5 mol/L NaOH + H2O2
DMSO
30
59 ( 8
0.372
31 ( 4
951 ( 126
0.5 mol/L NaOH
waterethanol
14
1218 ( 184
0.256
43 ( 3
18 ( 2
8 mol/L NH4OH
waterethanol
16
805 ( 160
0.144
43 ( 10
16 ( 3
reaction mixture
a
It should be noted that these SH groups are likely to be the groups present on particle surface and available for reacting with Ellman’s reagent.
sulfoxide (DMSO), NH4OH, and NaOH were laboratory grade reagents purchased from Fisher Scientific Ltd. (UK). 2.2. Synthesis of Thiolated Nanoparticles. Four sets of synthetic conditions were used for the preparation of organosilica nanoparticles: (1): 0.75 mL (0.7883 g) of MPTS was mixed with 20 mL of DMSO and 0.5 mL of 0.5 mol/L aqueous NaOH and stirred continuously using a magnetic stirrer; (2): 0.75 mL (0.7883 g) of MPTS was mixed with 20 mL of DMSO, 0.5 mL of 0.5 mol/L NaOH and 30 μL of 30% hydrogen peroxide, and stirred continuously using a magnetic stirrer; (3): 0.75 mL (0.7883 g) of MPTS was mixed with 13 mL of C2H5OH, 6.5 mL of deionized water and 0.5 mL of 0.5 mol/L aqueous NaOH and stirred continuously using a magnetic stirrer; (4): 0.75 mL (0.7883 g) of MPTS was mixed with 13 mL of C2H5OH, 6.5 mL of deionized water and 0.72 mL of 28% aqueous NH4OH. Conditions 14 correspond to entries 14 in Table 1. Three batches of nanoparticles were synthesized for each condition 14. After 24 h of stirring the reaction mixtures at room temperature, the nanoparticles were purified by dialysis against 5 L of deionized water for 48 h (8 changes of water in total). Dialysis tubing MWCO 1214 kDa (Medicell Int. Ltd., UK) was used for this purpose. The purified nanoparticles were stored in aqueous dispersions in sealed containers in a fridge.
2.3. Synthesis of Nanoparticles Labeled with a Fluorescent Dye. Fluorescent dye labeled nanoparticles were synthesized by mixing 0.10 mg of 5-iodacetamido fluorescein with 1 mL of nanoparticles dispersion prepared under condition 1 (above). The reaction mixture was stirred for 15 h at room temperature and then the nanoparticles were purified by dialysis against 5 L of deionized water similarly to the abovedescribed dialysis protocol. The fluorescently labeled nanoparticles were stored in a fridge in a sealed vial wrapped in aluminum foil to avoid exposure to light.
2.4. PEGylation of Fluorescently Labeled Nanoparticles. One milliliter of aqueous dispersion of fluorescently labeled nanoparticles were mixed with 20 mg of methoxyethylene glycol maleimide and the reaction mixture was stirred for 9 h at room temperature. The nanoparticles were purified by dialysis similarly to the above-described protocols. All obtained samples were stored in the dark in a fridge.
2.5. Dynamic Light Scattering and Zeta-Potential Measurements. Dynamic light scattering and zeta-potential measurements
were conducted with dilute dispersions of nanoparticles at 25 °C using Nano-S Zetasizer (Malvern Instruments, UK). Nanoparticle concentration in dispersions was around 0.18 mg/mL for each sample. Solution pH during dynamic light scattering/zeta-potential measurements was 5.8 ( 0.1. Each sample was analyzed at least three times and the mean values of particle size and zeta-potential were calculated. These analyses were performed for each batch synthesized and Table 1 presents the mean values ( standard deviation. 2.6. Transmission Electron Microscopy (TEM). TEM images of thiolated nanoparticles were acquired using a Philips CM20 Analytical TEM at 80 kV accelerating voltage. For sample preparation, the carboncoated Cu grids were brought into contact with aqueous dispersions of nanoparticles for 60 s, followed by exposure to 1 wt % uranyl acetate solution for 30 s and then dried off with a filter paper. 2.7. Turbidimetric Study of Reaction Kinetics. In this set of experiments the reaction mixtures were prepared according to condition
1 and were bubbled with air or nitrogen or the reaction was conducted without bubbling. Gas bubbling was conducted via gas-filled balloon fitted with a needle, immersed in the reaction mixture. Samples were taken from each reaction mixture at different time intervals and analyzed using a UV/vis-spectrophotometer (Jasco, V-530) at 340 nm. Each experiment was carried out at least 3 times and the turbidity values are presented as mean ( standard deviation. 2.8. Raman Spectroscopy. FT-Raman spectra were recorded using FT-Raman NXR 9600 (Thermo Scientific). Aqueous dispersions of nanoparticles were centrifuged for 45 min at 13 000 rpm to prepare more concentrated dispersions. Raman spectra were recorded in shortened NMR glass tubes. The Raman spectrum of MPTS was recorded in liquid form. Baseline correction was performed for all spectra. 2.9. Ellman’s Assay. The thiol groups content in nanoparticles was determined by Ellman’s assay.14 Before analysis, all nanoparticles were freeze-dried using Heto Power Dry LL 3000 freeze-drier (Thermo Electron Corporation). Two mg/mL of nanoparticles dispersions were prepared in 500 μL phosphate buffer solution (0.5 mol/L, pH 8) and were allowed to hydrate for 1 h. In the meantime, 3 mg of the Ellman’s reagent or DTNB was dissolved in 10 mL of 0.5 mol/L phosphate buffer solution at pH 8. Then 500 μL of DTNB solution was added to 500 μL of nanoparticles and incubated in the dark for 90 min. After that, the nanoparticle dispersion was centrifuged for 10 min at 13 000 rpm (Sanyo, MSE Micro Centaur) and 300 μL of the supernatant was placed in 96-well microtiter plate. Absorbance was measured at 405 nm with plate reader (Spectra max 340 PC). Thiol concentration was calculated from a calibration curve of cysteine hydrochloride prepared as a series of solutions under the same conditions and with a concentration range of 0.0200.793 μmol/mL. 2.10. Mucoadhesion Study. Microscopy was performed on a fluorescence microscope (Zeiss, Imager.A1) with AxioCam MRm Zeiss camera at 10 magnification, exposure time 250 μs and 1388 1040 pixels. The bovine eyes were obtained from the local abattoir immediately after the animals were slaughtered and were transported to the laboratory in a cold box. The eyes were stored in a fridge at 4 °C overnight and then used for mucoadhesion study. At the beginning of each mucoadhesive experiment, an eyeball was punctured to release the vitreous humor making the cornea flatten. The background microscopy images were recorded for each cornea prior to its exposure to 20 μL of nanoparticle dispersion. Then the microscopy image was recorded and 20 mL of artificial tear fluid (ATF: 3.35 g NaCl, 1 g NaHCO3, 0.0305 g CaCl2 made up to 500 mL with deionized water)15 was dripped onto the corneal surface at 3 mL/min using a syringe pump. The microscopy image was taken after each wash. The wash cycles were repeated several times and the fluorescence results are presented as a function of total volume of ATF used. The histograms of fluorescence distribution were obtained by analyzing the images using ImageJ in 8-bit grayscale. The mean fluorescence values (fluorescence, au) were calculated for each image from the histograms. These values were also normalized by subtracting the background fluorescence recorded for the eye prior to their exposure to fluorescent nanoparticles. Assessment of thiolated and PEGylated nanoparticles as well as control experiment with low molecular weight 5-iodoacetamido flourescein were carried out 3 times each with different corneal zones in a bovine eye sample and the results 9552
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Figure 1. Time-dependence of turbidity for 15 mL of 0.2 mol/L MPTS solutions in DMSO bubbled with air (1), nitrogen (2), and without bubbling (3) at room temperature. Reaction was initiated by addition of 0.5 mL of 0.5 mol/L NaOH. Insert: Images of reaction mixtures containing 0.2 mol/L MPTS solution bubbled with air (a), without bubbling (b), bubbled with nitrogen (c), with H2O2 addition (d), in DMSO (ad) and in 67:33 vol % waterethanol mixture without bubbling (e). Reaction time is 1 h. of fluorescence were calculated as a mean value ( standard deviation. Fluorescent images presented as inserts in Figure 6 are exemplar microphotographs.
3. RESULTS AND DISCUSSION 3.1. Synthesis and Characterization of Organosilica Nanoparticles. A rational selection of experimental conditions for
MPTS self-condensation allowed us to develop sub-100 nm thiolated nanoparticles with very good size and polydispersity control. We have selected dimethylsulfoxide (DMSO) as an aprotic medium to avoid direct solvent effects on the condensation of silane groups. To the best of our knowledge, the use of aprotic solvents for synthesis of organosilica materials has not been exploited previously. In predominately aprotic medium, the condensation reaction initiated by small portions of aqueous NaOH proceeds in a more controlled manner. Additionally, by conducting the synthesis in the presence of atmospheric oxygen we have utilized the ability of thiol groups to oxidize and form disulfide bridges. This unique property of thiolated silanes has not been recognized in the previous publications on the development of organosilica nanomaterials.1113 Atmospheric oxygen-mediated formation of disulfide bridges from thiol groups has previously been demonstrated and successfully used by Khutoryanskiy and Tirelli16 for cross-linking polysulfide-based nanoparticles. The role of thiol group (SH) oxidation in the formation of MPTS-based organosilica nanoparticles initially was demonstrated by following the reaction kinetics using a simple turbidimetric assay. Figure 1 shows the turbidity changes in MPTS solutions in DMSO bubbled with air, nitrogen, and without gas bubbling. Control experiments were also performed in which oxidation was achieved by addition of hydrogen peroxide, and in which synthesis was conducted in waterethanol (67:33 vol %) mixtures. Additionally, experiments were performed
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with 3-aminopropyltrimethoxysilane as a compound structurally similar to MPTS but having an amino group instead of a thiol group. Bubbling MPTS-based reaction mixtures with air results in a steady increase in turbidity indicating the formation of colloidal particles. No significant changes in turbidity were observed in the absence of oxygen. When the reaction was conducted without air bubbling the turbidity begins to increase after 2 h and proceeds with the formation of nanoparticles. This is related to the presence of oxygen dissolved in the solutions. Slightly cloudy dispersions of nanoparticles were achieved within 1 h when hydrogen peroxide (H2O2) was added to the mixture in DMSO. The control experiments performed in wateralcohol mixtures resulted in milky suspensions of larger particles, which is consistent with the results previously reported for condensation of MPTS in a protic medium.1113 This result confirms the importance of careful solvent selection for synthesis of organosilica nanomaterials. Protic solvents such as water, ethanol, or their mixtures take active part in reactions involving methoxysilane groups causing their hydrolysis and subsequent condensation resulting in a very quick particle growth and aggregation. DMSO is an aprotic solvent, in which the condensation proceeds with much slower reaction rate leading to sub-100 nm nanoparticles with excellent colloidal stability in aqueous dispersions. Only a small amount of aqueous 0.5 mol/L NaOH (0.5 mL) added to 20 mL of DMSO-based mixture ensured a good control over the reaction and resulted in sub-100 nm nanoparticles. When higher levels of NaOH were used the reaction resulted in formation of significantly larger particles (data not shown). The control experiments performed with APTS under experimental conditions identical to MPTS (bubbling with air or nitrogen or without bubbling) did not result in formation of nanoparticles. This observation provides a further evidence for the importance of SS bridge formation in MPTS self-condensation. The nanoparticles synthesized under various reaction conditions have been purified by extensive dialysis against deionized water and were characterized using dynamic light scattering (DLS), zeta-potential measurements (ξ), transmission electron microscopy (TEM), and Ellman’s assay to quantify the presence of thiol groups. The reaction conditions and characteristics of the synthesized nanoparticles are summarized in Table 1. The nanoparticles synthesized in DMSO in the presence of either oxygen or hydrogen peroxide have a small 5559 nm diameter, low polydispersities (PDI) and relatively high SH groups content on the surface, whereas the materials generated in waterethanol mixtures have significantly larger diameters (850 and 1218 nm) and lower levels of thiolation. Both types of particle have negative zeta-potential, which is likely related to the presence of negatively charged SiO and S groups at their surfaces. Raman spectroscopy was recognized as a powerful tool for structure characterization of organosilica materials, including those prepared from MPTS.10,17 The Raman spectrum of MPTS monomer with complete assignments can be found in Figure S1 of the Supporting Information. The investigation of the nanoparticles by Raman spectroscopy in aqueous dispersions revealed the presence of the strong band at 2568 cm1 due to SH stretching (νSH)10,17 and a band at 506 cm1, responsible for SS stretching (νSS) (Figure 2). Further bands were found at 653 cm1 - ν(CS), 1254 cm1 and 1427 cm1 - δ (CH2), 1639 cm1 - δ(H2O), 2916 cm1 - ν(CH) and 3371 cm1 - ν (OH from H2O). 9553
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Figure 2. Raman spectra of MPTS nanoparticles dispersed in deionized water (1) and freeze-dried (2). The bands responsible for SH (νSH) and SS (νSS) stretching are shown by the red arrows.
Figure 3. Proposed schematic structure of MPTS nanoparticles.
In Raman spectra recorded for the nanoparticles after freezedrying, the SS stretching mode appears as a strong band at 512 cm1. This band becomes more pronounced because the spectrum was recorded for a dry sample, providing a better intensity of all signals. No bands associated with the presence of water appear in the spectrum of dry sample (1639 and 3371 cm1). The band at 506 cm1 in the nanoparticles dispersed in deionized water indicates the presence of SS bonds that could only result from SH groups' oxidation during the synthesis. This Raman spectra interpretation is in good agreement with the data reported by Billinge et al.1a and Okabayashi et al.17 The turbidimetric results on MPTS condensation reaction under different experimental conditions as well as the characterization by Raman spectroscopy, dynamic light scattering, zetapotential, and Ellman’s assay confirm the following structural organization of the nanoparticles (Figure 3).
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Figure 4. Size distribution for nanoparticles formed from 0.2 mol/L MPTS in DMSO without bubbling. Nanoparticle concentration in dispersion is 0.18 mg/mL. Insert: (a) time-dependence of nanoparticle size in aqueous dispersion at room temperature, (b) TEM image of nanoparticles.
The synthesis of nanoparticles proceeds via polycondensation reaction involving the formation of both SiOSi and SS bonds. However, the methoxysilane groups in MPTS are likely to be predominately responsible for formation of 3D cross-linked nanostructure leaving numerous thiol groups intact. The degree of thiol groups involvement in disulfide bridging reaction may also be dependent on oxidation conditions chosen, kinetics of this process, and the porosity of resulting nanoparticles. For example, the nanoparticles prepared in the presence of H2O2 show surprisingly higher SH groups' content (951 ( 126 μmol/g) compared to the nanoparticles formed without air bubbling or H2O2. It may be related to the difference in the porous structure of the nanoparticles synthesized under different conditions and availability of SH groups for reacting with Ellman’s reagent. The structural difference between these types of nanoparticles becomes clearer from comparison of PDI values as the nanoparticles synthesized in the presence of H2O2 show greater polydispersity. The nanoparticles synthesized in DMSO without air bubbling have spherical shape and a narrow unimodal size distribution (Figure 4). The subsequent discussion will concern this type of nanoparticle. The DLS analysis of the nanoparticle size as a function of time in dilute aqueous solutions (0.18 mg/mL) for up to 1 month shows no changes confirming their excellent aggregation stability. However, when more concentrated dispersions of nanoparticles (8.87 mg/mL) were studied by TEM a very peculiar selforganization behavior was observed (Figure 5). It appears that the thiolated nanoparticles self-assemble into chains and necklaces in more concentrated dispersions, which is likely to be related to interparticle disulfide bridge formation. Perhaps, this interparticle assembly became possible during sample preparation for TEM experiment, when concentrated dispersion is dehydrated and individual particles are in close proximity with each other. This phenomenon of chains and necklaces formation is not unusual taking into consideration the ability of SH groups to form SS bridges, but it definitely deserves further investigation, which is outside of the scope of this work. 3.2. Mucoadhesive Properties of Nanoparticles. The presence of thiol groups on the surface of nanoparticles opens an 9554
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Figure 5. TEM image of MPTS nanoparticles in more concentrated dispersion. Nanoparticle concentration in dispersion is 8.87 mg/mL.
interesting opportunity for their application in drug delivery. Materials capable of adhering to biological tissues have been widely used in drug delivery for enhancing retention of dosage forms on mucosal surfaces. Typical mucoadhesive materials are hydrophilic polymers and their adhesive properties are due to noncovalent interactions (electrostatic attraction, hydrogen bonding, and hydrophobic effects) with mucosal glycoproteins (mucins).18 The ability of water-soluble polymers carrying pendant SH groups to exhibit superior adhesion to mucosal surfaces has previously been demonstrated by Bernkop-Schn€urch et al.19 and was related to their ability to form covalent disulfide bridges with mucins. More recently, the same group has reported a successful design of thiolated polymer nanoparticles through the complexation of thiol-carrying macromolecules with complementary polymers in aqueous solutions.20,21 These nanoparticles were found to be mucoadhesive and promising for oral delivery of insulin as demonstrated by in vitro and in vivo experiments. To test the mucoadhesive properties of our organosilica nanoparticles, we have synthesized samples labeled with a fluorescent dye. Additionally, a portion of fluorescently labeled nanoparticles was reacted with methoxypolyethylene glycol maleimide (MePEG) to achieve a PEGylated surface that is expected to be nonmucoadhesive. The DLS analysis of PEGylated nanoparticles confirmed a slight increase in their size and Raman spectroscopy showed the presence of MePEG in the samples (Figures S2 and S3 of the Supporting Information). Ellman’s assay confirmed that after PEGylation the concentration of SH groups in the nanoparticles dropped from 137 ( 6 to 58 ( 6 μmol/g. The mucoadhesive properties of fluorescently labeled thiolated and PEGylated nanoparticles were assessed by evaluating their retention on bovine ocular surfaces using fluorescence microscopy. The aqueous dispersions of nanoparticles were placed on bovine corneal surfaces and after an initial contact period of 3 min were washed with 20 mL of artificial tear fluid (ATF) several times using an automatic syringe pump. Fluorescent microphotographs were taken after each wash to monitor the presence of nanoparticles on the ocular surface and processed to quantify the fluorescence intensity (an exemplar fluorescence microphotograph can be found in Figure S4 of the Supporting Information). The thiolated nanoparticles are retained on the corneal surfaces even after 5 wash cycles with ATF, demonstrating their excellent mucoadhesive potential (Figure 6).
Figure 6. Fluorescence levels of thiolated (a) and PEGylated (b) nanoparticles on bovine cornea surfaces washed with ATF. Inserts show fluorescent microphotographs (size bar is 200 μm).
The PEGylated nanoparticles are removed from the corneal tissue more quickly and disappear completely after a third wash. A control experiment performed with low molecular weight fluorescein dye revealed even lower retention ability compared to PEGylated nanoparticles (Figure S5 of the Supporting Information). Thus, the thiolated organosilica nanoparticles exhibit excellent mucoadhesive ability similarly to thiolated water-soluble polymers (thiomers), extensively studied by Bernkop-Schn€urch and co-workers.19 These thiolated nanoparticle may be considered as a novel class of mucoadhesive materials.
4. CONCLUSIONS In this work, we have developed a novel approach for synthesis of sub-100 nm organosilica thiolated nanoparticles. These nanoparticles were formed by self-condensation of 3-mercaptopropyltrimethoxysilane in dimethylsulfoxide in contact with atmospheric oxygen or in the presence of hydrogen peroxide as an oxidizing agent. It was demonstrated that the formation of nanoparticles proceeds through the condensation of methoxysilane groups and simultaneous disulfide bridging caused by partial oxidation of thiol groups. These nanoparticles showed excellent colloidal stability in dilute aqueous dispersions but underwent further self-assembly into chains and necklaces at higher concentrations. The thiolated nanoparticles were found to exhibit excellent adhesion ability to mucosal surfaces, which was demonstrated using freshly excised bovine cornea. The mechanism of mucoadhesion 9555
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Langmuir is believed to be due to disulfide bond formation between thiol groups on the surface of nanoparticles and cystein-rich domains in mucins. These nanoparticles are believed to be promising for application in drug delivery, where an enhanced retention of a dosage form on mucosal surfaces is required. To the best of our knowledge, this is the first report of organosilica materials having mucoadhesive properties. The thiolated nanoparticles could easily be modified by reaction with methoxyethylene glycol maleimide under very mild experimental conditions. PEGylated nanoparticles were found to be not adhesive to mucosal surfaces but are expected to be able to penetrate through mucus gel easily, which is also a very useful property for certain drug delivery applications, that is in cystic fibrosis therapy when excessive mucus production in the airways hampers drug penetration.22
’ ASSOCIATED CONTENT
bS
Supporting Information. Additional data on Raman spectra, dynamic light scattering size distributions, results of control experiments with fluorescence microscopy. This material is available free of charge via the Internet at http://pubs.acs.org.
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(12) Nakamura, M.; Ishimura, K. Langmuir 2008, 24, 12228. (13) Nakamura, M.; Ozaki, S.; Abe, M.; Doi, H.; Matsumoto, T.; Ishimura, K. Colloids Surf., B 2010, 79, 19. (14) Bravo-Osuna, I.; Teutonico, D.; Arpicco, S.; Vauthier, C.; Ponchel, G. Int. J. Pharm. 2007, 340, 173. (15) Shen, J.; Deng, Y.; Jin, X.; Ping, Q.; Su, Z.; Li, L. Int. J. Pharm. 2010, 402, 248. (16) Khutoryanskiy, V. V.; Tirelli, N. Pure Appl. Chem. 2008, 80, 1703. (17) Okabayashi, H.; Izawa, K.; Yamamoto, T.; Masuda, H.; Nishio, E.; O’Connor, C. J. Colloid Polym. Sci. 2002, 280, 135. (18) (a) Khutoryanskiy, V. V. Macromol. Biosci. 2011, 11, 748. (b) Serra, L.; Domenech, J.; Peppas, N. A. Eur. J. Pharm. Biopharm. 2009, 71, 519. (19) Bernkop-Schn€urch, A. Adv. Drug Delivery Rev. 2005, 57, 1569. (20) Deutel, B.; Greindl, M.; Thaurer, M.; Bernkop-Schn€urch, A. Biomacromolecules 2008, 9, 278. (21) Albrecht, K.; Greindl, M.; Deutel, B.; Kremser, C.; Wolf, C.; Talasz, H.; Stollenwerk, M. M.; Debbage, P.; Bernkop-Schn€urch, A. J. Pharm. Sci. 2010, 99, 2008. (22) Khanvilkar, K.; Donovan, M. D.; Flanagan, D. R. Adv. Drug Delivery Rev. 2001, 48, 173.
’ AUTHOR INFORMATION Corresponding Author
*Fax: +44 (0) 118 378 4703; Tel: +44 (0) 118 378 6119; E-mail:
[email protected].
’ ACKNOWLEDGMENT G.S.I. is grateful to Bolashak Foundation (Kazakhstan) for providing international scholarship grant. The help of Dr. P. Harris (Centre for Advanced Microscopy) in TEM experiments is greatly appreciated. Special thanks to Mr S. Pountney for help with fluorescent microscopy and to Prof. J. Lawrence and Dr. L. Kudsiova (King’s College London) for support in ξ-potential measurements. Chemical Analysis Facility is acknowledged for providing access to Raman spectroscopy and Dr. O. Khutoryanskaya for help with these experiments. ’ REFERENCES (1) (a) Billinge, S. J. L.; McKimmy, E. J.; Shatnawi, M.; Kim, H. J.; Petkov, V.; Wermeille, D.; Pinnavaia, T. J. J. Am. Chem. Soc. 2005, 127, 8492. (b) Feng, X.; Fryxell, G. E.; Wang, L.-Q.; Kim, A. Y.; Liu, J.; Kemner, K. M. Science 1997, 276, 923. (2) (a) Cano-Serrano, E.; Blanco-Brieva, G.; Campos-Martin, J. M.; Fierro, J. L. G. Langmuir 2003, 19, 7621. (b) Lim, M. H.; Blanford, C. F.; Stein, A. Chem. Mater. 1998, 10, 467. (3) (a) Crudden, C. M.; Sateesh, M.; Lewis, R. J. Am. Chem. Soc. 2005, 127, 10045. (b) Dabre, R.; Schwammle, A.; Lammerhofer, M.; Lindner, W. J. Chromatogr., A 2009, 1216, 3473. (4) Hall, S. R.; Fowler, C. E.; Lebeau, B.; Mann, S. Chem. Commun. 1999, 201. (5) Margolese, D.; Melero, J. A.; Christiansen, S. C.; Chmelka, B. F.; Stucky, G. D. Chem. Mater. 2000, 12, 2448. (6) Mori, Y.; Pinnavaia, T. J. Chem. Mater. 2001, 13, 2173. (7) Shah, J.; Pinnavaia, T. J. Chem. Commun. 2005, 1598. (8) Gaslain, F. O. M.; Delacote, C.; Walcarius, A.; Lebeau, B. J. Sol-Gel Sci. Technol. 2009, 49, 112. (9) Prestidge, C. A.; Barnes, T. J.; Lau, C.-H.; Barnett, C.; Loni, A.; Canham, L. Expert Opin. Drug Deliv. 2007, 4, 101. (10) Moller, K.; Kobler, J.; Bein, T. J. Mater. Chem. 2007, 17, 624. (11) Nakamura, M.; Ishimura, K. J. Phys. Chem. C 2007, 111, 18892. 9556
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