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Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/chemcomm
Sugar and pH Dual-Responsive Snap-Top Nanocarriers Based on Mesoporous Silica-Coated Fe3O4 Magnetic Nanoparticles for Cargo Delivery Xi-Long Qiu,a,b Qing-Lan Li,a Yue Zhou,a Xiao-Yu Jin,a Ai-Di Qi*b and Ying-Wei Yang*a
A facile strategy to prepare snap-top magnetic nanocarriers has been developed where ultrasmall superparamagnetic Fe3O4 nanoparticle was used as a core with mesoporous silica as a shell followed by the covalent installation of a layer of β-cyclodextrins on the outer surfaces. The smart hybrid nanomaterials showed remarkable pH- and sugarresponsive cargo release property and low cytotoxicity as proved by an MTT assay with HEK 293T cell lines. With the tremendous advance of modern nanomedicine and bionanotechnology over the past decades, much effort has been devoted to (supra)molecular nanovalves that integrate diagnostic and therapeutic functions.1,2 Compared with traditional controlled drug release systems, mesoporous silica nanoparticles (MSNs),3 firstly discovered in the early 1990s,4 are ideal vehicles for incorporating switchable gating entities onto their surfaces, attributing to their inertness, finely tunable pore sizes, large pore volumes, high surface areas, ease of modification and relatively low cytotoxicity.5,6 Meanwhile, ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have attracted great attention in virtue of their biocompatibility and biodegradability.7 More importantly, they could preferentially guide drugs to the diseased tissues by using external magnetic field under physiological conditions.8 Nevertheless, for pure magnetic nanoparticles (MNPs), they are not discrete but normally in an aggregated state, which greatly limited their applications. Therefore, surface modification and functionalization of MNPs are generally necessary.9 Recently, the integration of biocompatible nanovalves or nanocap-based drug delivery systems with magnetic iron oxide nanoparticles to form core–shell composites and their future opportunities as targeted drug-delivery vehicles in clinical trials have been discussed.10 Zhao et al. reported a new synthetic method, that is, the surfactant-templated approach, to prepare sandwich-structured mesoporous silica microspheres (500 nm)
containing a silica-coated magnetite core and ordered silica shell with perpendicularly oriented channels.11a Thereafter, they synthesized large porous mesostructured cellular silica foam coated magnetic oxide composites with multilamellar vesicle shells by using commercial nonionic triblock copolymer Pluronic P123 as template.11b Moon, Hyeon and coworkers described discrete, monodisperse, and precisely size controllable core–shell MSNs, which are smaller than 100 nm and only comprised of Fe3O4 nanoparticles as core in silica nanoparticles.10b However, multifunctional magnetic fieldtargeted snap-top5c nanocarriers based on mesoporous silicacoated Fe3O4 nanoparticles for stimuli-responsive drug delivery has not yet been reported, to the best of our knowledge. In this Communication, by combining Fe3O4 magnetic nanoparticles and MSNs with bulky organic entities (β-CDs),12 we wish to design and synthesize such a biocompatible version of cargo delivery platform, namely Fe3O4@MSN@β-CDs (Scheme 1), for pH and sugar dual-responsive controlled cargo release in a targeted delivery fashion. On the other hand, boronic acids have been used as a recognition moiety in the construction of sensors for saccharides by forming a dioxaborolane ring between them,
a
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, International Joint Research Laboratory of NanoMicro Architecture Chemistry (NMAC), Jilin University, 2699 Qianjin Street, Changchun 130012, P. R. China. E-mail: [email protected] b College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P. R. China. † Electronic Supplementary Information (ESI) available: See DOI: 10.1039/c000000x/
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Scheme 1 Schematic illustration of (a) the synthetic procedure for the Fe3O4@MSN@β-CDs delivery system and its operation, and (b) the competitive cleaving process for D-fructose with β-CDs grafted on the mesoporous shell.
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likely the strongest single-pair reversible functional group interaction in an aqueous environment among organic compounds that can be readily used for the construction of molecular receptors.13 Based on this motif, we carefully design a cargo delivery system with MSN-coated Fe3O4 as nanocarrier, whose surface was (Fe3O4@MSN) functionalized with 4-carboxyphenylboronic acid (CBA) to give Fe3O4@MSN-CBA possessing sugar responsive characteristics in the medium of pH 9.8, and with rhodamine 6G (Rh6G) as cargo. The Fe3O4@MSN-CBA can form stable cyclic borate esters on its surfaces upon reacting with β-CDs at the pH level higher than the pKa of CBA (pKa 8.0)13a to result in CD-grafted Fe3O4@MSN-CBA, i.e., Fe3O4@MSN@β-CDs, where CDs serve as snap-top gatekeepers of the silica nanocontainers.14 In addition, removal of β-CD moieties from Fe3O4@MSN@β-CDs by using D-fructose which can bind more strongly to the boronic acid unit as compared with β-CDs, induced sustained cargo release from the nanocontainers.15 The release of cargo can be controlled by pH and the addition of Dfructose. Significantly, this biocompatible system with very low cytotoxicity can be further applied to the magnetic fieldoriented delivery and controlled release of cargo. Water-soluble, biocompatible USPIONs were prepared by a modified solvothermal method of FeCl3·6H2O in deionized water, using a natural nutrient, vitamin C, as a reducing agent by oxidizing its C=C double bond under mild hydrothermal conditions, and more strikingly its oxidized product (dehydroascorbic acid, DHAA) as a stabilizer and capping ligand for Fe3O4 nanoparticles.16 The controllable and slow condensation of iron hydroxides provided a possibility to avoid the adverse effects on the composition, size, morphology, and magnetic properties of the nanoparticles.17 Vitamin C, DHAA transformed from vitamin C, and DHAA-Fe3O4 nanoparticles were analyzed by Fourier transform infrared (FTIR) spectroscopy (Fig. S2). Vitamin C molecules exhibited the characteristic absorption bands at 1755 cm-1 (C=O stretching in the five-membered lactone ring) and 1674 cm-1 (C=C stretching vibrations coupled with the neighboring vibrations along the
Fig. 1 (a) TEM image of DHAA-Fe3O4 nanoparticles; (b) Selected-area electron diffraction pattern of DHAA-Fe3O4 nanoparticles; (c) SEM image of Fe3O4@MSN@β-CDs nanoparticles; (d) TEM image of Fe3O4@MSN@β-CDs nanoparticles.
2 | J. Name., 2012, 00, 1-3
Journal Name DOI: 10.1039/C4CC10413G
Fig. 2 (a) XRD pattern of the DHAA-Fe3O4 nanoparticles; (b) Hysteresis loop of DHAA-Fe3O4 and Fe3O4@MSN@β-CDs measured at 300 k (the lower-right inset shows the dispersion of DHAA-Fe3O4 nanoparticles in water before and after an external magnetic field is applied); (c) Thermogravimetric analysis of DHAA-Fe3O4 and Fe3O4@MSN@β-CDs; (d) N2 adsorption isotherm curves of Fe3O4@MSN-OH and Fe3O4@MSN@β-CDs.
conjugated system).18 FT-IR spectrum (Fig. S3) of the DHAA derivative obtained upon oxidation showed strong peaks at 1790 cm-1 (C=O stretching vibration), indicating the presence of carbonyl groups in the DHAA ring. The strong band at 584 cm-1 in the spectrum of the DHAA-Fe3O4 nanoparticles (Fig. S2b) is the Fe-O vibrations of magnetic nanoparticles. But, the C=O stretching vibrations in vitamin C and DHAA could not be detected in the as-prepared materials, suggesting that the carbonyl O atom coordinates with Fe on the surfaces of nanoparticles.19 X-ray photoelectron spectroscopy (XPS) of the DHAAFe3O4 nanoparticles exhibited two peaks at 710.6 and 724.1 eV, corresponding to the peaks of Fe 2p3/2 and Fe 2p1/2 in Fe3O4 nanoparticles, respectively (Fig. S5). There is no obvious shakeup satellite structure at the higher binding energy side of both main peaks (about 718.8 and 729.5 eV), which is the characteristic of Fe3O4 magnetic nanoparticles.20 The transmission electron microscopy (TEM) (Fig. 1a and S6a) confirmed that the prepared DHAA-Fe3O4 nanoparticles have a rough surface, a spherical shape and narrow size distribution with an average diameter of ca. 5 nm. Highresolution TEM provided more detailed structural information on the nanoparticles, and further validated that DHAA-Fe3O4 nanoparticles exhibited well-ordered single-domain crystallinity (Fig. S7a). Combined with TEM, selected-area electron diffraction (SAED) pattern reveals that the obtained DHAAFe3O4 nanoparticles possess the crystalline feature (Fig. 1b), in agreement with the presence of the magnetite crystal structure. The wide angle X-ray diffraction pattern (XRD) of DHAAFe3O4 nanoparticles shows six well-resolved diffraction peaks with high crystallinity (Fig. 2a). Owing to the superparamagnetic behavior and good surface coverage by DHAA ligands, the DHAA-Fe3O4 nanoparticles could be welldispersed in an aqueous solution without an external magnetic field, and possess reasonably high total magnetization, that is, the clusters could be easily separated by applying an external magnetic field, which is beneficial for applications in targeted drug delivery, cell separation, etc. (inset of Fig. 2b). The Fe3O4@MSN-OH nanoparticles were prepared using a template-directed sol–gel method, according to a modified
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Journal Name literature procedure.6d. (3-Aminopropyl) triethoxysilane (APTES) was reacted with Fe3O4@MSN-OH nanoparticles to achieve 3-aminopropyl-modified nanoparticles (Fe3O4@MSNNH2). Upon reaction with CBA in DMSO, borate-modified MSNs (Fe3O4@MSN-CBA) were obtained. Changes in the surface groups of MSNs were determined by FTIR (Fig. S8). Then the final cargo delivery systems were achieved after loading Fe3O4@MSN-CBA with Rh6G at room temperature for 24 h. The preparation of the snap-top carriers was completed upon addition of a sufficient amount of β-CDs into the reaction mixture, which led to the β-CDs being spread all over the surface of Fe3O4@MSN-CBA via covalent bonds (ESI). The Fe3O4@MSN@β-CDs can be well dispersed in polar solvents, which benefits from the installation of the subsequent mesoporous silica layer. SEM and TEM (Fig. 1c, 1d and Fig. S6c, and S7b) reveal that Fe3O4@MSN@β-CDs particles (80 nm in diameter) containing Fe3O4 core are uniformed spherical in shape and separated from one another, clearly demonstrating the uniformity of the nanoparticles and an MCM-41-type channel-like mesoporous structure. The monodispersity and homogeneous particle size of nanoparticles are also presented in TEM, indicating no aggregation occurred. Zeta potentials of the Fe3O4 and Fe3O4@MSN@β-CDs nanoparticles were measured to be -33.2 ± 1.6 and -29.2 ± 1.3 mV (Table S1), respectively, indicating that the newly synthesized materials can maintain certain stability and is strong enough to transport drugs in biological media. The magnetization data (Fig. 2b) of DHAA-Fe3O4 and Fe3O4@MSN@β-CDs up to 3.0 T at 300 K showed a hysteresis loop and have saturation magnetization values without any coercivity and remanence, respectively, demonstrating their superparamagnetic behavior. The magnetization value of Fe3O4@MSN@β-CDs (36.7 emu g-1) is as expected smaller than that of DHAA-Fe3O4 cores (51.7 emu g-1), because the magnetization value is a function of the domain size, the saturation magnetization of the nanoparticles, but the magnetic forces of these particles are good enough for separation and drug delivery, presented by their vivid separation process from the solution (Fig. S9, Video S1 and S2).21 Nevertheless, it is reasonable when compared to DHAA-Fe3O4 nanoparticles of comparable size prepared by the solvothermal and hightemperature decomposition processes.22 The blocking temperature (TB) was determined to be 25 K from zero field cooling (ZFC) and field cooling (FC) curves (Fig. S10). Thermogravimetric analysis (TGA) in N2 (Fig. 2c) shows a weight loss of only 10.3 wt% for DHAA-Fe3O4 nanoparticles in the range of 100–800 °C. A large weight loss of about 43.3 wt% for Fe3O4@MSN@β-CDs implies they contain considerable amount of organic species. Furthermore, the surface areas and pore sizes of Fe3O4@MSN-OH and Fe3O4@MSN@β-CDs were confirmed by Brunauer-EmmettTeller (BET) and Barrett-Joyner-Halenda (BJH) analyses (Fig. 2d, S11). The characteristic type IV adsorption isotherms with surface areas of 1045 and 583 cm2 g-1 and pore volumes of 1.014 and 0.541 cm3 g-1 indicated the presence of uniform mesopores of around 2.7 nm in diameter. The successful grafting of β-CDs on MSN surfaces caused the decreasing of surface area and pore volume of MSNs, while the good mesoporous characteristics was still maintained for cargo loading (Fig. 2d, S11). A series of control experiments have been done to further prove the functionalization of β-CDs on Fe3O4@MSN surfaces by comparing the release performance of different materials. To
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Fig. 3 Cumulative release profiles of Rh6G from Fe3O4@MSN@βCDs nanoparticles. (a) The drug release was conducted at different Dfructose concentrations, i.e., 0, 25, 50, and 100 mM at pH 9.8. (b) The pH-operated release of Rh6G from Fe3O4@MSN@β-CDs at pH 2, pH 7.4, and pH 9.8, respectively. The detection wavelength was 525 nm.
test the availability of cleavable gating β-CDs and the capacity by competitive D-fructose-triggered cargo release, UV-vis spectroscopy was employed to monitor the cargo release under different concentrations of materials (0, 25, 50, and 100 mM). There was only negligible premature release of Rh6G cargo (Fig. 3a). Furthermore, increasing percentages of cargo were released from the mesopores of the nanocomposites upon increasing the concentration of D-fructose, which means the drug release rate becomes faster and the release will be enhanced when the D-fructose concentration in the treated diseased region is greater. In order to better understand the mechanism of the pHresponsive model, the release property of Rh6G-loaded, Fe3O4@MSN@β-CDs was investigated in sodium phosphate buffer solutions (PBS). In Fig. 3b (pH 9.8), the negligible premature release implied the cargo molecules are held within the nanopores of Fe3O4@MSN@β-CDs at a pH level higher than the pKa of CBA (pKa 8.0), because the bulky β-CD entities on Fe3O4@MSN@β-CDs prevent cargo release. When the solution pH is lower than 8.0, the boronic-β-CD ester entities are cleaved off and the cargo is immediately released (Fig. 3b, pH7.4 and pH 2). To examine the biocompatibility of the obtained magnetic nanoparticles in bio-related fields, the cytotoxicity was investigated. The effect of DHAA-Fe3O4 and Fe3O4@MSN@βCDs nanoparticles on cell proliferation was assessed with normal human embryonic kidney (HEK) 293T cells by MTT assay, which revealed that the cell viability were not hindered by the presence of the nanoparticles up to a concentration of 100 µg mL-1. With the increase of concentration of the two materials, the cell viabilities showed a slight toxicity to normal human cells, which was deduced from the fact that the cell viabilities were higher than 75%, even though their concentration was as high as 100 µg mL-1 (Fig. 4). Overall, the materials possess negligible cytotoxicity at low concentrations, allowing them to be used as smart nanocarriers for controlled drug delivery. In conclusion, we designed and synthesized here a novel multifunctional magnetic mesoporous snap-top nanocarriers with superparamagnetic Fe3O4 core and mesoporous silica shell functionalized smartly with supramolecular caps (β-CDs) by covalent bond. The nanocomposites possess a uniform size, excellent dispersity, ordered mesoporosity and strong magnetization. The covalent cyclic esters of dioxaborolane rings served as effective drug anchorages to entrap cargo in the reservoirs and realize the release of cargo in response to pH variations and sugar molecules such as D-fructose, resulting in increased drug loading capacity and sustained release. The
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nanocomposites could not only effectively transport encapsulated drug into targeted sites, but also be used as sugar sensitive smart nanocarriers and provide diverse applications as an effective delivery system, by taking advantage of the good biocompatibility and cellular uptake properties. These studies suggest that Fe3O4@MSN@β-CDs could be very promising new candidates for future cancer diagnosis and therapy. This research is supported by the NNSFC (21272093 and 51473061) and the Fundamental Research Funds for the Central Universities (No. JCKY-QKJC05). We acknowledge the intellectual development of the basic theme, in line with our work on the binding and release mechanism, by professors Stoddart, Zink and his co-workers in their recently published paper.15
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Fig. 4 The in vitro cell viability of HEK 293T cells incubated with DHAA-Fe3O4 (red histograms) and Fe3O4@MSN@β-CDs (blue histograms) at different concentrations for 48 h.
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Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/chemcomm
Sugar and pH Dual-Responsive Snap-Top Nanocarriers Based on Mesoporous Silica-Coated Fe3O4 Magnetic Nanoparticles for Cargo Delivery Xi-Long Qiu,a,b Qing-Lan Li,a Yue Zhou,a Xiao-Yu Jin,a Ai-Di Qi*b and Ying-Wei Yang*a
A facile strategy to prepare snap-top magnetic nanocarriers has been developed where ultrasmall superparamagnetic Fe3O4 nanoparticle was used as a core with mesoporous silica as a shell followed by the covalent installation of a layer of β-cyclodextrins on the outer surfaces. The smart hybrid nanomaterials showed remarkable pH- and sugarresponsive cargo release property and low cytotoxicity as proved by an MTT assay with HEK 293T cell lines. With the tremendous advance of modern nanomedicine and bionanotechnology over the past decades, much effort has been devoted to (supra)molecular nanovalves that integrate diagnostic and therapeutic functions.1,2 Compared with traditional controlled drug release systems, mesoporous silica nanoparticles (MSNs),3 firstly discovered in the early 1990s,4 are ideal vehicles for incorporating switchable gating entities onto their surfaces, attributing to their inertness, finely tunable pore sizes, large pore volumes, high surface areas, ease of modification and relatively low cytotoxicity.5,6 Meanwhile, ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have attracted great attention in virtue of their biocompatibility and biodegradability.7 More importantly, they could preferentially guide drugs to the diseased tissues by using external magnetic field under physiological conditions.8 Nevertheless, for pure magnetic nanoparticles (MNPs), they are not discrete but normally in an aggregated state, which greatly limited their applications. Therefore, surface modification and functionalization of MNPs are generally necessary.9 Recently, the integration of biocompatible nanovalves or nanocap-based drug delivery systems with magnetic iron oxide nanoparticles to form core–shell composites and their future opportunities as targeted drug-delivery vehicles in clinical trials have been discussed.10 Zhao et al. reported a new synthetic method, that is, the surfactant-templated approach, to prepare sandwich-structured mesoporous silica microspheres (500 nm)
containing a silica-coated magnetite core and ordered silica shell with perpendicularly oriented channels.11a Thereafter, they synthesized large porous mesostructured cellular silica foam coated magnetic oxide composites with multilamellar vesicle shells by using commercial nonionic triblock copolymer Pluronic P123 as template.11b Moon, Hyeon and coworkers described discrete, monodisperse, and precisely size controllable core–shell MSNs, which are smaller than 100 nm and only comprised of Fe3O4 nanoparticles as core in silica nanoparticles.10b However, multifunctional magnetic fieldtargeted snap-top5c nanocarriers based on mesoporous silicacoated Fe3O4 nanoparticles for stimuli-responsive drug delivery has not yet been reported, to the best of our knowledge. In this Communication, by combining Fe3O4 magnetic nanoparticles and MSNs with bulky organic entities (β-CDs),12 we wish to design and synthesize such a biocompatible version of cargo delivery platform, namely Fe3O4@MSN@β-CDs (Scheme 1), for pH and sugar dual-responsive controlled cargo release in a targeted delivery fashion. On the other hand, boronic acids have been used as a recognition moiety in the construction of sensors for saccharides by forming a dioxaborolane ring between them,
a
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, International Joint Research Laboratory of NanoMicro Architecture Chemistry (NMAC), Jilin University, 2699 Qianjin Street, Changchun 130012, P. R. China. E-mail: [email protected] b College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P. R. China. † Electronic Supplementary Information (ESI) available: See DOI: 10.1039/c000000x/
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Scheme 1 Schematic illustration of (a) the synthetic procedure for the Fe3O4@MSN@β-CDs delivery system and its operation, and (b) the competitive cleaving process for D-fructose with β-CDs grafted on the mesoporous shell.
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likely the strongest single-pair reversible functional group interaction in an aqueous environment among organic compounds that can be readily used for the construction of molecular receptors.13 Based on this motif, we carefully design a cargo delivery system with MSN-coated Fe3O4 as nanocarrier, whose surface was (Fe3O4@MSN) functionalized with 4-carboxyphenylboronic acid (CBA) to give Fe3O4@MSN-CBA possessing sugar responsive characteristics in the medium of pH 9.8, and with rhodamine 6G (Rh6G) as cargo. The Fe3O4@MSN-CBA can form stable cyclic borate esters on its surfaces upon reacting with β-CDs at the pH level higher than the pKa of CBA (pKa 8.0)13a to result in CD-grafted Fe3O4@MSN-CBA, i.e., Fe3O4@MSN@β-CDs, where CDs serve as snap-top gatekeepers of the silica nanocontainers.14 In addition, removal of β-CD moieties from Fe3O4@MSN@β-CDs by using D-fructose which can bind more strongly to the boronic acid unit as compared with β-CDs, induced sustained cargo release from the nanocontainers.15 The release of cargo can be controlled by pH and the addition of Dfructose. Significantly, this biocompatible system with very low cytotoxicity can be further applied to the magnetic fieldoriented delivery and controlled release of cargo. Water-soluble, biocompatible USPIONs were prepared by a modified solvothermal method of FeCl3·6H2O in deionized water, using a natural nutrient, vitamin C, as a reducing agent by oxidizing its C=C double bond under mild hydrothermal conditions, and more strikingly its oxidized product (dehydroascorbic acid, DHAA) as a stabilizer and capping ligand for Fe3O4 nanoparticles.16 The controllable and slow condensation of iron hydroxides provided a possibility to avoid the adverse effects on the composition, size, morphology, and magnetic properties of the nanoparticles.17 Vitamin C, DHAA transformed from vitamin C, and DHAA-Fe3O4 nanoparticles were analyzed by Fourier transform infrared (FTIR) spectroscopy (Fig. S2). Vitamin C molecules exhibited the characteristic absorption bands at 1755 cm-1 (C=O stretching in the five-membered lactone ring) and 1674 cm-1 (C=C stretching vibrations coupled with the neighboring vibrations along the
Fig. 1 (a) TEM image of DHAA-Fe3O4 nanoparticles; (b) Selected-area electron diffraction pattern of DHAA-Fe3O4 nanoparticles; (c) SEM image of Fe3O4@MSN@β-CDs nanoparticles; (d) TEM image of Fe3O4@MSN@β-CDs nanoparticles.
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Fig. 2 (a) XRD pattern of the DHAA-Fe3O4 nanoparticles; (b) Hysteresis loop of DHAA-Fe3O4 and Fe3O4@MSN@β-CDs measured at 300 k (the lower-right inset shows the dispersion of DHAA-Fe3O4 nanoparticles in water before and after an external magnetic field is applied); (c) Thermogravimetric analysis of DHAA-Fe3O4 and Fe3O4@MSN@β-CDs; (d) N2 adsorption isotherm curves of Fe3O4@MSN-OH and Fe3O4@MSN@β-CDs.
conjugated system).18 FT-IR spectrum (Fig. S3) of the DHAA derivative obtained upon oxidation showed strong peaks at 1790 cm-1 (C=O stretching vibration), indicating the presence of carbonyl groups in the DHAA ring. The strong band at 584 cm-1 in the spectrum of the DHAA-Fe3O4 nanoparticles (Fig. S2b) is the Fe-O vibrations of magnetic nanoparticles. But, the C=O stretching vibrations in vitamin C and DHAA could not be detected in the as-prepared materials, suggesting that the carbonyl O atom coordinates with Fe on the surfaces of nanoparticles.19 X-ray photoelectron spectroscopy (XPS) of the DHAAFe3O4 nanoparticles exhibited two peaks at 710.6 and 724.1 eV, corresponding to the peaks of Fe 2p3/2 and Fe 2p1/2 in Fe3O4 nanoparticles, respectively (Fig. S5). There is no obvious shakeup satellite structure at the higher binding energy side of both main peaks (about 718.8 and 729.5 eV), which is the characteristic of Fe3O4 magnetic nanoparticles.20 The transmission electron microscopy (TEM) (Fig. 1a and S6a) confirmed that the prepared DHAA-Fe3O4 nanoparticles have a rough surface, a spherical shape and narrow size distribution with an average diameter of ca. 5 nm. Highresolution TEM provided more detailed structural information on the nanoparticles, and further validated that DHAA-Fe3O4 nanoparticles exhibited well-ordered single-domain crystallinity (Fig. S7a). Combined with TEM, selected-area electron diffraction (SAED) pattern reveals that the obtained DHAAFe3O4 nanoparticles possess the crystalline feature (Fig. 1b), in agreement with the presence of the magnetite crystal structure. The wide angle X-ray diffraction pattern (XRD) of DHAAFe3O4 nanoparticles shows six well-resolved diffraction peaks with high crystallinity (Fig. 2a). Owing to the superparamagnetic behavior and good surface coverage by DHAA ligands, the DHAA-Fe3O4 nanoparticles could be welldispersed in an aqueous solution without an external magnetic field, and possess reasonably high total magnetization, that is, the clusters could be easily separated by applying an external magnetic field, which is beneficial for applications in targeted drug delivery, cell separation, etc. (inset of Fig. 2b). The Fe3O4@MSN-OH nanoparticles were prepared using a template-directed sol–gel method, according to a modified
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Journal Name literature procedure.6d. (3-Aminopropyl) triethoxysilane (APTES) was reacted with Fe3O4@MSN-OH nanoparticles to achieve 3-aminopropyl-modified nanoparticles (Fe3O4@MSNNH2). Upon reaction with CBA in DMSO, borate-modified MSNs (Fe3O4@MSN-CBA) were obtained. Changes in the surface groups of MSNs were determined by FTIR (Fig. S8). Then the final cargo delivery systems were achieved after loading Fe3O4@MSN-CBA with Rh6G at room temperature for 24 h. The preparation of the snap-top carriers was completed upon addition of a sufficient amount of β-CDs into the reaction mixture, which led to the β-CDs being spread all over the surface of Fe3O4@MSN-CBA via covalent bonds (ESI). The Fe3O4@MSN@β-CDs can be well dispersed in polar solvents, which benefits from the installation of the subsequent mesoporous silica layer. SEM and TEM (Fig. 1c, 1d and Fig. S6c, and S7b) reveal that Fe3O4@MSN@β-CDs particles (80 nm in diameter) containing Fe3O4 core are uniformed spherical in shape and separated from one another, clearly demonstrating the uniformity of the nanoparticles and an MCM-41-type channel-like mesoporous structure. The monodispersity and homogeneous particle size of nanoparticles are also presented in TEM, indicating no aggregation occurred. Zeta potentials of the Fe3O4 and Fe3O4@MSN@β-CDs nanoparticles were measured to be -33.2 ± 1.6 and -29.2 ± 1.3 mV (Table S1), respectively, indicating that the newly synthesized materials can maintain certain stability and is strong enough to transport drugs in biological media. The magnetization data (Fig. 2b) of DHAA-Fe3O4 and Fe3O4@MSN@β-CDs up to 3.0 T at 300 K showed a hysteresis loop and have saturation magnetization values without any coercivity and remanence, respectively, demonstrating their superparamagnetic behavior. The magnetization value of Fe3O4@MSN@β-CDs (36.7 emu g-1) is as expected smaller than that of DHAA-Fe3O4 cores (51.7 emu g-1), because the magnetization value is a function of the domain size, the saturation magnetization of the nanoparticles, but the magnetic forces of these particles are good enough for separation and drug delivery, presented by their vivid separation process from the solution (Fig. S9, Video S1 and S2).21 Nevertheless, it is reasonable when compared to DHAA-Fe3O4 nanoparticles of comparable size prepared by the solvothermal and hightemperature decomposition processes.22 The blocking temperature (TB) was determined to be 25 K from zero field cooling (ZFC) and field cooling (FC) curves (Fig. S10). Thermogravimetric analysis (TGA) in N2 (Fig. 2c) shows a weight loss of only 10.3 wt% for DHAA-Fe3O4 nanoparticles in the range of 100–800 °C. A large weight loss of about 43.3 wt% for Fe3O4@MSN@β-CDs implies they contain considerable amount of organic species. Furthermore, the surface areas and pore sizes of Fe3O4@MSN-OH and Fe3O4@MSN@β-CDs were confirmed by Brunauer-EmmettTeller (BET) and Barrett-Joyner-Halenda (BJH) analyses (Fig. 2d, S11). The characteristic type IV adsorption isotherms with surface areas of 1045 and 583 cm2 g-1 and pore volumes of 1.014 and 0.541 cm3 g-1 indicated the presence of uniform mesopores of around 2.7 nm in diameter. The successful grafting of β-CDs on MSN surfaces caused the decreasing of surface area and pore volume of MSNs, while the good mesoporous characteristics was still maintained for cargo loading (Fig. 2d, S11). A series of control experiments have been done to further prove the functionalization of β-CDs on Fe3O4@MSN surfaces by comparing the release performance of different materials. To
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Fig. 3 Cumulative release profiles of Rh6G from Fe3O4@MSN@βCDs nanoparticles. (a) The drug release was conducted at different Dfructose concentrations, i.e., 0, 25, 50, and 100 mM at pH 9.8. (b) The pH-operated release of Rh6G from Fe3O4@MSN@β-CDs at pH 2, pH 7.4, and pH 9.8, respectively. The detection wavelength was 525 nm.
test the availability of cleavable gating β-CDs and the capacity by competitive D-fructose-triggered cargo release, UV-vis spectroscopy was employed to monitor the cargo release under different concentrations of materials (0, 25, 50, and 100 mM). There was only negligible premature release of Rh6G cargo (Fig. 3a). Furthermore, increasing percentages of cargo were released from the mesopores of the nanocomposites upon increasing the concentration of D-fructose, which means the drug release rate becomes faster and the release will be enhanced when the D-fructose concentration in the treated diseased region is greater. In order to better understand the mechanism of the pHresponsive model, the release property of Rh6G-loaded, Fe3O4@MSN@β-CDs was investigated in sodium phosphate buffer solutions (PBS). In Fig. 3b (pH 9.8), the negligible premature release implied the cargo molecules are held within the nanopores of Fe3O4@MSN@β-CDs at a pH level higher than the pKa of CBA (pKa 8.0), because the bulky β-CD entities on Fe3O4@MSN@β-CDs prevent cargo release. When the solution pH is lower than 8.0, the boronic-β-CD ester entities are cleaved off and the cargo is immediately released (Fig. 3b, pH7.4 and pH 2). To examine the biocompatibility of the obtained magnetic nanoparticles in bio-related fields, the cytotoxicity was investigated. The effect of DHAA-Fe3O4 and Fe3O4@MSN@βCDs nanoparticles on cell proliferation was assessed with normal human embryonic kidney (HEK) 293T cells by MTT assay, which revealed that the cell viability were not hindered by the presence of the nanoparticles up to a concentration of 100 µg mL-1. With the increase of concentration of the two materials, the cell viabilities showed a slight toxicity to normal human cells, which was deduced from the fact that the cell viabilities were higher than 75%, even though their concentration was as high as 100 µg mL-1 (Fig. 4). Overall, the materials possess negligible cytotoxicity at low concentrations, allowing them to be used as smart nanocarriers for controlled drug delivery. In conclusion, we designed and synthesized here a novel multifunctional magnetic mesoporous snap-top nanocarriers with superparamagnetic Fe3O4 core and mesoporous silica shell functionalized smartly with supramolecular caps (β-CDs) by covalent bond. The nanocomposites possess a uniform size, excellent dispersity, ordered mesoporosity and strong magnetization. The covalent cyclic esters of dioxaborolane rings served as effective drug anchorages to entrap cargo in the reservoirs and realize the release of cargo in response to pH variations and sugar molecules such as D-fructose, resulting in increased drug loading capacity and sustained release. The
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nanocomposites could not only effectively transport encapsulated drug into targeted sites, but also be used as sugar sensitive smart nanocarriers and provide diverse applications as an effective delivery system, by taking advantage of the good biocompatibility and cellular uptake properties. These studies suggest that Fe3O4@MSN@β-CDs could be very promising new candidates for future cancer diagnosis and therapy. This research is supported by the NNSFC (21272093 and 51473061) and the Fundamental Research Funds for the Central Universities (No. JCKY-QKJC05). We acknowledge the intellectual development of the basic theme, in line with our work on the binding and release mechanism, by professors Stoddart, Zink and his co-workers in their recently published paper.15
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Fig. 4 The in vitro cell viability of HEK 293T cells incubated with DHAA-Fe3O4 (red histograms) and Fe3O4@MSN@β-CDs (blue histograms) at different concentrations for 48 h.
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