High-yield hydrothermal synthesis of mesoporous silica hollow capsules
Graphical abstract
Introduction
Drug delivery systems are designed to deliver drugs safely and effectively to the sites where they are needed at concentrations required to minimize side effects and dosage, while maximizing the therapeutic efficacy. One of the promising strategies for realizing this concept is the utilization of drug carriers [1], [2], [3], [4], [5]. A drug carrier can protect the drug from degradation and prevent side effects, and the size and surface of the carrier can be tailored to achieve targeted delivery and controlled release. Mesoporous silica is one of the best candidates as a carrier material [4], [5], [6], [7], [8], [9], [10]; mesoporous silica nanoparticles with pore diameters of several nanometers are more resistant to mechanical and chemical stresses than polymer-based carriers and exhibit good biocompatibility [11], [12], [13]. The hydrolysis and condensation of silicon alkoxides (the so-called sol–gel reaction) extends the 3D network of ≡Si–O–Si≡ bonds, and bulk silica is formed [14]. When the sol–gel reaction is performed in the presence of surfactants, complexation between the silica and the surfactants occurs, with the cylindrical assemblies of surfactant aligned periodically. The mesoporous silica particles are formed following thermal decomposition of the surfactants via calcination [15], [16], [17], [18] or dissolution of the surfactants using an appropriate solvent [18], [19].
When the sol–gel reaction is performed in the presence of not only surfactants but also particles as templates for hollow structures, hollow capsules with mesoporous silica shells can be obtained as long as the particle templates can be removed after the reaction. The advantage of mesoporous silica hollow capsules (MSHCs) over mesoporous silica particles as drug carriers is the simultaneous reduction in the required dose and dosing frequency because of their higher capacity for drug loading [4]. Both loading and release properties of MSHCs, as well as their targeted delivery and controlled release performance, have been extensively studied [20], [21], [22], [23], [24], [25], [26].
To date, various types of templates have been used to generate the hollow structures of MSHCs, e.g., emulsions [27], [28], [29], [30], [31], [32], gas bubbles [33], [34], [35], vesicles [36], [37], [38], [39], polymers [40], [41], latex particles [42], [43], [44], [45], [46], [47], [48], [49], [50], and inorganic particles [51], [52], [53], [54], [55], [56], [57], [58], [59]. Organic templates are removed with the surfactants via calcination, while inorganic templates are subjected to dissolution or selective etching [57]. However, because the monodispersity of the MSHCs is determined by the hollow structure template, the monodispersity of the template is important. Polystyrene latex is one of the best candidates because of its excellent monodispersity [42], [43], [44], [45], [46], [47], [48]. Previously we developed a method for the synthesis of monodispersed MSHCs using polystyrene (PS) particles and showed that the coefficients of variation (CV) of the diameters of the PS particles and resultant MSHCs (outer diameters of 145–400 nm) were nearly the same [49]. Furthermore, repetition of the sol–gel reaction prior to template removal provided control of the MSHC shell thickness between 30 and 120 nm. The loading and release properties of the MSHCs were also investigated [50]. However, as pointed out in Ref. [49], removal of the templates via calcination resulted in fusion of the MSHCs and the yield of the monodispersed capsules was limited to approximately 30%, where the yield is defined as the number of monodispersed capsules divided by the number of template particles. Because the silanol groups can be cross-linked via dehydration in the temperature range from 400 to 700 °C [60], calcination at 550 °C in ambient air causes the fusion of the capsules. Thus, to improve the capsule yield, their formation and removal of the templates must be performed under milder conditions.
It has been reported in the literature that after the sol–gel reaction, hydrothermal treatment at approximately 100 °C was applied to the dispersion of the generated silica/surfactant complexes prior to removal of the templates [41], [61], [62], [63], [64], [65]. This hydrothermal treatment was performed to promote the gelation of the silica sol and extension of the 3D ≡Si–O–Si≡ network to fabricate a rigid silica framework [14]. On the other hand, hydrothermal treatment at a temperature higher than the melting point of PS was shown to remove the PS particles and form hollow titania capsules [66]. These reports inspired us to improve the capsule yield through the use of hydrothermal treatment, because the treatment temperature can be dramatically reduced from the calcination temperature of 550 °C. Herein, we report a revised method that provides an improved yield of the monodispersed MSHCs. A sol–gel reaction is performed in the presence of surfactants and PS particles to form silica/surfactant complexes on the particles, as previously described [49], [50]. A first hydrothermal treatment (1st HT) is then performed to increase the rigidity of the silica framework of silica/surfactant complexes on the particles. A second hydrothermal treatment (2nd HT) is then performed using nitric acid to efficiently decompose the organic templates at a lower temperature. The conditions of the process have been optimized to maximize the capsule yield. Specifically, the heating and cooling rates during the 1st and 2nd HTs and the compositions of the dispersions in both HT steps were important parameters.
Section snippets
Materials
Aqueous dispersions of PS particles (5% w/v) with average diameters of 147 nm (standard deviation: 7 nm) were purchased from microParticles GmbH (Berlin Germany). Cetyltrimethylammonium bromide (CTAB, >99%) and tetraethoxysilane (TEOS, >99.9%) were purchased from Sigma–Aldrich Co. Limited Liability Company (Missouri, USA) and Alfa Aesar, A Johnson Matthey Company (Lancashire, UK), respectively. Ethanol (EtOH, >99.5%), aqueous ammonia (NH3(aq), 25% w/w), and aqueous nitric acid (HNO3(aq), 60%
Process (a)
TEM images of the bare PS particles and those coated by the silica/surfactant complexes obtained after Process (a) are shown in Fig. 4. It can be clearly seen that the diameters of the coated particles after the sol–gel reaction (Fig. 4b) increased compared to those of the bare particles (Fig. 4a) and the shells composed of the silica/surfactant complexes exhibited a slightly different contrast from the PS core. The average diameter of the coated particles determined from the TEM images was
Conclusion
We succeeded in improving the yield of monodispersed MSHCs. By utilizing hydrothermal treatments rather than calcination at 550 °C in ambient air, the loss of monodispersed MSHCs due to fusion and aggregation during calcination was suppressed and the yield was increased by more than a factor of two to approximately 85%. In the proposed method, HT must be performed twice after formation of silica/surfactant complexes on the PS particles via the sol–gel reaction. The 1st HT (100 °C for 48 h)
Acknowledgments
Financial support by The Institute of Science and Technology, Meiji University is gratefully acknowledged. The authors also acknowledge significant experimental support from H. Tajika.
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