Polymer Hybrid Hollow

Nov 9, 2010 - The silica/polymer hybrid hollow nanoparticles with channels and ... inner thermoresponsive PNIPAM as gatekeepers and channels in the si...
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Facile Strategy for Synthesis of Silica/Polymer Hybrid Hollow Nanoparticles with Channels Chenglin Wu, Xin Wang, Lizhi Zhao, Yaohua Gao, Rujiang Ma, Yingli An, and Linqi Shi* Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin, 300071, P. R. China Received September 9, 2010. Revised Manuscript Received October 13, 2010 The silica/polymer hybrid hollow nanoparticles with channels and gatekeepers were successfully fabricated with a facile strategy by using thermoresponsive complex micelles of poly(ethylene glycol)-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM) and poly(N-isopropylacrylamide)-b-poly(4-vinylpyridine) (PNIPAM-b-P4VP) as the template. In aqueous solution, the complex micelles (PEG-b-PNIPAM/PNIPAM-b-P4VP) formed with the PNIPAM block as the core and the PEG/P4VP blocks as the mixed shell at 45 °C and pH 4.0. After shell cross-linking by 1,2-bis(2-iodoethoxyl)ethane (BIEE), tetraethylorthosilicate (TEOS) selectively well-deposited on the P4VP block and processed the sol-gel reaction. When the temperature was decreased to 4 °C, the PNIPAM block became swollen and further soluble, and the PEG-b-PNIPAM block copolymer escaped from the hybrid nanoparticles as a result of swelled PNIPAM and weak interaction between PEG and silica at pH 4.0. Therefore, the hybrid hollow silica nanoparticles with inner thermoresponsive PNIPAM as gatekeepers and channels in the silica shell were successfully obtained, which could be used for switchable controlled drug release. In the system, the complex micelles, as a template, could avoid the formation of larger aggregates during the preparation of the hybrid hollow silica nanoparticles. The thermoresponsive core (PNIPAM) could conveniently control the hollow space through the stimuli-responsive phase transition instead of calcination or chemical etching. In the meantime, the channel in the hybrid silica shell could be achieved because of the escape of PEG chains from the hybrid nanoparticles.

1. Introduction Hybrid hollow silica nanoparticles have attracted enormous attention because of their diverse potential applications in drug release and gene delivery, confine-space catalysis, enzyme immobilization, and so on.1-5 An effective approach for preparing these hollow nanoparticles was based on the use of a template.6-14 However, the removal of the core template may damage the silica shell, and these hollow nanoparticles could not be readily dispersed in water because of the sintering caused by the calcination.13 Furthermore, substance exchange between the inside hollow space and the outside milieu was prohibited because of the compact silica shell. Surfactant had been used as a template for *To whom correspondence should be addressed. E-mail: shilinqi@nankai. edu.cn.

(1) Yeo, K. M.; Shin, J.; Lee, I. S. Chem. Commun. 2010, 46, 64–66. (2) Yan, E. Y.; Ding, Y.; Chen, C. J.; Li, R. T.; Hu, Y.; Jiang, X. Q. Chem. Commun. 2009, 19, 2718–2720. (3) Corma, A.; Dı´ az, U.; Arrica, M.; Fernandez, E.; Ortega, I. Angew. Chem., Int. Ed. 2009, 48, 6247–6250. (4) Yang, J.; Lee, J.; Kang, J. Y.; Lee, K.; Suh, J. S.; Yoon, H. G.; Huh, Y. M.; Haam, S. Langmuir 2008, 24, 3417–3421. (5) Li, G. L.; Liu, G.; Kang, E. T.; Neoh, K. G.; Yang, X. L. Langmuir 2008, 24, 9050–9055. (6) Walsh, D.; Hopwood, J. D.; Mann, S. Science 1994, 264, 1576–1578. (7) Yamaguchi, A.; Kaneda, H.; Fu, W. S.; Teramae, N. Adv. Mater. 2008, 20, 1034–1037. (8) Zhao, D. Y.; Feng, J. L.; Huo, Q. S.; Melosh, N.; Fredrickson, G. H.; Chmelka, B. Y.; Stucky, G. D. Science 1998, 279, 548–552. (9) Schmidt, H. T.; Ostafin, A. E. Adv. Mater. 2002, 14, 532–535. (10) Khanal, A.; Inoue, Y.; Yada, M.; Nakashima, K. J. Am. Chem. Soc. 2007, 129, 1534–1535. (11) Steinmetz, N. F.; Shah, S. N.; Barclay, J. E.; Rallapalli, G.; Lomonossoff, G. P.; Evans, D. J. Small 2009, 5, 813–816. (12) Blas, H.; Save, M.; Pasetto, P.; Boissiere, C.; Sanchez, C.; Charleux, B. Langmuir 2008, 24, 13132–13137. (13) Fujiwara, M.; Shiokawa, K.; Tanaka, Y.; Nakahara, Y. Chem. Mater. 2004, 16, 1325–1331. (14) Lynch, D. E.; Nawaz, Y.; Bostrom, T. Langmuir 2005, 21, 6572–6575.

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the synthesis of mesoporous silica nanoparticles (MSNs),15-19 but in fact, the mesopore formed in the surface of the silica nanoparticles was difficult to access, which limited their applications in practice. Therefore, the hollow nanoparticles with stable structure and channels that penetrate the silica shell for exchanging substance between the inside and the outside are undoubtedly of great interest for practical applications. Polymeric micelle with core-shell structure as the template makes it convenient to control the size and morphology of the nanoparticles. In these systems, the core acts to control the hollow space, and the shell acts to adsorb the precursor of the inorganic material during construction of the hollow nanoparticles. However, polymeric micelles become unstable when the precursor is sorbed into the shell of the micelles. Nakashima et al. used triblock copolymer (ABC) micelle with core-shell-corona structure as a template, which had an advantage over AB diblock and ABA triblock micelles in avoiding the formation of second-order or higher-order aggregates.10 Du et al. prepared the hollow silica nanoparticles using thermosensitive poly(N-isopropylacrylamide) (PNIPAM) as a recyclable template.20 Among the applications of the hybrid hollow silica nanoparticles, one of the most interesting studies is to control drug release (15) Schacht, S.; Huo, Q.; Voigt-Martin, I. G.; Stucky, G. D.; Sch€uth, F. Science 1996, 273, 768–771. (16) Deng, Y. H.; Qi, D. W.; Deng, C. H.; Zhang, X. M.; Zhao, D. Y. J. Am. Chem. Soc. 2008, 130, 28–29. (17) Tan, B.; Lehmler, H.; Vyas, S.; M. Knutson, B. L.; Rankin, S. E. Adv. Mater. 2005, 17, 2368–2371. (18) Beck, J. S.; Vartuli, J. C.; Roth, W. J.; Leonowicz, M. E.; Kresge, C. T.; Schmitt, K. D.; Chu, C. T. W.; Olson, D. H.; Sheppard, E. W.; McCullen, S. B.; Higgeins, J. B.; Schlenker, J. L. J. Am. Chem. Soc. 1992, 114, 10834–10843. (19) Chen, Y. L.; Li, Y.; Chen, Y. X.; Liu, X. J.; Zhang, M.; Li, B. Z. Chem. Commun. 2009, 34, 5177–5179. (20) Du, B. Y.; Cao, Z.; Li, Z. B.; Mei, A. X.; Zhang, X. H.; Nie, J. J.; Xu, J. T.; Fan, Z. Q. Langmuir 2009, 25, 12367–12373.

Published on Web 11/09/2010

DOI: 10.1021/la103629v

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Wu et al. Doxorubicin hydrochloride (DOX 3 HCl) was purchased from Zhejiang Hisun Pharmaceutical. All other chemicals and reagents were of analytical grade. The water used was purified through a Millipore system.

Synthesis and Characterization of the Diblock Copolymers.

Figure 1. Schematic formation of the hybrid hollow nanoparticles with channels in shell and thermoresponsive gatekeepers using complex micelles as the template.

based on opening and closing the pores.21-27 Magnetic nanoparticles, cadmium sulfide, and gold nanoparticles as gatekeepers were employed to regulate the encapsulation and release of the drug molecules.22,23 However, more effective application of these hybrid nanoparticles is limited by the irreversibility of the pore opening. Herein, we report a facile strategy to synthesize the hybrid hollow nanoparticles with channels and gatekeepers using the thermoresponsive complex micelles of poly(ethylene glycol)b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM) and poly(Nisopropylacrylamide)-b-poly(4-vinylpyridine) (PNIPAM-b-P4VP) as template (Figure 1). As a template for hybrid hollow silica nanoparticles, such complex micelles (AB/AC) with the mixed shell (B/C) could avoid the formation of large aggregates because one block (B) was soluble.10 The thermoresponsive core (A) could conveniently form the volume through controlling the stimuliresponsive phase transition instead of calcination. In the meantime, the channel in the hybrid silica shell could be obtained because eof the escape of one block copolymer (AB) from the hybrid nanoparticles. Thermoresponsive polymers (A) could be used as gatekeepers to control drug release.

2. Experimental Section Materials. N-Isopropylacrylamide (NIPAM) (97%, Aldrich) was purified by recrystallization in n-hexane and dried in vacuum. Methoxy poly(ethylene glycol) (mPEG) (Mw=5000, polydispersity index (PDI) = 1.05, Fluka) was dried in vacuum for 24 h prior to use. 4-Vinylpyridine (Aldrich) was stirred with a small amount of CaH2 at 40-50 °C for 2 h and then distilled under vacuum. Tetraethylorthosilicate (TEOS) and 1,2-bis(2-iodoethoxy)ethane (BIEE) were purchased from Alfa and used as received. Tris[2-(dimethylamino)ethyl]amine (Me6TREN) was synthesized according to ref 28. CuCl was purified according to ref 29. (21) Slowing, I. I.; Vivero-Escoto, J. L.; Wu, C.; Lin, V. S. Y. Adv. Drug Delivery Rev. 2008, 60, 1278–1288. (22) Lai, C-Y.; Trewyn, B. G.; Jeftinija, D. M.; Jeftinija, K.; Xu, S.; Jeftiniji, S.; Lin, V. S. Y. J. Am. Chem. Soc. 2003, 125, 4451–4459. (23) Giri, S.; Trewyn, B. G.; Stellmaker, M. P.; Lin, V. S.-Y. Angew. Chem., Int. Ed. 2005, 44, 5038–5044. (24) Mal, N. K.; Fujiwara, M.; Tanaka, Y. Nature 2003, 421, 350–353. (25) Park, C.; Oh, K.; Lee, S. C.; Kim, C. Angew. Chem., Int. Ed. 2007, 46, 1455– 1457. (26) Angelos, S.; Yang, Y.-W.; Patel, K.; Stoddart, J. F.; Zink, J. I. Angew. Chem., Int. Ed. 2008, 47, 2222–2226. (27) You, Y. Z.; Kalebaila, K. K.; Brock, S. L.; Oupicky, D. Chem. Mater. 2008, 20, 3354–3359. (28) Ciampolini, M.; Nardi, N. Inorg. Chem. 1966, 5, 41–44. (29) Xia, J. H.; Zhang, X.; Matyjaszewski, K. Macromolecules 1999, 32, 3531– 3533.

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Block copolymer PEG-b-PNIPAM was synthesized by atom transfer radical polymerization (ATRP) of NIPAM with PEG-Br as the macroinitiator and CuCl/Me6TREN as the catalyst.30 Block copolymer PNIPAM-b-P4VP was synthesized by sequential ATRP of NIPAM and 4VP with 1-chlorophenylethane (PECl) as the initiator and CuCl/Me6TREN as the catalyst.31 These block copolymers can be denoted as PEG114-b-PNIPAM80 and PNIPAM88-b-P4VP220 with the subscripts indicating the number of the repeating units. The PDIs of PEG114-b-PNIPAM80 and PNIPAM88-b-P4VP220 are 1.21 and 1.23, respectively. The 1H NMR spectra were record on a Varian UNITY-plus400 spectrometer. Gel permeation chromatography (GPC) was measured on a waters 600E system, CHCl3 and THF were used as eluent, and narrowly distributed polystyrene was used as the calibration standard. Synthesis of the Hybrid Hollow Nanoparticles. Block copolymers of PEG114-b-PNIPAM80 (10 mg) and PNIPAM88-bP4VP220 (10 mg) were first molecularly dissolved in deionized water (100 mL) at pH 4.0. The solution was then heated to 45 °C to enable the formation of the complex micelles with the PNIPAM block as the core and the mixed PEG/P4VP blocks as the shell. The colloid solution was strongly stirred overnight to avoid the appearance of transient morphologies. After that, BIEE (5.4 mg) as a shell cross-linking agent of P4VP (targeting degree of quaternization = 60%) was added and reacted for 72 h. TEOS (342 μL) was slowly dropped in the solution and stirred for 48 h. Then, the solution was stored for 120 h without stirring at 45 °C to allow the silica network to be formed by the sol-gel reaction. The solution was decreased to 4 °C so that the block copolymer of PEG114-b-PNIPAM80 became well soluble and escaped from the hybrid nanoparticles. Therefore, the hybrid hollow nanoparticles with channels in silica shell and thermoresponsive gatekeepers were formed.

Drug Loading and Release from the Hybrid Hollow Nanoparticles. The loading of DOX inside in the hybrid hollow nanoparticles was achieved as follows. The drug of DOX 3 HCl (15.0 mg) and the triethylamine (TEA, 1.5 mol equiv to DOX 3 HCl) were added to the hybrid hollow nanoparticles (30 mL) aqueous solution and stirred for 48 h at room temperature. Then, the drug-loaded hybrid hollow nanoparticles were isolated by centrifugation at 5000 rpm. The DOX content was calculated using the formula drug content (% w/w) = (total drugs in hybrid hollow nanoparticles)/(total drugs in hybrid hollow nanoparticles þ hybrid hollow nanoparticles)  100. The drug content was determined by UV-vis 2550 spectrophotometer at 485 nm analyses to be ∼21.4%. The release process of DOX from the hybrid hollow nanoparticles was studied in phosphate buffer solution (PBS) (pH 7.4, 0.05 M) using a UV-vis 2550 spectrophotometer. The drugloaded solution (4 mL) was transferred to a dialysis bag (molecular weight cut off: 7000 Da), which was immersed in release media (PBS, 16 mL) at 37 or 25 °C at a given stirring. The release medium (16 mL) was removed for analysis at given time intervals and replaced with the same volume of fresh release media.

Characterizations. Transmission Electron Microscopy (TEM). Samples were prepared by depositing the solutions onto a preheated carbon-coated copper EM grid and dried under atmospheric pressure. Analyses were conducted using a Philips T20ST electron microscopy at an acceleration voltage of 200 kV. (30) Zhang, W. Q.; Shi, L. Q.; Wu, K.; An, Y. L. Macromolecules 2005, 38, 5743–5747. (31) Xu, Y. L.; Shi, L. Q.; Ma, R. J.; Zhang, W. Q.; An, Y. L.; Zhu, X. X. Polymer 2007, 48, 1711–1717.

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Figure 2. Temperature dependence of the relative scattering intensities measured at the scattering angle of 90°.

Dynamic Light Scattering and Static Light Scattering. Studies were performed on a laser light scattering spectrometer (BI-200SM) equipped with a digital correlator (BI-9000AT) at 636 nm and given temperatures. Filtering solutions through a 0.45 μm Millipore filter into a clean scintillation vial was manipulated to obtain the samples for characterization.

Figure 3. TEM images of (A) PEG-b-PNIPAM/PNIPAM-b-

3. Results and Discussion The formation process of hybrid hollow nanoparticles with channels and gatekeepers using thermoresponsive complex micelles as template is shown in Figure 1. With increasing the temperature of PEG-b-PNIPAM/PNIPAM-b-P4VP mixed aqueous solution, the complex micelles formed with the PNIPAM block as the core and the mixed soluble PEG/P4VP blocks as the shell at pH 4.0. Shell cross-linking of the complex micelles was achieved using BIEE as a bifunctional agent. After that, silica selectively well-deposited on the P4VP block of the complex micelles at pH 4.0.10,32 The hybrid nanoparticles formed a core-shell-corona structure with PNIPAM as the core, P4VP/silica as the shell, and soluble PEG extending outside the mixed shell as the corona to avoid the hybrid nanoparticle further aggregates. The PEG channels through which H2O molecule could pass were obtained because of the phase separation between the silica shell and the PEG chains.33 When temperature was decreased to 4 °C, the PNIPAM block became swollen and further soluble, and the PEG-b-PNIPAM block copolymer escaped from the nanoparticles as a result of swelled PNIPAM and weak interaction between PEG and silica within the pH range 2.0-7.0.8 Therefore, the hollow nanoparticles with channels and thermoresponsive gatekeepers were achieved. Formation of the Complex Micelles. The AB and AC block copolymers, which have a common hydrophobic block A and different hydrophilic block B and C, could cooperatively selfassemble into complex micelles instead of a simple mixture of two micelles in dilute solution.33-35 PNIPAM is a well-known thermoresponsive polymer, and the lower critical solution temperature (LCST) of homopolymer PNIPAM is ∼32 °C.36 P4VP could

be well-soluble at low pH (pH < 4.7) owing to repulsive forces among the protonated 4VP units.37 At pH 4.0 and 25 °C, water is cosolvent for the PNIPAM, PEG, and P4VP blocks, and thus PEG-b-PNIPAM and PNIPAM-b-P4VP can be molecularly dissolved in water to form a transparent solution. It was confirmed by dynamic light scattering (DLS) measurement that no particles >10 nm in diameter were in the solution, and the scattering intensity was very low. Figure 2 shows the temperature dependence of the relative light scattering intensity of the polymer solution. With increasing temperature, a change in the relative light scattering intensity of the polymeric solution happened at the temperature of 35 °C, indicating that the LCST of PNIPAM is ∼35 °C. The relative light scattering intensity of complex micelles was almost unchanged at higher temperatures (38-45 °C). It demonstrated that the stable complex micelles of PEG-b-PNIPAM/PNIPAM-b-P4VP with PNIPAM block as the core and the PEG/P4VP as the mixed shell formed at 45 °C and pH 4.0. Formation of the Hybrid Hollow Nanoparticles. The morphologies of the complex micelles and hybrid nanoparticles were investigated by transmission electron microscopy (TEM). Figure 3A illustrates the TEM image of the complex micelles (PEG-b-PNIPAM/PNIPAM-b-P4VP 1/1, w/w). The complex micelles were spherical, and their average diameters were ∼33 nm. Shell cross-linking by BIEE ensured the covalent stabilization of the complex micelles templates. The diameters of the complex micelles, after shell cross-linking, were ∼50 nm (Figure 3B). The silica was supposed to well-deposit selectively on the P4VP block of the complex micelles at pH 4.0 because the protonated or quaternization P4VP block was an acid catalysis of TEOS under mild conditions and also a physical scaffold for silica deposition.10,32 Figure 3C shows the TEM image of the hybrid nanoparticles with PNIPAM as the core and mixed PEG/P4VP/silica as the shell at 45 °C. The diameters of the hybrid nanoparticles were ∼50 nm. The double-layer structure of the hybrid nanoparticles could be clearly seen in the image (Figure 3C) because of the marked

(32) Yuan, J. J.; Mykhaylyk, O. O.; Ryan, A. J.; Armes, S. P. J. Am. Chem. Soc. 2007, 129, 1717–1723. (33) Li, G. Y.; Shi, L. Q.; Ma, R. J.; An, Y. L.; Huang, N. Angew. Chem., Int. Ed. 2006, 45, 4959–4962. (34) Wu, C. L.; Ma, R. J.; He, H.; Zhao, L. Z.; Gao, H. J.; An, Y. L.; Shi, L. Q. Macromol. Biosci. 2009, 9, 1185–1193. (35) Zhuang, Y.; Lin, J. P.; Wang, L. Q.; Zhang, L. S. J. Phys. Chem. B 2009, 113, 1906–1913. (36) Schild, H. G. Prog. Polym. Sci. 1992, 17, 163–249.

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P4VP complex micelles (w/w, 1/1), (B) shell cross-linked complex micelles by BIEE (target degree of shell cross-linking = 60%), (C) the hybrid nanoparticles with PNIPAM as the core and mixed PEG/P4VP/silica as the shell at 45 °C, and (D) the hybrid hollow silica nanoparticles.

(37) idorov, S. N.; Bronstein, L. M.; Kabachii, Y. A.; Valetsky, P. M.; Soo, P. L.; Maysinger, D.; Eisenberg, A. Langmuir 2004, 20, 3543–3550.

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Figure 6. Illustration of the structure of the hybrid hollow nanoparticles and the PEG-b-PNIPAM block copolymer in solution changed with the temperature.

Figure 4. Hydrodynamic diameter distribution f (Dh) and angular dependence of the translational diffusion coefficient (insets) of the nanoparticles in solution. All of the DLS measurements were performed at 25 °C.

Figure 7. Cumulative release of DOX from the hybrid hollow nanoparticles at different temperature (25 and 37 °C) in PBS (pH 7.4, 0.05 M).

Figure 5. Hydrodynamic diameter distribution f (Dh) of the nanoparticles in solution at different temperatures.

contrast of silica and PNIPAM. As the temperature decreased to 4 °C (lower than the LCST of PNIPAM), the thermoresponsive PNIPAM block became hydrophilic. The block copolymer of PEG-b-PNIPAM escaped from the nanoparticles as a result of swelled PNIPAM and weak interaction between PEG and silica within the pH range 2.0-7.0. Interestingly, the hybrid hollow nanoparticles with water-soluble PNIPAM as the stabilizing agent formed. A hollow sphere structure with a dark shell was clearly visualized (Figure 3D). The mean diameters of the hybrid nanoparticles were ∼50 nm, and the thickness of silica was ∼9 nm. We also used DLS and static light scattering (SLS) to demonstrate the structure of the hollow nanoparticles. Figure 4 shows the diameter distribution and angular dependence of the translational diffusion coefficient Dt (insets) of the nanoparticles in solution at 25 °C. The Dh0 of the nanoparticles was ∼105.6 nm. The Rg/Rh0 value (Rh0 = 0.5Dh0) could reveal the morphology of the nanoparticles dispersed in solution,38 and that of the hybrid nanoparticles was 1.05, which further proved that the hollow structure of the nanoparticles was formed. Two peaks could be observed in Figure 4. One was centered at 7.9 nm, which could be ascribed to the existence of a free chain of PEG-b-PNIPAM that escaped from the nanoparticles as a result of swelled PNIPAM and weak interaction between PEG and silica within the pH range 2.0-7.0 in solution. This has been proved in the following discussions. The other centered at 88.5 nm was contributed by (38) Tu, Y.; Wan, X.; Zhang, D.; Zhou, Q.; Wu, C. J. Am. Chem. Soc. 2000, 122, 10201–10205.

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the hybrid hollow nanoparticles. The narrow peak at 88.5 nm indicated that the hybrid hollow nanoparticles had a narrow diameter distribution. To demonstrate further that the diameter of 7.9 nm was caused by the PEG-b-PNIPAM free chains that escaped from the hybrid nanoparticles, the hydrodynamic diameters of the nanoparticles in solution were measured by DLS at different temperatures, where the solution was equilibrated for ∼1 h at each temperature (Figure 5). When the solution temperature was 25 °C, the thermoresponsive PNIPAM was hydrophilic and soluble in water, and the PEG-b-PNIPAM was thus well-soluble in water. As the solution temperature increased above 34 °C, the diameter centered at 7.9 nm changed to 20.5 nm because thermoresponsive PEG-b-PNIPAM block copolymer formed micelles with the PNIPAM block as the core and PEG block as the shell, and the diameter centered at 88.5 nm was almost unchanged because of the hybrid hollow nanoparticles (Figure 6). The diameter at 223 nm at 40 °C accounted for the larger aggregate of the PEG-bPNIPAM.30 It was indicated that PEG-b-PNIPAM block copolymer existed as free chain in the solution at 25 °C (Figure 6). That means the PEG-b-PNIPAM block copolymer could escape from the hybrid nanoparticles, so the hybrid hollow nanoparticles with the channels in silica shell were formed. Release of DOX from the Thermoresponsive Hybrid Hollow Nanoparticles. DOX, an anticancer drug, was used as a model drug for this study. The cumulative release of DOX from the hybrid hollow nanoparticles at 25 (below LCST) and 37 °C (above LCST) is shown in Figure 7. The soluble PNIPAM chains inside the hybrid hollow nanoparticles uncovered the entrance of channels at 25 °C, below the phase transition temperature of PNIPAM. This was demonstrated by a gradual release of DOX from the hybrid hollow nanoparticles. PNIPAM chains are insoluble in PBS at 37 °C, and the channels are blocked by the collapsed PNIPAM chains, and thus the release rate of DOX at 37 °C is slower, as shown in Figure 7. Furthermore, the controllable release rate of DOX from the hybrid hollow Langmuir 2010, 26(23), 18503–18507

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large aggregates and control the structure and morphology of the nanoparticles. The most important thing was that the hybrid hollow nanoparticles with channels in silica shell could enable substance exchange between the inside hollow space and the outside and the thermoresponsive polymer PNIPAM could be used as the gatekeeper to control drug release. Figure 8. Schematic illustration of the controlled drug release from the silica/polymer hybrid hollow nanoparticles.

nanoparticles could be repeated by altering the temperature of the release medium. It indicates that the drug release from the thermoresponsive hollow nanoparticles can be switched on and off at will (Figure 8).

4. Conclusions An effective method was used to synthesize the silica/polymer hybrid hollow nanoparticles with thermoresponsive gatekeepers and channels using a template of the thermoresponsive complex micelles of PEG-b-PNIPAM and PNIPAM-b-P4VP. Thermoresponsive complex micelles could easily avoid the formation of

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Acknowledgment. This work was supported by the National Natural Science Foundation of China (grant no. 20774051, 50830103) and the Outstanding Youth Fund (no. 50625310). Supporting Information Available: Synthesis of PEG-bPNIPAM and PNIPAM-b-P4VP diblock copolymers, 1H NMR spectra of PEG-b-PNIPAM and PNIPAM-b-P4VP block copolymers, GPC results of PEG-Br and PEG-bPNIPAM, GPC results of PNIPAM and PNIPAM-bP4VP, and release profiles of DOX from the silica/polymer hybrid hollow nanoparticles at different temperature. This material is available free of charge via the Internet at http:// pubs.acs.org.

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