Article pubs.acs.org/JPCB
Controlled Drug Loading and Release of a Stimuli-Responsive Lipogel Consisting of Poly(N‑isopropylacrylamide) Particles and Lipids Naiyan Lu,† Kai Yang,† Jingliang Li,§ Yuyan Weng,† Bing Yuan,*,† and Yuqiang Ma*,†,‡ †
Center for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, Suzhou 215006, P. R. China National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, P. R. China § Institute for Frontier Materials, Deakin University, Waurn Ponds, Vic 3216, Australia ‡
S Supporting Information *
ABSTRACT: Environmentally responsive materials are attractive for advance biomedicine applications such as controlled drug delivery and gene therapies. Recently, we have introduced the fabrication of a novel type of stimuli-sensitive lipogel composite consisting of poly(N-isopropylacrylamide) (pNIPAM) microgel particles and lipids. In this study, we demonstrated the temperature-triggered drug release behavior and the tunable drug loading and release capacities of the lipogel. At room temperature (22 °C), no calcein was released from the lipogel over time. At body temperature (37 °C), the release process was significantly promoted; lipids in the lipogel acted as drug holders on the pNIPAM scaffold carrier and prolonged the calcein release process from 10 min to 2 h. Furthermore, the loading and release of calcein could be effectively controlled by modulating the relative amount of lipids incorporated in the lipogel, which can be realized by the salt-induced lipid release of the lipogel. ature (LCST) of around 32 °C.17,18 Below the LCST, pNIPAM chains are fully soluble and the polymer is in a swollen state in water. Above the LCST, water is excluded from the vicinity of the pNIPAM chains, leading to significant shrinkage of the hydrogel.19 Although pNIPAM as an environmentally sensitive polymeric matrix, such as a hydrogel for drug carrying, has been investigated intensively, pNIPAM microgel particles as spherical mesoporous containers for the fabrication of new types of stimuli-responsive composites have received less attention.20,21 Recently, we have successfully developed a novel type of stimuli-sensitive lipogel by the incorporation of lipids with pNIPAM microgel particles. The lipogel displays environmentally responsive transformation behaviors because of the volume phase transition of the pNIPAM scaffold.20 In this work, we will show that the lipid incorporation endows the lipogel with not only improved and prolonged cargo retention ability but also tunable loading capacity and stimuli-responsive release of the payloads. Furthermore, because of the multicomponents of the lipogel, the presence of hydrophilic and lipophilic cavities created by lipids offers the possibility for the encapsulation and delivery of various hydrophilic and lipophilic substances.22
1. INTRODUCTION There has been enormous interest in the exciting area of manufactured microcarriers for drug and gene delivery, among which the systems based on mesoporous inorganic nanoparticles (such as gold, silica, and Fe3O4) are regarded to be the most attractive.1−4 However, the in vivo applications of these materials are very limited because of their insufficient drug loading and holding capacities. Linear polymers and supported lipid membranes were exploited to encapsulate these conventional mesoporous particles to achieve higher drug loading capacity, prolonged cargo retention, and controlled drug release within cells.5−8 Multicomponent composites, including those that introduce new components to conventional materials, have become more attractive in recent years because of their diverse structures and combined, even improved, properties over the original components. These materials are of high importance in material and biomedical science.9−14 On the other hand, environmentally sensitive materials are promising candidates in “smart” bioengineering systems.15 Among different kinds of stimuli, temperature is the most widely used because it is easy to control and has practical advantages both in vitro and in vivo.8,16 As a classic example of such a “smart” polymer, poly-N-isopropylacrylamide (pNIPAM) has attracted considerable attention and has been studied for diverse biomedical applications because of its biocompatibility.8,17,18 When dissolved in water, pNIPAM shows temperature-, pH-, or ionic strength-responsive volume phase transition at a so-called lower critical solution temper© XXXX American Chemical Society
Received: March 22, 2013 Revised: June 10, 2013
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2. MATERIALS AND METHODS 2.1. Materials. 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(lissaminerhodamine B sulfonyl) (Rh-PE) were purchased from Avanti Polar Lipids and used as received. Chloroform (99.7%), ethanol (99.0%), Na2CO3, PDMS, and calcein (analytical reagent) were purchased from Shanghai Chemical Reagents Company and used without further purification. The pNIPAM particle was synthesized as reported (φ ∼ 0.5).23 It consisted of 90% NIPAM monomer, 10% positively charged AEME monomer, and a small amount of cross-linking agent BIS-acrylamide. 2.2. Lipogel Preparation. Lipogels were fabricated via a facile solvent-exchange method.24 A 0.2 mg sample of lipid (DOPC labeled by 0.5 mol % Rh-PE, red fluorescence) was first dissolved in chloroform (2.0 mg mL−1) and dried overnight under vacuum. The dry lipid film was rehydrated with a 0.1 mL mixture of 40 vol % ethanol and 60 vol % pNIPAM aqueous suspensions (containing about 10 10 pNIPAM particles). Distilled water (1 mL) was then added to the mixture. A micelle-to-bilayer transition and liposome deposition occur during this solvent-exchange process. The bulk solution was centrifuged at 6000 rpm for 10 min. The wash and centrifugation were repeated three times to remove excessive lipids. The precipitates were resuspended in 500 μL of distilled water for use. 2.3. Characterization. The size distribution and ζ potential of the pNIPAM and lipogel particles were determined using a Zetasizer Analyzer (ZETASIZER Nano-ZS90, Malvern Instrument Ltd., U.K.). The morphology of the particles was characterized on a scanning electron microscopy (SEM) instrument (Raith Pioneer) after the particles were freeze-dried. The optical observation was performed on an inverted confocal fluorescence microscope (Zeiss, LSM 710) equipped with a 100× oil objective. Rh-PE and calcein were excited at 543 and 488 nm, and fluorescence was collected in the red and green channels, respectively. The temperature of the system was set and stabilized with the native temperature control components from Zeiss. All the experiments were carried out at room temperature (22 °C) except stated otherwise. Before each observation, 500 μL of particle dispersions (pNIPAM or lipogel) was pretransferred to a homemade sample cell with a PDMS-coated glass coverslip as substrate and stabilized for 2 h for particle immobilization (to a density of ∼500 particles per cm2).25 For the calcein release tests, 100 μL of saturated calcein solution was added to the particle dispersion in situ directly preceding observation, and the particles were infiltrated with calcein immediately. The settings, including the laser power and amplifier offset, were maintained constant throughout the release period.26 The fluorescence intensity of calcein integrated from a model calcein-loaded particle was used to calculate the cumulative calcein release percentages: cumulative calcein release at certain time (%) = (1 − fluorescence intensity integrated from the calcein-loaded particle at certain time/fluorescence intensity at initial state) × 100%.
pNIPAM particle (Figure S1, Supporting Information), presents a different sunlike morphology.20 The lipogel can be imaged clearly through the fluorescence channel under confocal microscopy because of the presence of the rhodamine-labeled lipid components (Figure 1). An encircling coating layer of
Figure 1. Transmission and fluorescence micrographs of a native pNIPAM particle (a, b) and a lipogel consisting of pNIPAM particle and lipids (c, d) at 22 (a, c) and 37 °C (b, d). (e) A schematic illustration of the structures of the particle and lipogel showing the transformations when crossing the LCST of pNIPAM. The red fluorescence of the lipogel originates from the Rh-PE-labeled lipids. All the scale bars represent 2 μm.
separated lipid assemblies (mostly vesicles or micelles), which flares brightly in the fluorescence channel, is found adsorbed to the surface of the pNIPAM scaffold. The existence of these lipid assemblies is also confirmed by SEM (Supporting Information, Figure S2). Beneath a dense layer of hydrophilic pNIPAM polymers which presents obviously in the transmission channel but flames feebly in fluorescence, a spherical core of the lipogel can be distinguished in both the fluorescence and transmission channels, indicating a loose aggregate of polymer chains (mostly hydrophobic) incorporated with a large amount of lipid molecules. The lipogels are stable for days under ambient conditions. On the basis of the volume phase transition of pNIPAM polymer when crossing the LCST of ∼32 °C, the most pronounced character of the lipogel is its thermo-responsive transformation.17,18,20 Figure 1 shows the morphological transitions of both a native pNIPAM particle and a lipogel sphere when the temperature was increased from 22 to 37 °C. Both the particle and lipogel contracted to a much smaller size of 1.7 ± 0.1 μm (a ∼40% decrease in diameter). When the temperature was lowered to 22 °C again, the spheres recovered their initial shape and volume and the lipids of the lipogel recovered their initial fluorescence distributions. For both the pNIPAM and lipogel spheres, such temperature-dependent reversible transformations can be repeated more than 10 times. 3.2. Temperature-Triggered Lipid Release. Besides being an important component of cell membranes, lipids are also a typical class of biomolecules with potential applications for therapy and diagnosis.27 Additionally, they can be designed to be optimal assemblies for accessory transfer agents for cargo delivery.28 The diversity of lipids in terms of molecular structure and ligand decorations enables functionalization of
3. RESULTS AND DISCUSSION 3.1. Structural Characterization of Lipogel. At room temperature, the native pNIPAM microgel particles have a core−shell structure with a size of 2.7 ± 0.1 μm.20 However, the lipogel, with a size comparable to that of the original B
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lipids, and consequently the lipogel, for advanced biochemical applications such as targeted drug release and gene therapy.5−7,28,29 Thus, in our experiments the lipid is also viewed as model drug. Figure 2 shows the dynamic release
Figure 3. (a) Release kinetics of calcein from a native pNIPAM particle at 22 °C. (b) Corresponding intensity profiles of fluorescence signals across the lipogel, marked by red arrows in (a).
of calcein from the lipogel was found even after 2 h (Figure 4). In our experiment, the construction of such a lipogel with encapsulated calcein was imaged through different channels under confocal microscopy (Figure 4c). Calcein (green) was located and blocked within the encircling coating of lipid assemblies (red) surrounding the pNIPAM scaffold of the lipogel. This formulation demonstrated stability over time, with little release or leakage of either lipid or calcein. Obviously, the incorporation of the amphiphilic lipids significantly improves the loading capacity and prolongs the retention of hydrophilic substances such as calcein within the lipogel, especially in the central portion. The calcein-loaded capacity of the lipogel is estimated to be 466.9 μg g−1 (Supporting Information). When the temperature was increased to 37 °C (above the LCST of pNIPAM), the release of calcein from both the native pNIPAM and lipogel systems was significantly promoted. The calcein in the native pNIPAM particles was completely released within 10 min (along with the obvious volume contraction of the particle, Figure 5a,b), consistent with previous reports.33 In striking contrast, for the lipogel system, the calcein release process was significantly prolonged to about 2 h under the same conditions (Figure 5c and Supporting Information, Figure S3). The release profile can be roughly divided into two stages with distinctly different release rates. The initial burst release might result from the temperature-triggered phase transition and volume contraction of the lipogel, which induce the expelling of much of the encapsulated water (with the watersoluble calcein) from the lipogel to bulk solution. After that, the second stage is a slow release of the remaining calcein until equilibrium is reached. An initial burst release followed by a sustained slow release provides the potential benefit of achieving the best possible therapeutic effect.13 This indicates that the lipogel sphere can function as a slow release vehicle for entrapped aqueous species at body temperature; the pNIPAM scaffold serves as a drug carrier and the lipids act to slow down the release of drug molecules. Although prolonged drug release has also been accomplished in previous studies in which macromolecules such as polyethylene glycol and chitosan were applied to control the release from pNIPAM polymers,34,35 the release kinetics was still largely determined by the volume of the bulk hydrogel. For our lipogel, in view of the stable calcein
Figure 2. Release kinetics of lipids from the model lipogels at 22 (a) and 37 °C (b). Release profiles of lipids in (c) were obtained by integrating the residual fluorescence intensity of the lipogel at predetermined times. The white circles in (a) and (b) represent the area for integration. The red fluorescence originates from the Rh-PElabeled lipids.
process of lipids from the lipogel at 22 and 37 °C. At room temperature, the fluorescence intensity of the lipogel slightly changes over time (with only 20% release after 8 h and then stays constant for days), indicating that the most incorporated lipids still stay inside the lipogel (Figure 2a). However, at 37 °C (above the LCST), the fluorescence intensity of the lipogel decreases with time quickly (i.e., the cumulative lipid release increases) in an approximately linear manner, and reaches equilibrium after about 7 h (Figure 2b). Not much quenching of rhodamine occurs under similar experimental conditions;26 therefore, this phenomenon corresponds to a dynamic process of lipid release from the lipogel. 3.3. Controlled Calcein Loading and Release. To further explore the ability of the lipogel as an advanced multidrug carrier, the loading and release of calcein were also investigated. As one of the generally used fluorophores, calcein has been intensively used as a model drug in related studies because of its water-soluble and membrane-impermeable properties.30 3.3.1. Release of Calcein at Different Temperatures. Figure 3 shows the release of calcein from the native pNIPAM particles at 22 °C. It is noted that the calcein in pNIPAM particles can be released completely within 30 min. The final fluorescence intensity of calcein in the pNIPAM particle is even lower than that of the bulk solution. Such instability of drug encapsulation, even at room temperature, explains why pNIPAM has rarely been used in particle form for drug immobilization and delivery.31,32 In sharp contrast, little leakage C
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Figure 4. (a) The release of calcein from lipogel spheres over time at 22 °C. (b) Corresponding intensity profiles of fluorescence signals across the lipogel, marked by red arrows and dashed squares in (a). (c) Confocal micrographs, including fluorescence, transmission, and overlaid images, of a lipogel (with encapsulated calcein). Red, Rh-PE-labeled lipids; green, calcein.
3.3.2. Controlled Release Kinetics of Calcein by Lipids in a Lipogel. As described in Release of Calcein at Different Temperatures, lipids strongly influenced the loading and release of calcein from a lipogel. Thus, the amount of lipids in the lipogel undoubtedly affects the release behavior of calcein. Although an excessive amount of lipids was always needed for the preparation of lipogels during the lipogel fabrication process, the relative quantity of lipid molecules incorporated in each lipogel can be modulated through a salt-induced lipid release process of the lipogel, which controls the loading capacity and release kinetics of calcein. In one of our previous studies, we demonstrated that adjusting the salt content of solution would lead to a controlled cycle of lipid release from the lipogel into bulk solution.20 That is, a salt incubation would trigger an immediate release of the coating lipid assemblies of the lipogel into bulk solution. After that, a water incubation would induce the recovery of the lipogel morphology to the initial state. Such salt-induced lipidrelease processes can be repeated for more than five cycles, during which the fluorescence intensity of the lipogel, indicating the relative amount of lipids left within the lipogel, decreases successively. As a result, in this work we selected lipogel samples individually at three different stages during this process: the initial lipogel sphere (named Lipogel-A) and the lipogels after the first (Lipogel-B) and second (Lipogel-C) incubation cycles (Figure 6a). The distribution of the fluorescence intensities of the three lipogels proves that the relative amount of retained lipids reduces sequentially (Figure 6b). We took the lipogels as drug carriers and mixed them separately with the same amount of calcein for the loading. After that, the dynamic releasing processes of calcein from the corresponding carriers at the same temperatures were monitored.
Figure 5. (a) Release kinetics of calcein from a model pNIPAM particle at 37 °C. (b) Corresponding intensity histograms of fluorescence signals from the calcein loaded in the pNIPAM particle, marked by red arrows in the graphs above. (c) Release profile of calcein from a model calcein-loaded lipogel at 37 °C.
encapsulation at room temperature, such temperature-triggered calcein release of the lipogel (including an initial burst release followed by a slow release process until equilibrium) indicates that the lipogel is an attractive candidate for addressing the problem of premature drug release. D
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Figure 6. (a) Incubation series of a model lipogel in salt (0.3 M Na2CO3) and water, successively. The three types of lipogels, Lipogel-A, -B, and -C, were marked referring to the corresponding stages. (b) Fluorescence intensity distributions indicating the relative amount of lipids within the three lipogels. (c, d) Normalized calcein-releasing profiles and schematic images of the calcein-loaded lipogels corresponding to Lipogel-A, -B, and -C at 37 °C.
such lipid-incorporated lipogels might be excellent drug carriers for combined delivery and controlled drug release for treatment of diseases.
Figure 6c presents the normalized calcein releasing profiles of the three types of lipogels. It is found that the release rate of calcein becomes lower from A to B and C, and the time needed to achieve equilibrium is ∼120, ∼60, and ∼30 min for A, B, and C, respectively. Moreover, the absolute quantity of calcein that is released cumulatively also follows the order of A > B > C. Such observations are reasonable considering that with the decrease in lipid content from A to B and C, the ability of the lipogels to encapsulate and retain calcein decreases, and as a result, it becomes easier for the calcein in the lipogels to reach equilibrium. This result demonstrates that by adjusting the quantity of lipids within a lipogel, we can effectively modulate the loading capacity and release kinetics of calcein (Figure 6d).
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ASSOCIATED CONTENT
S Supporting Information *
SEM images of pNIPAM and lipogel spheres, ζ potential profile of pNIPAM, and release kinetics of calcein from lipogel over time. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Tel/fax: 86 512 65220239 (B.Y.), 86 25 83592900 (Y.M.). Email:
[email protected] (B.Y.),
[email protected] (Y.M.).
4. CONCLUSIONS We demonstrated the temperature-triggered release of both lipids and a hydrophilic model drug, calcein, from a lipogel made from pNIPAM microgel particles and lipids; moreover, the thermo-responsive property makes the lipogel act as an on/ off switch by blocking calcein leakage because of the presence of lipids when the temperature is below the LCST. Lipids act as drug holders on the pNIPAM scaffold within the lipogel. As a result, adjusting the relative amount of lipids incorporated in the lipogels leads to effective modulation of the loading capacity as well as the release kinetics of calcein. Our work suggests that
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the National Science Foundation of China (91027040, 31061160496, 21106114, 11104192, and 21204058), the National Basic Research Program of China (2012CB821500), and the Natural Science Foundation of Jiangsu Province of China (BK2012177). K.Y. E
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Coarsening and Nanotubulation within Giant Unilamellar Vesicles. J. Am. Chem. Soc. 2011, 133, 18046−18049. (18) Zhang, Y. J.; Furyk, S.; Bergbreiter, D. E.; Cremer, P. S. Specific Ion Effects on the Water Solubility of Macromolecules: PNIPAM and the Hofmeister Series. J. Am. Chem. Soc. 2005, 127, 14505−14510. (19) Makino, K.; Hiyoshi, J.; Ohshima, H. Kinetics of Swelling and Shrinking of Poly (N-isopropylacrylamide) Hydrogels at Different Temperatures. Colloid Surf., B 2000, 19, 197−204. (20) Lu, N. Y.; Yang, K.; Zhang, Z. X.; Li, J. L.; Yuan, B.; Ma, Y. Q. Controlled Transformation and Release of a Poly(N-isopropylacrylamide) Particle and Lipid Based Lipogel. Nanoscale, submitted for publication. (21) Saleem, Q.; Liu, B. X.; Gradinaru, C. C.; Macdonald, P. M. Lipogels: Single-Lipid-Bilayer-Enclosed Hydrogel Spheres. Biomacromolecules 2011, 12, 2364−2374. (22) Irache, J. M.; Esparza, I.; Gamazo, C.; Agueros, M.; Espuelas, S. Nanomedicine: Novel Approaches in Human and Veterinary Therapeutics. Vet. Parasitol. 2011, 180, 47−71. (23) Pelton, R. H.; Chibante, P. Preparation of Aqueous Lattices with N-Isopropylacrylamide. Colloids Surf. 1986, 20, 247−256. (24) Hohner, A. O.; David, M. P. C.; Radler, J. O. Controlled Solvent-Exchange Deposition of Phospholipid Membranes onto Solid Surfaces. Biointerphases 2010, 5, 1−8. (25) Staykova, M.; Holmes, D. P.; Read, C.; Stone, H. A. Mechanics of Surface Area Regulation in Cells Examined with Confined Lipid Membranes. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 9084−9088. (26) Ungaro, F.; Biondi, M.; d’Angelo, I.; Indolfi, L.; Quaglia, F.; Netti, P. A.; La Rotonda, M. I. Microsphere-Integrated Collagen Scaffolds for Tissue Engineering: Effect of Microsphere Formulation and Scaffold Properties on Protein Release Kinetics. J. Controlled Release 2006, 113, 128−136. (27) Seida, J. C.; Mager, D. R.; Hartling, L.; Vandermeer, B.; Turner, J. M. Parenteral ω-3 Fatty Acid Lipid Emulsions for Children With Intestinal Failure and Other Conditions: A Systematic Review. JPEN, J. Parenter. Enteral Nutr. 2013, 37, 44−55. (28) Bolinger, P.-Y.; Stamou, D.; Vogel, H. Integrated Nanoreactor Systems: Triggering the Release and Mixing of Compounds inside Single Vesicles. J. Am. Chem. Soc. 2004, 126, 8594−8595. (29) Nayak, S.; Lee, H.; Chmielewski, J.; Lyon, L. A. Folate-Mediated Cell Targeting and Cytotoxicity Using Thermoresponsive Microgels. J. Am. Chem. Soc. 2004, 126, 10258−10259. (30) Liu, J. W.; Jiang, X. M.; Ashley, C.; Brinker, C. J. Electrostatically Mediated Liposome Fusion and Lipid Exchange with a NanoparticleSupported Bilayer for Control of Surface Charge, Drug Containment, and Delivery. J. Am. Chem. Soc. 2009, 131, 7567−7569. (31) Liu, Y. Y.; Shao, Y. H.; Lu, J. Preparation, Properties and Controlled Release Behaviors of pH-Induced Thermosensitive Amphiphilic Gels. Biomaterials 2006, 27, 4016−4024. (32) Liu, Y.; Li, Z. C.; Liang, D. H. Behaviors of Liposomes in a Thermo-Responsive Poly(N-isopropylacrylamide) Hydrogel. Soft Matter 2012, 8, 4517−4523. (33) Biswas, C. S.; Patel, V. K.; Vishwakarma, N. K.; Mishra, A. K.; Bhimireddi, R.; Rai, R.; Ray, B. Synthesis, Characterization, and Drug Release Properties of Poly(N-isopropylacrylamide) Gels Prepared in Methanol-Water Cononsolvent Medium. J. Appl. Polym. Sci. 2012, 12, 2000−2009. (34) Wang, H.; An, Y. L.; Huang, N.; Ma, R. J.; Li, J. B.; Shi, L. Q. Contractive Polymeric Complex Micelles as Thermo-Sensitive Nanopumps. Macromol. Rapid Commun. 2008, 29, 1410−1414. (35) Duan, C. X.; Zhang, D. R.; Wang, F. H.; Zheng, D. D.; Jia, L. J.; Feng, F. F.; Liu, Y.; Wang, Y. C.; Tian, K. L.; Wang, F. S.; et al. Chitosan-g-Poly(N-isopropylacrylamide) Based Nanogels for Tumor Extracellular Targeting. Int. J. Pharm. 2011, 409, 252−259.
thanks the support of the Key Project of Chinese Ministry of Education (210208) and the Applied Basic Research Program (2010CD091). The authors thank Prof. Zexin Zhang (Soochow University) for the pNIPAM synthesis.
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REFERENCES
(1) Daniel, M. C.; Astruc, D. Gold Nanoparticles: Assembly, Supramolecular Chemistry, Quantum-Size-Related Properties, and Applications toward Biology, Catalysis, and Nanotechnology. Chem. Rev. 2004, 104, 293−346. (2) Lu, J.; Liong, M.; Li, Z. X.; Zink, J. I.; Tamanoi, F. Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small 2010, 6, 1794−1805. (3) Meng, H.; Xue, M.; Xia, T.; Zhao, Y. L.; Tamanoi, F.; Stoddart, J. F.; Zink, J. I.; Nel, A. E. Autonomous in Vitro Anticancer Drug Release from Mesoporous Silica Nanoparticles by pH-Sensitive Nanovalves. J. Am. Chem. Soc. 2010, 132, 12690−12697. (4) Xie, J.; Xu, C.; Kohler, N.; Hou, Y.; Sun, S. Controlled PEGylation of Monodisperse Fe3O4 Nanoparticles for Reduced NonSpecific Uptake by Macrophage Cells. Adv. Mater. (Weinheim, Ger.) 2007, 19, 3163−3166. (5) Liu, J. W.; Jiang, X. M.; Ashley, C.; Brinker, C. J. Electrostatically Mediated Liposome Fusion and Lipid Exchange with a NanoparticleSupported Bilayer for Control of Surface Charge, Drug Containment, and Delivery. J. Am. Chem. Soc. 2009, 131, 7567−7569. (6) Ashley, C. E.; Carnes, E. C.; Phillips, G. K.; Padilla, D.; Durfee, P. N.; Brown, P. A.; Hanna, T. N.; Liu, J.; Phillips, B.; Carter, M. B.; et al. The Targeted Delivery of Multicomponent Cargos to Cancer Cells by Nanoporous Particle-Supported Lipid Bilayers. Nat. Mater. 2011, 10, 389−397. (7) Cauda, V.; Engelke, H.; Sauer, A.; Arcizet, D.; Brauchle, C.; Radler, J.; Bein, T. Colchicine-Loaded Lipid Bilayer-Coated 50 nm Mesoporous Nanoparticles Efficiently Induce Microtubule Depolymerization upon Cell Uptake. Nano Lett. 2010, 10, 2484−2492. (8) Wang, Y. Y.; Wu, G. L.; Li, X. M.; Chen, J. T.; Wang, Y. N.; Ma, J. B. Temperature-Triggered Redox-Degradable Poly(ether urethane) Nanoparticles for Controlled Drug Delivery. J. Mater. Chem. 2012, 22, 25217−25226. (9) Taylor-Pashow, K. M. L.; Della Rocca, J.; Huxford, R. C.; Lin, W. B. Hybrid Nanomaterials for Biomedical Applications. Chem. Commun. 2010, 46, 5832−5849. (10) Yuan, B.; Xing, L. L.; Zhang, Y. D.; Lu, Y.; Mai, Z. H.; Li, M. Self-Assembly of Highly Oriented Lamellar Nanoparticle-Phospholipid Nanocomposites on Solid Surfaces. J. Am. Chem. Soc. 2007, 129, 11332−11333. (11) Mart, R. J.; Liem, K. P.; Webb, S. J. Magnetically-Controlled Release from Hydrogel-Supported Vesicle Assemblies. Chem. Commun. 2009, 2287−2289. (12) Mai, Y.; Eisenberg, A. Controlled Incorporation of Particles into the Central Portion of Vesicle Walls. J. Am. Chem. Soc. 2010, 132, 10078−10084. (13) Ahmed, A.; Hearn, J.; Abdelmagid, W.; Zhang, H. F. DualTuned Drug Release by Nanofibrous Scaffolds of Chitosan and Mesoporous Silica Microspheres. J. Mater. Chem. 2012, 22, 25027− 25035. (14) Yang, S.; Chen, D. Y.; Li, N. J.; Mei, X.; Qi, X. X.; Li, H.; Xu, Q. F.; Lu, J. M. A Facile Preparation of Targetable pH-Sensitive Polymeric Nanocarriers with Encapsulated Magnetic Nanoparticles for Controlled Drug Release. J. Mater. Chem. 2012, 22, 25354−25361. (15) Qiu, Y.; Park, K. Environment-Sensitive Hydrogels for Drug Delivery. Adv. Drug Delivery Rev. 2001, 53, 321−339. (16) He, C. L.; Kim, S. W.; Lee, D. S. In Situ Gelling StimuliSensitive Block Copolymer Hydrogels for Drug Delivery. J. Controlled Release 2008, 127, 189−207. (17) Wegrzyn, I.; Jeffries, G. D. M.; Nagel, B.; Katterle, M.; Gerrard, S. R.; Brown, T.; Orwar, O.; Jesorka, A. Membrane Protrusion F
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