The Preparation and Characterization of Amphiphilic Star Block

Jul 28, 2010 - Asad Ullah , Shakir Ullah , Gul Shehzada Khan , Syed Mujtaba Shah , Zakir Hussain , Saz Muhammad , Muhammad Siddiq , Hazrat Hussain. Eu...
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J. Phys. Chem. C 2010, 114, 13471–13476

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The Preparation and Characterization of Amphiphilic Star Block Copolymer Nano Micelles Using Silsesquioxane As the Core Caihua Ni,*,† Geng Wu,† Changping Zhu,‡ and Bolong Yao† School of Chemical and Material Engineering, Jiangnan UniVersity, Wuxi, China, and College of Computer and Information Engineering, Hohai UniVersity, Changzhou, China ReceiVed: April 12, 2010; ReVised Manuscript ReceiVed: June 16, 2010

Amphiphilic star-shaped block copolymers of poly(ε-caprolactone-star-N-isopropylacrylamide) were synthesized by using hydroxyl-functionalized polyhedral oligomeric silsesquioxanes (POSS) as a core to initiate ring-opening polymerization of ε-caprolactone, followed by atom transfer radical polymerization of N-isopropylacrylamide. The sizes of the core and shell could be controlled through adjusting feed ratios of the reactants. The structure of the star block copolymers were confirmed by FTIR, 1HNMR, 29SiNMR, and DSC. Nano micelles were formed by adding water to the copolymer solution (DMF). The critical water concentration for the formation of the micelles were determined by UV. The results of TEM and DLS showed that the micelles were well-defined three-dimensional spherical particles with an average diameter of 155 nm. A hydrophobic drug ibuprofen could be loaded on the micelles effectively, and the release behavior was temperature dependent. 1. Introduction Nanostructure micelles have received great attention due to their potential applications as drug delivery devices for releasing hydrophobic drug molecules in a controlled way.1 With polymeric micelles, targeting can be achieved through an enhanced permeation and retention effect (EPR effect).2,3 Linear amphiphilic block copolymers in selective media can yield nano micelles through self-assembly. However, their sizes and size distribution are significantly affected by the hydrophilicity of the arms, temperatures, concentrations, and mechanical shear. Therefore, the morphology of the micelles is variable or easy to deform. In a star-shaped amphiphilic polymer each macromolecule becomes an individual, and its architecture mimics a micellar structure.4-7 An interesting feature of amphiphilic starshaped block copolymers is that they can form micelles which are stable in selective media at relatively high concentrations without association and at infinite dilution without dissociation. Another advantage is that star or/and branched copolymer micelles possess larger interior space which can accommodate more drugs than linear polymer micelles. The important structural design for preparation of a star polymer is to select a core molecule because it significantly affects morphology and properties of the polymers prepared. Some star-shaped polymers with three, four, or five arms have been extensively studied.8-13 However, their structures with fewer arms are easily deformed. Dendrimers have also been proposed as optimum candidates to prepare unimolecular micelles due to the presence of a large number of branch sites per molecule.14 However, the structures and sizes of many dendrimers are hard to be controlled, and some dendrimers are not biocompatible. Therefore, it is interesting and challenging work to develop new cores for preparing star-shaped polymers. * To whom correspondence should be addressed. E-mail: nicaihua2000@ 163.com Telephone: +86-510-85073593. † Jiangnan University. ‡ Hohai University.

Polyhedral oligomeric silsesquioxanes (POSS) are novel type of silica nano material. In 1995, Lichtenhan and co-workers developed and patented a closed-cage POSS or molecular silica.15 These molecules are composed of two cyclic rings of oxygen and silicon in accordance with the stoichometric formula (SiO1.5)n. The POSS molecules possess a well-defined threedimensional structure having an inorganic core surrounded by eight organic arms which can be functionalized to form an inorganic/organic hybrid. These hybrids have promising applications as future biomedical materials. Some related researches have already been reported. Kaneshiro et al. synthesized well-defined poly-L-lysine-octa(3-aminopropyl)silsesquioxane as drug carriers for gene delivery.16 Balas et al. prepared ordered mesoporous silica-based materials and used them for the controlled release of bisphosphonates in the therapy of bone diseases.17 As a promising biomedical material POSS has many attractive advantages such as being nontoxic, biocompatible, chemically inert, mechanically stable, nano sized, having well-defined threedimensional structure, and having reasonable branched arms which are easy to be functionalized. POSS has been appreciated as “the next-generation material for biomedical applications”.18 Poly(ε-caprolactone) is a biodegradable and biocompatible material which is an applicable candidate serving as a reservoir for hydrophobic drugs. Poly(N-isopropylacrylamide) is a wellknown thermal responsive polymer, and its controlled release feature has been well-recognized. It is expected that drug delivery can be controlled by using thermosensitive micelles with the method of local heating and cooling. In terms of the considerations mentioned above we have prepared a hydroxyl-functionalized POSS, employed it as a core molecule, and synthesized amphiphilic star block copolymers by means of ring-opening polymerization of ε-caprolactone and living polymerization of N-isopropylacrylamide. Finally thermosensitive nanomicelles based on the copolymers of poly (εcaprolactone) and poly(N-isopropylacrylamide) have been prepared and characterized. The micelles are expected to have well-

10.1021/jp103260h  2010 American Chemical Society Published on Web 07/28/2010

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defined structure and desired properties in drug-controlled release. To the best of our knowledge this work is a novel concept. 2. Experimental Section 2.1. Materials. γ-Aminopropyl triethoxysilane (KH-550), glycidol, ε-caprolactone (CL), and N-isopropylacrylamide (NIPAM) were purchased from Aldrich. Stannous 2-ethylhexanoate (Sn(OCt)2) and 2-bromoisobutyryl bromide were purchased from National Chemical Groups. Tris(2-dimethylaminoethyl)amine (Me6TREN) was kindly provided by the Polymer Institute of Nankai University. NIPAM was recrystallized from n-hexane before use, and other chemicals were used as received. 2.2. Preparation of Hydroxyl-Functionalized Silsesquioxane POSS(OH)32. The POSS(OH)32 was prepared with the method described in the literature.19-21 In a three-neck flask 22.1 g (0.1 mol) of γ-aminopropyl triethoxysilane was slowly added into 14.8 g (0.2 mol) of glycidol, with stirring at icecooling temperature, and the mixture was kept at 23 °C for one hour with stirring. The product above was dissolved in 180 mL of methanol, and 5.56 g of hydrofluoric acid aqueous solution (3.22w %) was added, and further reaction was carried out at ambient temperature for 2 h with stirring. The solvent and byproduct were removed in a vacuum, and the glassy solid product was obtained after being dried at 40 °C. The product was labeled as POSS(OH)32. 2.3. Preparation of POSS[(CL)m]32. ε-Caprolactone (CL) and the as prepared POSS(OH)32 were put into a three-neck flask in a certain molar ratio. The flask was degassed by three freeze-pump-thaw cycles, backfilled with N2, and then placed in an oil bath with temperature at 115 °C, stirring for 5 min. A toluene solution of Sn(OCt)2 (0.6 wt % with respect to the CL) was added through a syringe. The reaction was performed at 115 °C for 24 h. The product was purified by dissolving in dichloromethane and precipitating in n-hexane for three cycles. The product was dried at 40 °C in vacuum for 48 h. It was labeled as POSS[(CL)m]32. (m ) number of CL units). 2.4. Syntheses of Star Block Copolymer of POSS[(CL)m(NIPAM)n]32. The as synthesized POSS[(CL)m]32 was dissolved in chloroform in a reactor with an ice bath, and a certain amount of triethylamine was added. 2-bromoisobutyryl bromide in trichloromethane solution was added dropwise into the mixture above. The molar ratio of 2-bromoisobutyryl bromide, hydroxyl groups of POSS[(CL)m]32 and triethylamine was 1.2:1:1. The reaction was performed at ambient temperature for 24 h. Afterward, the product was successively washed with 1 mol/L of Na2CO3, 1 mol/L of HCl and excess deionized water. The macro initiator, POSS[(CL)mBr]32, was obtained after drying at 35 °C in vacuum for 48 h. In the second step, the monomer NIPAM was initiated by POSS[(CL)mBr]32 and polymerized following a mechanism of atom transfer radical polymerization(ATRP). Briefly, POSS[(CL)mBr]32 (0.445 g), NIPAM(1.29 g) and DMF(3 mL) were put into a reactor, CuCl(56 mg, 0.56 mmol) and ME6TREN(130 mg, 0.56 mmol) were dissolved in dimethylformamide (DMF) solution and degassed by three freeze-pump-thaw cycles. The reaction was continuously carried out at 22 °C for 3 h. The sample was diluted with DMF, passed through a basic alumina column to remove copper salts, and then precipitated in cold n-hexane. The product experienced a dialysis in deionized water for 5 days. After being dried in a vacuum at 40 °C for 48 h, the final product was obtained. A series of copolymers with stoichiometric amount of feed ratios were prepared. They are labeled as POSS[(CL)m(NIPAM)n]32, (where m, n stand for the numbers of structural units of CL and NIPAM in the copolymers, respectively).

Ni et al. 2.5. Micellization of the Star Copolymer. The as-synthesized star copolymer POSS[(CL)m(NIPAM)n]32 (100 mg) was dissolved in DMF(10 mL) to form a solution with a concentration of 1.0 w % and the solution was subjected to filtration through a microporous membrane. Ultra pure water was added dropwise to the solution by stirring until micelles were observed, the absorbance was monitored at 500 nm, 25 °C on UV. The micelle solution was dialysized (in a bag with cutoff mass14,000) for five days against ultra pure water which was renewed frequently. 2.6. Characterization of the Star Block Copolymers and Micelles. The structures of POSS(OH)32, POSS[(CL)m]32, and POSS[(CL)m(NIPAM)n]32 were characterized by means of Fourier transform infrared spectroscopy (FTIR, FTLA 2000, Boman, Canada), nuclear magnetic resonance (1H NMR, 29Si NMR, Digital NMR Spectrometer, AVANCE III 400 MHz, Bruker Corporation, Switzerland); differential scanning calorimetry(DSC822e, Mettler Toledo, Switzerland). The molecular weights of [POSS(CL)m]32, and POSS[(CL)m(NIPAM)n]32 were determined by gel permeation chromatography (GPC, Agillent1100, America); The sizes of the micelles were determined by dynamic laser scattering with wavelength of 632 nm (DLS, ALV-5000, Germany) and transmission electron microscopy (TEM, Hitachi 7000A, Japan) respectively. 2.7. Drug Loading. The model drug ibuprofen (100 mg) and the POSS[(CL)16.8(NIPAm)9.1]32 copolymer (200 mg) were dissolved in DMF. Deionized water was added dropwise to initiate micellization. After turbidity the solution was stirred for an additional 3 h, and then the solution was put into a dialysis bag (MWCO 3.5 kDa) and was subjected to dialysis against water which was renewed every 8 h. After dialysis the micelle solution was frozen and lyophilized on an freeze-dryer instrument. The loading rate (LR) and embedding rate (ER) of the drug are defined as follows:

LR(%) )

WD × 100% WS

(1)

ER(%) )

WD × 100% WDT

(2)

where WD, WS and WDT refer to the weight of the drug in the sample, the weight of the sample, and the weight of the total drug involved, respectively. 2.8. In Vitro Drug Release. The drug-loaded micelle solution with a certain concentration was put in a dialysis bag which was immersed into 200 mL of distilled water. In the course of drug release 5 mL of the solution was withdrawn at appropriate time intervals. The volume of solution was held constant by adding 5 mL of distilled water after each sampling. The concentration of the drug released from micelles was measured using UV monitored at 265 nm. 3. Results and Discussion 3.1. The Preparation and Characterization of POSS(OH)32. Hydroxyl-functionalized silsesquioxane POSS(OH)32 has been prepared in two steps. At first γ-aminopropyl triethoxysilane(KH-550) reacts with glycidol through ring-opening addition under mild conditions. The adduct is further converted into POSS(OH)32 through hydrolysis and condensation at the presence of HF solution (Figure 1). The infrared analysis for the structure of POSS(OH)32 shows that there is a wide peak

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J. Phys. Chem. C, Vol. 114, No. 32, 2010 13473 TABLE 1: Synthetic Results of POSS(CL)m sample ID

feed (mol) OHa: CL

found of CL unitsb

Mn

PDI

POSS(CL)10.4 POSS(CL)16.8 POSS(CL)35.8 POSS(CL)50.2

1: 20 1: 39 1: 78 1: 117

10.4 16.8 35.8 50.2

40,000 63,300 132,700 185,000

1.08 1.14 1.19 1.23

a OH stands for the number of hydroxyl groups in POSS(OH)32. CL units: The average number of CL units in each arm of the branched polymer POSS(CL)m. b

Figure 1. Synthetic scheme of hydroxyl-functionalized POSS(OH)32.

Figure 2. (A) 1H NMR spectrum of POSS(OH)32. Solvent: deuterated methanol. (B) 29Si NMR spectrum of POSS(OH)32.

round 3400 cm-1 which indicates the stretch vibration of OH groups; the peak at 2940 cm-1 is ascribed to C-H stretching; a strong broad band peak observed at 1030-1150 cm-1 results from Si-O-Si stretching according to literature.19,20 The 1H NMR spectrum of POSS(OH)32 in deuterated methanol can be seen in Figure 2(A). The peak signals at 0.6-0.8 ppm, 1.7 ppm,

Figure 3. Synthetic scheme of POSS[(CL)m(NIPAM)n]32.

and 2.5-2.8 ppm correspond to hydrogen of R, β, and γ positions with respect to silica atom. The peaks of 3.5 ppm and 3.8 ppm are attributed to CHO and CH2O respectively. The peak of OH should appear within 3-4 ppm, but it may overlap with signal of CHO. The spectrum of 29Si NMR for POSS-(OH)32 shows a peak with the maximum around -67 ppm, which indicates that the chemical environment around Si atoms is about the same (Figure 2B). It is concluded that caged silsesquioxane structure of POSS(OH)32 is indeed formed. However, the peak position is slightly extended nearby -67 ppm. It is explained that some various structures such as ladders, or partially caged POSS may be formed at the same time. This phenomenon is in agreement with the literature.19 3.2. The Synthesis of Star Polymer of POSS[(CL)m]32. The preparation of the star-shaped copolymer of POSS[(CL)m(NIPAM)n]32 includes three consecutive steps: the polymerization of CL initiated by POSS(OH)32, the reaction of OH with 2-bromoisobutyryl bromide to create an initiator for the following polymerization, and finally the atom transfer radical polymerization of NIPAM. The synthetic route is shown in Figure 3. CL is a lactone and is able to be polymerized through initiation of OH at the presence of a catalyst Sn(Oct)2. Some reports about this type of polymerization can be seen in the literature.21-24 In order to investigate the size dependence of PCL on the feed ratio, we have prepared four samples of POSS[(CL)m]32 with varied feed molar ratios of POSS(OH)32 to CL (Table 1). The table shows that the molecular weight

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Figure 4. Molecular weight of POSS[(CL)16.8 (NIPAM)n]32 dependence on the molar ratio of monomer NIPAM to initiator Br groups. Figure 6. 1HNMR spectra of POSS[(CL)16.8]32 and POSS[(CL)16.8(NIPAM)9.1]32. Solvent: CDCl3; internal reference: tetramethyl silane (TMS).

Figure 5. Infrared spectrum of products: (a) POSS[(CL)16.8]32; (b) POSS[(CL)16.8Br]32; and (c) POSS[(CL)16.8(NIPAM)9.1]32.

increases as CL content increases in the feed. The average polydispersity index (PDI) is between 1.08-1.23, which suggests the molecular weight distribution is narrow. This is because the mechanism of the ring-opening polymerization catalyzed by Sn(Oct)2 possesses some living polymerization features. 3.3. The Synthesis of Star Copolymer of POSS[(CL)m(NIPAM)n]32 by ATRP. In the following step the end-groups (hydroxyl) of (CL)m are converted into macro initiators for ATRP by reacting with excess 2-bromoisobutyryl bromide. It is found that nearly all the OH groups have reacted with 2-bromoisobutyryl bromide, and the residual OH groups are 0.1% with respect to the original amount. Finally NIPAM is initiated and polymerized according to the mechanism of ATRP. The molecular weight dependence on the molar ratio of NIPAM to the initiator is displayed in Figure 4. Obviously the molecular weight increases nearly in proportional to the increase of monomer NIPAM. When the molar ratios of monomer NIPAM to the Br initiator group are 10, 20, 30, and 40, the number of NIPAM units in each arm are 6.1, 9.1, 10.1, and 12.6, respectively, which demonstrates the living polymerization features. 3.4. IR Spectra of the Star Copolymer. Figure 5 shows the FTIR spectra of POSS[(CL)16.8(NIPAm)9.1]32 and POSS[(CL)16.8]32. It can be seen in Figure 5a that peaks of 2954 cm-1 and 2854 cm-1 stand for the stretch vibration of CH2. Apparently the peak of 1750 cm-1 is ascribed to CdO adsorption of the ester group. Meanwhile the Si-O-Si stretch

vibration can be seen around 1170 cm-1[ 21,22]. For the copolymer of POSS[(CL)16.8(NIPAM)9.1]32 (Figure 5c), some new peaks have emerged apart from the ones that appear in Figure 5a. There are two equal peaks at 1370 cm-1 and 1387 cm-1 which are attributed to the bend vibration of isopropyl groups; 1645 cm-1 belongs to the CdO stretch of the amino bond, and 1547 cm-1 indicates the adsorption of C-N. 3.5. 1H NMR Analysis of the Copolymers. Figure 6 displays the 1HNMR spectra of POSS[(CL)16.8]32 and POSS[(CL)16.8(NIPAm)9.1]32. In the diagram below, the peaks of a (δ 2.3 ppm), b (δ 1.6 ppm), c (δ 1.4 ppm), and d (δ 4.1 ppm) are indications of CH2 protons at different positions respectively in (CL)m units. In the upper diagram (POSS[(CL)16.8(NIPAM)9.1]32) some new peaks from (NIPAM)n units can be seen. Apparently the peak (δ 1.1 ppm) shows the existence of CH3 of isopropyl groups which is absent in the diagram below. Additionally the signals of e (δ 1.8 ppm), f (δ 3.7 ppm), and g (δ 2.1 ppm) are ascribed to the protons from (NIPAM)n units as indicated in the figure. It is confirmed that the block copolymer has been produced. 3.6. DSC Diagrams of the Copolymers. The differential scanning calorimetry (DSC) has been carried out for the samples of linear PCL, POSS[(CL)16.8]32 and POSS[(CL)16.8(NIPAM)9.1]32 (Figure 7). There is a lower melting point temperature (38 °C) for the star polymer POSS[(CL)16.8]32 comparing with that of the linear PCL (59 °C). This observation complies with the general fact that star polymers possess lower melting point than that of linear PCL polymers. On the curve of POSS[(CL)16.8(NIPAM)9.1]32, the melting point of PCL segment and the lower critical solution temperature of PNIPAM segment can be seen. The result suggests that the copolymers possess a branched structure and may have larger space for accommodation of drugs than some linear copolymers. 3.7. Formation of the Micelles Observed by UV Spectrometer. The star copolymer POSS[(CL)16.8(NIPAM)9.1]32 is amphiphilic which is soluble in DMF. If water is gradually added to the solution, the PNIPAM chains can uptake the water added. However, when the water uptake is saturated, excess water will cause coagulation of the PCL segment due to its hydrophobicity and eventually lead to the formation of star micelles. The micelles are stable under the protection of the hydrophilic shell below the lower critical solution temperature (LCST) of the PNIPAM. Figure 8 shows that, as water is added to the copolymer solution, the absorbance keeps almost constant

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Figure 7. DSC of linear PCL, POSS[(CL)16.8]32 and POSS[(CL)16.8(NIPAM)9.1]32.

Figure 9. TEM for the micelles of POSS[(CL)16.8(NIPAM)9.1]32 (1.0 wt %); the insert diagram at the lower right corner is a result of DLS with wavelength of 632 nm at 20 °C.

TABLE 2: Drug Content and the Drug Loading Efficiency in Star-Shaped Block Copolymer Micelles

Figure 8. UV determination of critical water concentration (cwc) for the formation of micelles of POSS[(CL)16.8(NIPAM)9.1]32 (the original star copolymer concentration is 1 wt % in DMF).

at the initial period of time. However, when the water addition reaches up to 29.4 wt %, a sudden increase in the absorbance can be seen. This suggests that micelles start to form at this point which is defined as critical water concentration (cwc). This approach illustrates that the copolymer POSS[(CL)16.8(NIPAM)9.1]32 can form micelles effectively. The saturated water content is 53.5 w % in which all the star copolymer molecules form stable micelles. Further addition of water will dilute the micelle concentration, which causes a slight decease in the absorbance. 3.8. TEM Image and DLS Determination. Transmission electron microscopy (TEM) and dynamic laser scattering (DLS) are employed to further characterize the structure of the micelles. The image of the nanomicelles of POSS[(CL)16.8(NIPAM)9.1]32 is observed as exhibited in Figure 9. The inset diagram at the lower right corner shows the radius distribution of the micelles. It is seen that the micelles display approximate spherical shape with diameter of 145-160 nm. This shape regularity is attributed to the well-defined three-dimensional framework structure of the POSS, and the feature of living polymerization of NIPAM. 3.9. Drug Release of the Micelles. The micelles are used as the drug vehicle, and the controlled release behaviors are investigated. Table 2 shows that the loading yield and embedding yield of the drug increase as the core size increases. It is known that ibuprofen is a hydrophobic molecule due to the isobutyl benzene group in the molecule, and the drug has a good

sample ID

drug loading yield (%)

embedding yield (%)

POSS(CL)10.4(NIPAM)9.1 POSS(CL)16.8(NIPAM)9.1 POSS(CL)35.8(NIPAM)9.1

28.4 34.9 38.6

65.3 69.4 70.6

miscibility with the hydrophobic core (CL)m. The larger the core size, the more drug can be loaded. The release of the drug from the matrix can be slowed down because of hydrophobic interaction between ibuprofen and the core (CL)m. The release is performed at two temperatures. Figure 10 shows that the release is faster at 40 °C and cumulative release at equilibrium is higher than releases at room temperature (25 °C). The release was observed to be fast during the initial period of time and then was getting slow after a while. Basically, the release behavior corresponds to first-order kinetics as shown in Figure 10 in which the solid curves describe the fittings of first-order kinetics.

Figure 10. Drug release behaviors of the micelles at different temperatures. The solid lines describe the fitting of first-order kinetics.

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4. Conclusions Multihydroxyl-functionalized polyhedral oligomeric silsesquioxane is prepared and used as a starting molecule to initiate polymerization of CL, followed by the atom transfer radical polymerization of NIPAM. The reactions lead to the production of star-shaped amphiphilic block copolymers of POSS[(CL)m(NIPAM)n]32. The nano micelles are formed by dissolving the copolymer in water. The study shows that the sizes of the copolymers can be controlled by adjusting the feed ratio. The size distribution of the micelles is narrow, the micelle morphology is well-defined regular spherical particles, and they are stable in both concentrated and dilute solutions. The product has potential applications as a drug vehicle for controlled release. Acknowledgment. We are grateful for the financial support from the National Natural Science Foundation of China (No: 10974044). Supporting Information Available: TEM for the micelles at different concentration and temperature, and the molecular structure of ibuprofen drug. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Teng, Y.; Morrison, M. E.; Munk, P.; Webber, S. E.; Prochazka, K. Macromolecules 1998, 31, 3578–3587. (2) Neradovic, D.; Soga, O.; Van Nostrum, C. F.; Hennink, W. E. Biomaterials 2004, 25, 2409–2418. (3) Lee, E. S.; Na, K.; Bae, Y. H. J. Controlled Release 2003, 91, 103–113. (4) Meier, M. A. R.; Gohy, J. F.; Fustin, C. A.; Schubert, U. S. J. Am. Chem. Soc. 2004, 126, 11517–11521.

Ni et al. (5) Kreutzer, G.; Ternat, C.; Nguyen, T. Q.; Plummer, C. J. G.; Månson, J. A. E.; Castelletto, V.; Hamley, I. W.; Sun, F.; Sheiko, S. S.; Klok, H. A. Macromolecules 2006, 39, 4507–4516. (6) Xu, J.; Luo, S. Z.; Shi, W. F.; Liu, S. Y. Langmuir 2006, 22, 989– 997. (7) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Saunders, M. J.; Grossman, S. H. Angew. Chem. 1991, 103, 1207–1209. (8) Lele, B. S.; Leroux, J. C. Polymer 2002, 43, 5595–5606. (9) Yamaguchi, N.; Kiick, K. L. Biomacromolecules 2005, 6, 1921– 1930. (10) Whittaker, M. R.; Monteiro, M. J. Langmuir 2006, 22, 9746–9752. (11) Yuan, W.; Yuan, J.; Zheng, S.; Hong, X. Polymer 2007, 48, 2585– 2594. (12) Angiolini, L.; Benelli, T.; Giorgini, L.; Salatelli, E. Macromolecules 2006, 39, 3731–3737. (13) Hao, Q.; Li, F.; Li, Q.; Li, Y.; Jia, L.; Yang, J.; Fang, Q.; Cao, A. Biomacromolecules 2005, 6, 2236–2247. (14) Urbani, C. N.; Bell, C. A.; Lonsdale, D.; Whittaker, M. R.; Monteiro, M. J. Macromolecules 2008, 41, 76–86. (15) Lichtenhan, J. D. Comments Inorg. Chem. 1995, 17, 115–130. (16) Kaneshiro, T. L.; Wang, X. L.; Lu, Z. R. Mol. Pharm. 2007, 4, 759–768. (17) Balas, F.; Manzano, M.; Horcajada, P.; Vallet-Regi, M. J. Am. Chem. Soc. 2006, 128, 8116–8117. (18) Kannan, R. Y.; Salacinski, H. J.; Butler, P. E.; Seifalian, A. M. Acc. Chem. Res. 2005, 38, 879–884. (19) Mori, H.; Lanzendofer, M. G.; Muller, A. H. E.; Klee, J. E. Macromolecules 2004, 37, 5228–5238. (20) Pescarmona, P. P.; Maschmeyer, T. Aust. J. Chem. 2001, 54, 583– 596. (21) Meng, F. L.; Xu, Z. G.; Zheng, S. X. Macromolecules 2008, 41, 1411–1420. (22) Lin, Y.; Liu, X. H.; Dong, Z. M.; Li, B. X.; Chen, X. S.; Li, Y. S. Biomacromolecules 2008, 9, 2629–2636. (23) Wang, F.; Bronich, T. K.; Kabanov, A. V.; Rauh, R. D.; Roovers, J. Bioconjugate Chem. 2008, 19, 1423–1429. (24) Deng, G. H.; Zhang, L. W.; Liu, C. D.; He, L. H.; Chen, Y. M. Eur. Polym. J. 2005, 41, 1177–1186.

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