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Bioinspired Core-Crosslinked Micelles from Thymine-Functionalized Amphiphilic Block Copolymers: Hydrogen Bonding and Photo-Crosslinking Study
Gagan Kaur,1 Shery L. Y. Chang,2 Toby D. M. Bell,3 Milton T. W. Hearn,1 Kei Saito1
1 2

Centre for Green Chemistry, Monash University, Clayton, Victoria 3800, Australia Monash Centre for Electron Microscopy and School of Chemistry, Monash University, Clayton, Victoria 3800, Australia 3 School of Chemistry, Monash University, Clayton, Victoria 3800, Australia Correspondence to: K. Saito (E-mail: kei.saito@monash.edu) Received 10 February 2011; accepted 17 June 2011; published online 12 July 2011 DOI: 10.1002/pola.24853

ABSTRACT: Bioinspired core-bound polymeric micelles, based on hydrogen bonding and photo-crosslinking, of thymine have been prepared from poly(vinylbenzylthymine)-b-poly(vinylbenzyltriethylammonium chloride). The amphiphilic block copolymer was synthesized by 2,2-tetramethylpiperidin-1-oxylmediated living radical polymerization in water/ethylene glycol solution. Micelle characterization and critical micelle concentration measurements demonstrated that the hydrogen bonding

of the attached thymine units stabilizes the micelles. Further, core-crosslinked polymeric micelles were formed by ultraviolet (UV) radiation showing that the stability of the micelle could be controlled by the UV crosslinking of the attached thymines. C V 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 49: 41214128, 2011
KEYWORDS: biomimetic; block copolymer; core-shell polymers

INTRODUCTION Bioinspired mechanisms are used to create alternative materials based on the principles of green chemistry.1,2 Nature provides abundant and elegant examples of the synthesis of molecules in terms of both atom economy and energy required. Thymine, one of the nucleic bases in DNA, has the ability to form both relatively strong hydrogen bonds and to be photo-crosslinked.35 The hydrogen bonding capabilities of thymine are well known to stabilize the double helix structure of DNA. The photodimerization of thymine, a ultraviolet (UV)-induced 2p 2p photocyclization, results in the covalent dimerization of adjacent thymines, leading to the disruption of the helical structure of DNA. This process has been linked with the development of certain forms of skin cancer. This photo-crosslinking of thymine occurs when irradiated at wavelengths >270 nm UV. The 2p electron system of the 5 and 6 carbons of two adjacent thymines form a cyclobutane crosslink. Crosslinking can be reversed either by irradiation at <249 nm or enzymatically. By using these mechanisms, thymine-functionalized chemical compounds can be photo-crosslinked and photodecrosslinked.610

stabilizes the hydrophobic core by acting as an interface between the aqueous phase and the hydrophobic region. This unique assembly makes polymeric micelles suitable candidates as chemical capsules for various applications such as industrial surfactants, nanocapsules for biomedical usage, electronic pollution control devices, removal agents for organic contaminates in water, and in other nanofabricated materials.1117 Chemicals may be loaded into the core by physical entrapment, conjugation, or complexation.15,1823 Furthermore, the controlled release of encapsulated guest materials from the polymeric micelles can be triggered by changes in temperature and pH, by chemical stimuli, by enzymes, or by application of light, ultrasound or magnetic field.2428 For polymeric micelles to have broad application use, it is critical that the amphiphilic block copolymer micelles must be stable. Critical micelle concentration (CMC) provides a measure of stability of polymeric micelles. CMC is the threshold concentration at or above which the micelles form. Lower CMC values favor stable micelles even in dilute solutions. Stability of the polymeric micelles is affected by the nature of interactions between chains in the core.29,30 Crosslinking has been used by researchers to increase the structural stability of polymeric micelles in dilute solutions and even in organic solvents. Crosslinking may be induced in the shell or in the core. Shell crosslinked micelles can be

Amphiphilic block copolymers form nanoscopic self-assembling core/shell structures called polymeric micelles in the bulk aqueous medium. During the formation of these micelles, the hydrophobic segment forms the core while the hydrophilic segment forms the shell. The hydrophilic shell

Additional Supporting Information may be found in the online version of this article.
C V 2011 Wiley Periodicals, Inc.

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FIGURE 1 Core bound thymine-functionalized polymeric micelle.

prepared by UV irradiation, by addition of multifunctional crosslinking reagents, or by the direct reaction between the polymer chains.3136 Core crosslinked micelles have been prepared by photo-crosslinking, free radical polymerization within the core, solgel chemistry, and condensation reactions.16,3739 Photo-crosslinking is the method of choice as it is non toxic, economical, and does not produce any by-products. Furthermore, suitable photo-crosslinking does not affect the micellar shape and size.40 Recently, our group has investigated core-crosslinked micelles containing thymine groups as photo-crosslinkable units.41,42 We have reported that enhanced stability can be achieved with nano polymeric micellar aggregates derived from amphiphilic block copolymers of vinylbenzylthymine (VBT) and styrenesulfonate (VPS).41 In this previous work, we reported the synthesis of a block copolymer of VBT and VPS and characterization of the micelles formed from it.41 However, the hydrogen bonding in the core of the micelles and their thermostability were not investigated in detail in our previous work. In this article, we report the synthesis of a related bioinspired core-shell thymine-containing polymeric micellar system derived from the amphiphilic block copolymerization of VBT and vinylbenzyltriethylammonium chloride (VBA). The hydrogen bonding and photo-crosslinking attributes (Fig. 1) of these new polymer micelles are documented focusing particularly on hydrogen bonding in the micelle core at higher temperature. Copolymers of VBA with 1-pyrenylmethyl methacrylates, (4-vinylbenzyl)-cinnamate, and VBT have been reported in literature,4347 but amphiphilic block copolymers of VBT and VBA have never been synthesized before. We chose VBA as the hydrophilic block because polymers with quaternary ammonium groups are known to possess high antimicrobial activities.4853 The amphiphilic block copolymers, poly(vinylbenzylthymine)-b-poly(vinylbenzyltriethylammonium chloride) (poly(VBT-b-VBA)) were synthesized by 2,2-tetramethylpiperidin1-oxyl (TEMPO)-mediated living radical polymerization in water/ethylene glycol solution. Hydrogen bonded micelles, core-photo-crosslinked micelles, and nonhydrogen bonded micelles were prepared from these block copolymers and their morphology and stability examined by dynamic light scattering (DLS), transmission electron microscopy (TEM), and CMC measurements. The stability of micelles was further investigated by measuring the CMC values at higher temper-

ature (60  C) and also from in situ TEM observations of morphological changes of micelles while heating the micelle samples (from room temperature to 200  C). These higher temperature studies have been used to examine the effect of hydrogen bonding and photo-crosslinking on the thermostability of the micelles.
EXPERIMENTAL

Materials All reagents and materials were purchased from SigmaAldrich in the purest form available and used as received. VBT and methylated vinylbenzylthymine (VMT) were synthesized from thymine and vinylbenzyl chloride as described previously.41 Synthesis of VBA In a round bottom flask, vinylbenzylchloride (12.5 mL, 0.08 mol) and triethylamine (12.5 g, 0.125 mol) were dissolved in methanol (15 mL). The reaction mixture was stirred at 30  C overnight. The reaction mixture was then poured into excess of dry ether, which resulted in formation of white solid. The solid was recovered by filtration and the white product is dried under vacuum. The white solid obtained was then recrystallized in 2-propanol. Yield: 99%. 1H NMR: (400 MHz, CDCl3) d1.30 (t, 9H, ACH3), 3.16 (q, J 7.2 Hz, 6H, ANACH2A), 4.46 (s, 2H, ACH2A), 5.38 (d, J 10.8 Hz, 1H, vinyl CAH), 5.95 (d, J 17.2 Hz, 1H, vinyl CAH), 6.798 (dd, J 6.8 Hz, 1H, vinyl CAH), 7.49 (d, J 8 Hz, 2H, aromatic CAH), 7.60 (d, J 8 Hz, 2H, aromatic CAH). Synthesis of Poly(VBT-b-VBA) VBA (1.0 g, 3.94 mmol) was dissolved in 50% (v/v) ethylene glycol/water (10 mL) and TEMPO (62 mg, 0.39 mmol) was added to the solution. The reaction mixture was stirred at 60  C until the TEMPO completely dissolved giving the solution an orange color. Na2S2O5 (50 mg, 0.26 mmol) and K2S2O8 (60 mg, 0.22 mmol) were then added to the solution and stirring continued at 60  C under nitrogen until the reaction mixture became clear. The reaction mixture was then heated at 125  C for 20 h under nitrogen to prepare homo VBA polymer. VBT (0.95 g, 3.94 mmol) was then added to the homo-VBA polymer solution and heating continued for further 24 h at 125  C under nitrogen with stirring. The polymerized product was purified by adding the

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reaction mixture drop wise to acetone (300 mL) while stirring. The resulting solids were collected by filtration and dried under vacuum. Yield: 100%. 1H NMR: (400 MHz, DMSO-d6) d0.801.90 (br, 18H, ANACH2ACH3, ACH3), 4.65 (br, 2H, ACH2A), 6.05 7.80 (br, 8H, aromatic CAH), 11.3 (br, 1H, NAH). IR: mNAH 3421, mC 1684. Mn 1.16 104, Mw/Mn 1.8. O Synthesis of Poly(VMT-b-VBA) Poly(VMT-b-VBA) was synthesized by a similar method as used for synthesis of poly(VBT-b-VBA). Yield: 100%. 1H NMR: (400 MHz, DMSO-d6) d0.702.10 (br, 18H, ANACH2ACH3, ACH3), 3.16 (br, 3H, NACH3) 4.75 (br, 2H, ACH2A), 6.108.30 (br, 8H, aromatic CAH). IR: mNAH 3405, mC 1678. Mn 1.01 104, Mw/Mn 2.4. O Polymer Characterization NMR spectra were taken on a Bruker 400 MHz NMR spectrometer. Molecular weights were determined by gel permeation chromatography (GPC) performed on a Tosoh Ecosec HLC-8320GPC equipped with both refractive index and UV detectors (UV-detection, k 280 nm) using Tosoh alpha 4000 and 2500 columns. Dimethylformamide (DMF) containing LiBr (10 mM) was used as the solvent. Calibration curves were obtained using polystyrene standards. To determine molecular weight of the hydrophilic block poly(VBA), aqueous mobile phase was used (0.5 M aqueous NaBr [80% v/v] containing acetonitrile [20% v/v]). Calibration curves were obtained using polyethylene glycol standards. Micelle Formation A typical block copolymer (0.1 g) in DMSO (10 mL) was transferred through a 0.45-lm filter into a preswollen semipermeable membrane (Spectra/Por, SPEC-TRUM, molecular weight cutoff, 3500) and dialyzed against water (3 L) for 72 h to form a micelle. The dialysate water was exchanged at 2, 5, and 8 h intervals. Micelle Characterization The polymeric micelles were characterized by DLS and TEM. The DLS measurements were performed using a Brookhaven particle size analyzer equipped with a laser operating at a wavelength of 659 nm at 25  C. ZetaPlus particle sizing software version 4.04 was used to calculate the average effective diameter of the micelles. Approximately 1.0 mg mL1 block copolymer micelle solution was filtered and used for the measurement. For the TEM specimen preparations, block copolymer micelle solutions were stained with 0.2% uranyl acetate solution. All the measurements were done above the CMCs. The sample solution was drop cast on a copper TEM grid coated with holey amorphous carbon film. The TEM images were taken using a JEOL 2100F TEM operated at 200 kV. For investigation of stability of micelles at elevated temperature, the micelle samples were heated in situ in JEOL 2100F using a heating holder (Gatan Inc.). The specimens were initially observed at room temperature and then heated up to 200  C with 20  C intervals. At each step, the temperature remained constant for at least 10 min.

Photo-Crosslinking of Micelles A solution of the block copolymer micelles (6.7 mg mL1) was crosslinked in a quartz cuvette by irradiation in a short wave (254 nm) crosslinker (CL-1000 Crosslinker, UVP Ltd.) with 4, 6.5, and 8 J cm2. After photo-crosslinking, the UV absorption spectrum of each solution was obtained using Hitachi U-1800 UV/Vis Spectrophotometer. The absorption spectra were recorded for wavelength range of 220350 nm. Critical Micelle Concentration The CMCs of the copolymers were estimated by fluorescence spectroscopy using the dye Nile Red as a probe. The micellar solutions were diluted to a concentration range of 1.00 105 to 1.00 mg mL1. An acetone solution of nile red (1 mg mL1) was prepared. Approximately 30 lL of dye solution was added to 3 mL of each of the diluted solutions. The acetone was then evaporated from the solutions. The fluorescence was then measured for each solution using a Cary Eclipse Fluorescence Spectrophotometer. The measurements were carried out at 20  C using an excitation wavelength of 550 nm and emission wavelengths in the range 570800 nm. To measure the CMC of the crosslinked micelle, the crosslinked micelle solutions were also diluted to a concentration range of 1.0 105 to 1.0 mg mL1 and fluorescence was measured by the same procedure as the uncrosslinked micelles. The CMC measurements were also carried out at 60  C for poly(VBT-b-VBA) micelles (before and after 8 J cm2 dose of UV radiation) and poly(VMT-bVBA) micelles.
RESULTS AND DISCUSSION

Poly(VBT-b-VBA) and Poly(VMT-b-VBA) Synthesis The thymine-functionalized monomer VBT was synthesized from p-vinylbenzylchloride and thymine in aqueous ethanol as reported previously.46 The amphiphilic block copolymer synthesis was carried out by a TEMPO-mediated living radical polymerization system in a water/ethylene glycol mixture (Scheme 1). It is worth noting that this living radical polymerization system can be carried out as an aqueous mixture, a principle of green chemistry. The use of water also allows the polymerization of VBA without any additional treatment. To achieve the synthesis of the block copolymers, the homopolymer of VBA was prepared first and then VBT was added to the reaction solution to prepare the block copolymer with equal mole ratios. In this manner, poly(VBT-b-VBA) (Mn 1.16 104, Mw/Mn 1.8) was prepared. In addition, 3methyl-1-(4-vinylbenzyl)thymine (VMT) was prepared by methylation of VBT as a surrogate molecule to block the hydrogen bond donating ability of the monomer. The amphiphilic block copolymer of VMT and VBA, poly(VMT-b-VBA) (Mn 1.01 104, Mw/Mn 2.4), was then synthesized to examine the effect of hydrogen bonding on the stability of micelles. The polydispersity values of the block copolymers are high when compared with other TEMPO-mediated living radical polymerizations.54 However, it is worth noting that the polydispersity values obtained are low when compared with previously reported block copolymer synthesis using

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SCHEME 1 Synthesis of amphiphilic block copolymers.

TEMPO-mediated living radical polymerization in aqueous solvent systems.54,55 Polymer structures were characterized by 1H NMR and IR. The molecular weights of the formed block copolymers were measured by GPC in 10 mM LiBrDMF as the mobile phase using polystyrene standards for calibration curves. GPC also confirmed the formation of block copolymer as it showed a single main peak (Fig. 2). The molar ratios of VBT and VBA in the poly(VBT-b-VBA) and those of VMT and VBA in the poly(VMT-b-VBA) were determined by 1H NMR as 1:0.89 and 1:1.17, respectively. Furthermore, the conversion of first monomer VBA resulting in the formation of hydrophilic block poly(VBA) was also characterized to confirm the quantitative consumption of a VBA in the first block segment of block copolymers. A quantitative yield was obtained for the conversion of VBA and molecular weight of the poly(VBA) was determined by GPC using aqueous mobile phase (0.5M aqueous NaBr [80% v/v] containing acetonitrile [20% v/v]) using polyethylene glycol standards for calibration curves (Mn 4.07x 103, Mw/Mn 1.45, [Monomer]0/[Initiator]0 15). Molecular weight of the hydrophilic block using aqueous mobile phase was found to be in the range as expected from the molecular weight of the block copolymers obtained using 10 mM LiBrDMF mobile phase and mole ratios of two monomers in the polymer obtained from 1H NMR.

Block Copolymer Micelle Formation, Characterization, and UV Crosslinking It is known that an amphiphilic block copolymer with a suitable hydrophilic/hydrophobic balance will form micelles in aqueous solution. Dialysis method was used to form polymeric micelles and the size of the block copolymer micelles was analyzed by DLS. Table 1 summarizes the size of the formed block copolymer micelles. Photo-crosslinked micelles were prepared by pouring the micelle solution into a quartz cell and irradiating at 254 nm with 4, 6.5, and 8 J cm2. After each irradiation, the UV spectrum of the micelle solution was measured. The absorbance was observed to reach a maximum value at 272 nm. With increased time of UV exposure, the intensity of the absorption at 272 nm decreased (Fig. 3). It is well known that thymine has an absorption at 270 nm and that this peak decreases as a result of 2p 2p photodimerization. It is clear that the amount of crosslinking is related to the UV irradiation used. After irradiation of the micelle samples at power settings of 4, 6.5, and 8 J cm2, UV spectra (Fig. 3) showed that conversion of thymines to crosslinked product is not complete but at least 17% of the thymines were photodimerized. This suggests that the crosslinking has mostly occurred between the neighboring polymer chains and hence the micellar core is not completely crosslinked. However, the crosslinking of polymers inside the micelle core was enough to enhance the stability of the micelle. DLS measurements were also carried out on crosslinked micellar solutions. DLS results indicate a decrease in the size of micelles upon photo-crosslinking. These results suggest
TABLE 1 Size of Block Copolymer Micelles by DLSa Irradiation (J cm2) 0 4 6.5 8 0 Number Average Diameter (nm) 103 95 87 82 122

Entry 1 2 3 4 5 FIGURE 2 GPC trace of poly(VBT-b-VBA) and poly(VMT-b-VBA) in 10 mM LiBrDMF as the mobile phase.

Polymer poly(VBT-b-VBA) poly(VBT- b-VBA) poly(VBT- b-VBA) poly(VBT-b-VBA) poly(VMT-b-VBA)

a All of the measurement was carried out using 1.0 mg mL1 micelle solution.

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block copolymer micelles proceeds only inside the core and did not change the spherical morphology of the micelles. Furthermore, the in situ heating TEM results indicated differences between the micelle samples when heated up to 200  C (Fig. 5). It was observed that poly(VBT-b-VBA) micelles were stable to heating to 60  C. However, the TEM image of the micelle started to fade when the sample was heated above 60  C. In comparison, the crosslinked poly(VBTb-VBA) micelles were stable even at 200  C, which supports the stability enhancement of the micelles by crosslinking. The higher temperature study indicated that the thermostable property of the micelles can be controlled by the irradiation. CMC Measurements CMC measurements can be used to assess the stability of micelles. A lower CMC value indicates higher stability. The CMCs of the block copolymer micelles were determined by fluorescence measurements in aqueous solution using Nile Red as a probe (see Supporting Information). The CMC is identified as the break point on a plot of fluorescence intensity versus concentration (Fig. 6). Nile Red has a strong fluorescence in a hydrophobic environment, but in a polar environment such as water, fluorescence quenching is greatly enhanced, significantly reducing fluorescence emission. Thus, the CMC can be determined by measuring the concentration point at which the fluorescence emission intensity of Nile Red dye becomes constant. The CMCs of poly(VBT-b-VBA) micelles after UV crosslinking (irradiation doses: 0, 4, 6.5, and 8 J cm2) were also measured to determine the effect of photo-crosslinking on the stability of the micelles. In addition, the CMC of poly(VMT-b-VBA) micelles was measured to examine the effect of hydrogen bonding on the stability of the micelles. Data for the measured CMCs (at 20  C) of the block copolymer micelles are summarized in Table 2. Most significantly, the poly(VMT-b-VBA) micelles, which are incapable of forming self-assembled hydrogen bond dimers in the core because of methylation, have a much higher CMC value when

FIGURE 3 The UV absorption spectra of poly(VBT-b-VBA) micelle solution upon UV exposure with 0, 4, 6.5, and 8 J cm2.

that photo-crosslinking because of photodimerization of thymines between adjacent polymer chains brings the polymer chains closer in the core causing the micelles to shrink in size. Moreover, DLS results show a decrease in the size of micelles, confirming that photo-crosslinking is occurring in the core of the micelles and not between micelles which would have resulted in increase in micelle size. Furthermore, the size remained constant after 8 J cm2 of UV irradiation. This result might be due to the maximum limit of crosslinking reached. Examination of the micelle solution by IR was carried out in an attempt to demonstrate the hydrogen-bonding of thymine units but this was inconclusive because of the many broad peaks around 35003000 cm1 due to ANH bond in thymine. The bright-field TEM images (Fig. 4) of the stained poly(VBTb-VBA) micelles were taken before and after crosslinking. TEM images of the poly(VBT-b-VBA) micelle samples, before and after photo-crosslinking, demonstrated largely spherical objects in the range of 3060 nm. These results also indicate that crosslinking of attached thymine in these

FIGURE 4 Bright-field TEM images of poly(VBT-b-VBA) micelles before and after UV crosslinking (8 J cm2).

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FIGURE 5 Bright-field TEM images of (a) poly(VBT-b-VBA) micelle at room temperature, 60, 100, and 200  C as well as (b) corecrosslinked poly(VBT-b-VBA) micelle at room temperature, 60, 100, and 200  C.

compared with poly(VBT-b-VBA) micelles that are capable of hydrogen bonding in the core. The CMC of poly(VMT-b-VBA) was found to be approximately 80% higher than poly(VBT-bVBA). These observed differences in the CMC values of the poly(VMT-b-VBA) micelles and the poly(VBT-b-VBA) micelles are consistent with a functional role for hydrogen bonding of the thymine units. In addition, these observations confirm that hydrogen bonding of the attached thymines enhances the stability of the block copolymer micelles. The CMC of the poly(VBT-b-VBA) micelles decreases with increased UV irradiation. With 8 J cm2 of UV irradiation, the CMC of the poly(VBT-b-VBA) micelle decreased by approximately 45% when compared with the uncrosslinked sample. The CMC values were also measured at 60  C (Table 3). At 60  C, poly(VMT-b-VBA) micelles have the greatest CMC

value indicating the lowest stability, whereas the crosslinked poly(VBT-b-VBA) micelles had the lowest CMC value indicating highest stability. The CMC of crosslinked poly(VBT-bVBA) micelles measured at 60  C was still low (39 lg mL1) when compared with the CMC of the uncrosslinked micelle (46 lg mL1) consistent with the stability enhancement of the micelles due to crosslinking. Collectively, these results clearly indicate that the stability of the micelles is enhanced by the core-photo-crosslinking of the attached thymines and the stability of the micelles can be modulated by the UV irradiation.
CONCLUSIONS

We have synthesized an amphiphilic block copolymer of VBT and VBA by TEMPO-mediated living radical polymerization and used this novel material to prepare polymeric micelles in aqueous solution. DLS, TEM, and CMC measurements demonstrated that the amphiphilic block copolymers of VBT and VBA can form stability-enhanced self-assembling micelles based on hydrogen bonding of the attached thymines in the core and that this stability can be further
TABLE 2 Critical Micelles Concentration (CMC) of Block Copolymer Micelles at 20 8C Irradiation (J cm2) 0 0 4 6.5 8 CMC at 20  C (lg mL1) 62 35 27 25 19

Entry 1 2 3 FIGURE 6 Fluorescence intensity of Nile Red at its emission maximum versus copolymer concentration. 4 5

Polymer poly(VMT-b-VBA) poly(VBT-b-VBA) poly(VBT-b-VBA) poly(VBT-b-VBA) poly(VBT-b-VBA)

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ARTICLE 15 Adams, M. L.; Lavasanifar, A.; Kwon, G. S. J Pharmaceut Sci 2003, 92, 13431355. 16 Henselwood, F.; Liu, G. Macromolecules 1997, 30, 488493. 17 Savic, R.; Luo, L.; Eisenberg, A.; Maysinger, D. Science 2003, 300, 615618. 18 Kataoka, K.; Matsumoto, T.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Fukushima, S.; Okamoto, K.; Kwon, G. S. J Contr Release 2000, 64, 143153. 19 Gao, Z.; Lukyanov, A. N.; Singhal, A.; Torchilin, V. P. Nano Lett 2002, 2, 979982. 20 Lukyanov, A. N.; Gao, Z.; Torchilin, V. P. J Contr Release 2003, 91, 97102. 21 Nishiyama, N.; Bae, Y.; Miyata, K.; Fukushima, S.; Kataoka, K. Drug Discov Today Tech 2005, 2, 2126. 22 Qiu, L.; Zheng, C.; Jin, Y.; Zhu, K. Expert Opin Ther Pat 2007, 17, 819830. 23 Nishiyama, N.; Kato, Y.; Sugiyama, Y.; Kataoka, K. Pharmaceut Res 2001, 18, 10351041. 24 Nishiyama, N.; Kataoka, K. Pharmacol Therapeut 2006, 112, 630648. 25 Dimitrov, I.; Trzebicka, B.; Muller, A. H. E.; Dworak, A.; Tsve tanov, C. B. Prog Polym Sci 2007, 32, 12751343. 26 Oerlemans, C.; Bult, W.; Bos, M.; Storm, G.; Nijsen, J. F. W.; Hennink, W. E. Pharmaceut Res 2010, 27, 25692589. 27 Bae, Y.; Kataoka, K. Adv Drug Deliv Rev 2009, 61, 768784. 28 Alvarez-Lorenzo, C.; Concheiro, A. Mini Rev Med Chem 2008, 8, 10651074. 29 Jones, M. C.; Leroux, J. C. Eur J Pharmaceut Biopharmaceut 1999, 48, 101111. 30 Haag, R. Angew Chem Int Ed 2004, 43, 278282. 31 Zhang, Y.; Jiang, M.; Zhao, J.; Zhou, J.; Chen, D. Macromolecules 2004, 37, 15371543. 32 Pilon, L. N.; Armes, S. P.; Findlay, P.; Rannard, S. P. Langmuir 2005, 21, 38083813. 33 Pilon, L. N.; Armes, S. P.; Findlay, P.; Rannard, S. P. Eur Polym J 2006, 42, 14871498. 34 Jiang, X.; Luo, S.; Armes, S. P.; Shi, W.; Liu, S. Macromolecules 2006, 39, 59875994. 35 Liu, S.; Armes, S. P. J Am Chem Soc 2001, 123, 9910 9911. 36 Butun, V.; Wang, X. S.; de Paz Banez, M. V.; Robinson, K. L.; Billingham, N. C.; Armes, S. P.; Tuzar, Z. Macromolecules 1999, 33, 13. 37 Bronich, T. K.; Keifer, P. A.; Shlyakhtenko, L. S.; Kabanov, A. V. J Am Chem Soc 2005, 127, 82368237. 38 Wang, G.; Henselwood, F.; Liu, G. Langmuir 1998, 14, 15541559. 39 Tao, J.; Stewart, S.; Liu, G.; Yang, M. Macromolecules 1997, 30, 27382745. 40 Chen, Y.; Tavakley, A. E.; Mathiason, T. M.; Taton, T. A. J Polym Sci Part A Polym Chem 2006, 44, 26042614. 41 Saito, K.; Ingalls, L. R.; Lee, J.; Warner, J. C. Chem Commun 2007, 25032505. 42 Saito, K.; Warner, J. C. Green Chem Lett Rev 2009, 2, 7176. 43 Tazuke, S.; Takasaki, R. J Polym Sci Polym Chem Ed 1983, 21, 15291534. 44 Cannon, A. S.; Warner, J. C. J Macromol Sci Pure Appl Chem 2005, 42A, 15071514. 45 Martino, D. M.; Reyna, D.; Estenoz, D. A.; Trakhtenberg, S.; Warner, J. C. J Phys Chem A 2008, 112, 47864792.

TABLE 3 Critical Micelles Concentration (CMC) of Block Copolymer Micelles at 60 8C Irradiation (J cm2) 0 0 8 CMC (lg mL1) 93 46 39

Entry 1 2 5

Polymer poly(VMT-b-VBA) poly(VBT-b-VBA) poly(VBT-b-VBA)

controlled by core-photo-crosslinking of the attached thymines. As such, polymeric micelles obtained from poly(VBTb-VBA) have the potential to allow the encapsulation of guest materials by hydrogen bonding due to the attached thymines in the core. Furthermore, the control of the CMC of the block copolymer micelles by UV photo-crosslinking provides a new opportunity for the controlled release of materials encapsulated in the micelles. Thus, based on a bioinspired mechanism, these investigations provide a novel approach for the design and use of stable and controllable nano micelles.
ACKNOWLEDGMENT

This work was supported by Monash University Faculty of Science Early Career Research Fund and Australian Research Council. The authors thank Roy Jackson, Tony Patti, and Warwick Raverty for fruitful discussions, and Monash Centre for Electron Microscopy for providing access to the JEOL 2100F TEM.

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