Miktoarm Star Copolymer Capsules Bearing pH-Responsive

Article pubs.acs.org/Macromolecules

Miktoarm Star Copolymer Capsules Bearing pH-Responsive Nanochannels Heng Hu and Guojun Liu* Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, Canada K7L 3N6 S Supporting Information *

ABSTRACT: Despite the diversity of nanostructures that have been created from block copolymers over the past two decades, the challenging fabrication of polymer nanocapsules bearing regularly sized nanochannels has not been possible until now. In this study, a pseudo miktoarm copolymer μ(PtBA)(PCEMA)(PEO)1.14 was prepared. The copolymer consisted of 1 poly(tert-butyl acrylate) (PtBA) chain, 1 poly(2-cinnamoyloxyethyl methacrylate) (PCEMA) chain, and an average 1.14 poly(ethylene oxide) (PEO) chains. This polymer formed vesicles in a tetrahydrofuran/water solvent mixture with the soluble PEO block as the corona. At 100 units long, the PtBA chains formed cylinders that permeated the wall made of PCEMA chains at 130 units long. Photo-cross-linking the PCEMA wall and hydrolyzing the PtBA chains in the cylindrical domains yielded unprecedented capsules bearing regularly packed uniform poly(acrylic acid)-gated nanochannels. These capsules exhibited pH-responsive reagent release in aqueous media.

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INTRODUCTION Capsules can separate reagents of interest from their surroundings. Drugs, fertilizers, fragrances, and hormones are encapsulated to control the time, location, and rate of their release.1−3 Encapsulation is also used to regulate the rate and outcome of chemical reactions.4 Capsules in the form of vesicles or polymersomes can be selfassembled in water from amphiphilic diblock copolymers that incorporate a hydrophilic block and a hydrophobic block.5−18 In a vesicle, the hydrophobic block forms the wall and the hydrophilic block stretches into water from both the inner and outer walls.19,20 The regulation of reagent transport across the polymersome walls is critical for many applications. For this purpose, a transmembrane protein has, for example, been incorporated into the walls of polymersomes.20,21 More traditional approaches have involved using a stimuli-responsive polymer block to form the polymersome walls.2,22 These polymers changed their degree of swelling,23 integrity,24 or conformation25 upon exposure to light, heat, a magnetic field, or a chemical. However, polymer capsules bearing uniform pores with diameters potentially ranging between one and tens of nanometers have not been reported. Large pores increase the solvent flux, which has been shown to facilitate the application of encapsulated paramagnetic species in magnetic resonance imaging.26 Regularly sized nanochannels should also facilitate size-selective transport of reagents such as proteins with sizes in the nanometer range. Therefore, this report describes the preparation of capsules that bear permeating uniform nanochannels gated by pH-responsive polymer chains. © 2014 American Chemical Society

The capsules were prepared from a pseudo miktoarm star copolymer μ-(PtBA)(PCEMA)(PEO)1.14. This copolymer incorporated 1 poly(tert-butyl acrylate) (PtBA) chain, 1 poly(2-cinnamoyloxyethyl methacrylate) (PCEMA) chain, and an average of 1.14 poly(ethylene oxide) (PEO) chains. This sample was prepared from a modular “association-andreaction” approach (Scheme 1a). First, a linear triblock copolymer PtBA-b-PCOOH-b-PCEMA and a diblock copolymer PEO-b-PNH2 were prepared, where b denoted block, while PCOOH and PNH2 were carboxyl- and amine-bearing blocks that were each five units long. In addition, the repeat unit numbers of the PtBA, PCEMA, and PEO blocks were 100, 130, and 114, respectively. In the second step, the triblock and diblock copolymer precursors were mixed to facilitate the association of the PCOOH and PNH2 blocks. The associated dimers or trimers were covalently linked in the third step via the amidation of PCOOH and PNH2. A pseudo miktoarm star copolymer was prepared because a traditional μ-(PtBA)(PCEMA)(PEO) sample with a precisely defined composition is challenging to synthesize. Additionally, PCOOH and PNH2 blocks rather than single carboxyl and amino groups were used because the attractive force between a single pair of carboxyl and amino groups was insufficient to bring the different chains together. Received: May 27, 2014 Revised: July 16, 2014 Published: July 31, 2014 5096

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Scheme 1. (a) Preparation of a μ-(PtBA)(PCEMA)(PEO) Molecule by the “Association-and-Reaction” Strategy and (b) Preparation of Vesicles Permeated by pH-Responsive Nanochannelsa

a From 1 → 2, μ-(PtBA)(PCEMA)(PEO)1.14 self-assembles into a vesicle with PtBA and PCEMA forming the wall and PEO stretching into the solvent phases. The vesicular walls consist of a PCEMA matrix that is permeated by PtBA cylinders. The PCEMA matrix is then photo-cross-linked (2 → 3). The cleavage of the tert-butyl groups from the PtBA phase yields nanochannels that are gated by pH-responsive PAA chains (3 → 4). In acidic media, these PAA chains are H-bonded and assume compact conformations. For example, these chains may form gelled rings that gate the nanochannels (4′). In basic media, the PAA chains expand and may escape from the nanochannels due to entropy gain (4″).

Scheme 2. Synthetic Pathway for PtBA-b-PCOOH-b-PCEMA

To prepare the targeted capsules, vesicles were prepared first (1 → 2, Scheme 1b). This involved dissolving μ-(PtBA)(PCEMA)(PEO)1.14 in tetrahydrofuran (THF) and then slowly

adding water. In this water-rich solvent mixture, only the PEG chains were soluble, and thus the insoluble PtBA and PCEMA chains formed the vesicular walls (Scheme 1b, 1 → 2). Since 5097

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Scheme 3. Synthetic Pathway toward PEO-b-PNH2

PtBA-b-PCOOH-b-PCEMA determined from SEC based on polystyrene standards using DMF containing tetrabutylammonium bromide (5 mg/mL) as the eluent was 58 kg/mol, which compared well with the design molecular weight of 48 kg/mol. Further, the polydispersity index of the sample was low at 1.05. The required diblock copolymer PEO-b-PNH2 sample was prepared using a commercial precursor: poly(ethylene oxide) monomethyl ether, PEO-OH. The reactions leading to PEO-bPNH2 are depicted in Scheme 3. First, PEO-OH with a number-average molar mass of 5.0 kg/mol was reacted with 2bromopropionyl bromide to produce a macroinitiator PEOBr.30 PEO-Br was then used to grow an average of 5 HEA-TMS (2-trimethylsiloxyethyl acrylate) units by atom transfer radical polymerization (ATRP).31 The TMS protecting groups were subsequently removed under acidic conditions, and the resultant hydroxyl groups in the poly(2-hydroxyethyl acrylate), PHEA, block were further reacted with N-carbobenzyloxyglycine (Z-glycine) to yield a P(HEA-GlyCbz) block. The cleavage of the carbobenzyl group yielded PEO-b-PNH2. The sample at different derivatization stages was carefully characterized by NMR and SEC, and the detailed results are reported in the Supporting Information. In summary, the average repeat units for the PNH2 block was 5, and the polydispersity index was low at 1.04 for the final PEO-b-PNH2 sample. To prepare μ-(PtBA)(PCEMA)(PEO)1.14, PEO-b-PNH2 and PtBA-b-PCOOH-b-PCEMA at a molar ratio of 2.0/1.0 were stirred in THF for 2 h to associate the polymers32 before 2chloro-1-methylpyridinium iodide and triethylamine33,34 were added to covalently couple the different chains. While 2-chloro1-methylpyridinium iodide served as a coupling agent, triethylamine neutralized HCl or HI generated during the reaction. After 6 h, THF was removed by rota-evaporation, and the resultant solid residues were extracted with water to remove unreacted PEO-b-PNH2. Figure 1 compares the SEC traces of PEO-b-PNH2, PtBA-bPCOOH-b-PCEMA, a coupling product of the former two before and after its purification by water extraction. The SEC trace of the crude product evidently contained a peak

the PtBA volume fraction was 30%, PtBA formed cylinders that permeated their surrounding PCEMA matrix. During the next step, the vesicles were photolyzed by UV light to cross-link the PCEMA matrix to yield permanent capsules (2 → 3). The cleavage of the tert-butyl groups from the PtBA phase in the fourth step yielded nanochannels that were “gated” by the pHresponsive poly(acrylic acid) (PAA) chains (3 → 4). These PAA chains most likely gated the entrances rather than stayed confined within the nanochannels because of translational entropy gain associated with their escape from the channels.

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RESULTS AND DISCUSSION Polymer Synthesis and Characterization. The triblock copolymer PtBA-b-PCOOH-b-PCEMA required for μ-(PtBA)(PCEMA)(PEO)1.14 synthesis was prepared in five steps (Scheme 2). First, PtBA-b-P(HEMA-tBDMS)-b-P(HEMATMS) was prepared via anionic polymerization, where P(HEMA-tBDMS) and P(HEMA-TMS) denote poly[2-(tertbutyldimethylsiloxy)ethyl methacrylate] and poly[2(trimethylsiloxy)ethyl methacrylate], respectively. Since P(HEMA-tBDMS) was more stable than P(HEMA-TMS),27−29 the TMS protecting groups were selectively removed in step 2 (Scheme S1) to yield PtBA-b-P(HEMA-tBDMS)-b-PHEMA, where PHEMA denotes poly(2-hydroxyethyl methacrylate). The PHEMA block was then reacted with cinnamoyl chloride in step 3 to yield a PCEMA block. This was followed by the cleavage of the tBDMS protecting groups in step 4 to yield PtBA-b-PHEMA-b-PCEMA. The reaction of the PHEMA block with succinic anhydride in step 5 yielded PtBA-b-PCOOH-bPCEMA. The triblock copolymer at different derivatization steps was carefully characterized by 1H NMR and size-exclusion chromatography (SEC), and these results are summarized and discussed in the Supporting Information. For anionic polymerization, the targeted repeat unit numbers for tBA, HEMA-tBDMS, and HEMA-TMS were 100, 5, and 130, respectively. These molar ratios agreed well with those that we determined experimentally from 1H NMR (Supporting Information). The number-averaged molecular weight of 5098

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f and g peaks, we calculated an average number of PEO chains per star copolymer of 1.14. Vesicle Formation. μ-(PtBA)(PCEMA)(PEO)1.14 was dissolved in THF, and water was then slowly added until the water volume fraction f H2O reached 80% to enable vesicle formation. The formed vesicles were aero-sprayed (as a liquid that was atomized into a fog to accelerate solvent evaporation35) onto nitrocellulose-covered copper grids and then stained with OsO4 vapor for transmission electron microscopic (TEM) analysis. Prior to atomic force microscopic (AFM) analysis, a vesicle solution was photolyzed to cross-link the PCEMA matrix until a double bond conversion of ∼20% was achieved.36 The structurally locked particles were then aero-sprayed onto a freshly cleft mica surface and dried. Figure 3a shows a TEM image of an un-cross-linked μ-(PtBA)(PCEMA)(PEO)1.14 vesicular specimen, while Figure 4a,b shows AFM topography and phase images of these vesicles after they had been cross-linked. The microscopic images of Figures 3 and 4 suggested that the particles with diameters greater than 50 nm were most likely vesicles. First, the cross-linked particles were round, as revealed by the AFM topography image in Figure 4a. Second, the particles were not solid but hollow as revealed by the TEM image in Figure 3a. If the particles were solid, the electron path length through the polymer would have increased from the edge to the center of the particles. Thus, the TEM images of solid particles would have appeared darker at their centers than at their edges. This trend was not seen in Figure 3a. Rather, some particles had centers that were lighter than their edges. As is fully explained in the Supporting Information, the particles with a light “crater” in the center likely corresponded to partially collapsed vesicles. The most striking observations were the light circles of a diameter of 9 ± 2 nm and light stripes of a similar width in Figure 3a and the circular dark domains with a diameter of ∼10 nm in the AFM phase image of Figure 4b. The light circles in Figure 3a (e.g., the regions marked by red circles) are likely projections of the unstained standing PtBA cylinders (lying along the TEM beam direction) dispersed in a stained PCEMA wall. We believe that the stripes at the edges of the particles (e.g., the regions marked by red arrows) are projections of PtBA domains that were lying horizontally or perpendicular to the TEM beam. The ends of these PtBA cylinders appeared as dark circular domains in the AFM images because the PEO layer was thin and could not dampen the viscoelastic effects of the underlying PCEMA and PtBA domains probed by AFM tip in the tapping mode. These results support the chain packing motif illustrated in structure 2 of Scheme 1b. This kind of chain packing motif should not be surprising because it has been theoretically shown to exist37 and has been observed previously for a different family of μ-(PA)(PB)(PC) copolymers.27,38,39 The cross-linked vesicles were also characterized by dynamic light scattering after their solution in THF/water was dialyzed against water to change the solvent completely to water, whose refractive index and viscosity were accurately known for DLS data analysis. At a scattering angle of 90°, the measured hydrodynamic diameter dh and polydispersity K12/K2 values were 188 nm and 0.169, respectively. Capsule Preparation and Loading. The cross-linked vesicles were stirred with trifluoroacetic acid for 12 h to hydrolyze the PtBA chains, thus generating nanocapsules with permeating nanochannels (3 → 4, Scheme 1b). The selectivity

Figure 1. SEC traces of (a) PtBA-b-PCOOH-b-PCEMA, (b) PEO-bPNH2, and μ-(PtBA)(PCEMA)(PEO)1.14 (c) before and (d) after water extraction.

corresponding to PEO-b-PNH2 and a peak at 20.75 min corresponding to an impurity in the original PEO-OH sample. However, the peaks corresponding to PEO-b-PNH2 and its impurity disappeared after the crude product was extracted with water. The purified μ-(PtBA)(PCEMA)(PEO)1.14 sample exhibited a main SEC peak and a small shoulder. The PS-equivalent peak molar masses of the two were 76 and 156 kg/mol, respectively. The polydispersity index of the main peak including the shoulder was 1.11. The μ-(PtBA)(PCEMA)(PEO)1.14 main peak was wider than the PtBA-b-PCOOH-b-PCEMA peak because the former contained contributions from PtBA-bPCOOH-b-PCEMA, μ-(PtBA)(PCEMA)(PEO), and μ(PtBA)(PCEMA)(PEO)2, etc. We suspect that the shoulder peak corresponded to trimer μ-(PtBA)2(PCEMA)2(PEO) which was formed from the coupling of two PtBA-bPCOOH-b-PCEMA chains with one PEO-b-PNH2 chain. Since the relative content of the shoulder component was low, we did not purify the sample further to eliminate it. Figure 2 shows a 1H NMR spectrum of the purified μ(PtBA)(PCEMA)(PEO)1.14 sample in CDCl3. By comparing the integration ratios between the protons of the l peak and the

Figure 2. 1H NMR spectrum of μ-(PtBA)(PCEMA)(PEO)1.14 together with peak assignments for the different protons. 5099

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Figure 3. TEM images of (a) a μ-(PtBA)(PCEMA)(PEO)1.14 vesicle sample and (b) a capsular sample that was loaded with PEG45-Py. The first sample was aero-sprayed from THF/water at f H2O = 80%, and the second sample was aero-sprayed from an aqueous solution at pH = 2.85. The dried specimens were stained by OsO4 vapor.

[PEO45−Py] in the rinsing liquids decreased rapidly in the initial four rinsing cycles (Figure S10). After this stage, [PEO45−Py] in the rinsing liquid remained low and constant. These data suggested that most of the external PEO45−Py was removed during the initial four rinsing cycles. To determine the amount of PEO45−Py that remained in a capsular sample after it had been rinsed five times with aqueous HCl (pH = 2.85), a PEO45−Py-loaded capsule sample was dried, weighed, and stirred overnight in a basic aqueous solution that gave a final pH of 11.23. The Py absorbance of this solution at 342 nm was subsequently measured. Using the absorbance value, the measured sample weight, and a molar extinction coefficient ε of 3.5 × 104 M−1 cm−1 that we measured for dilute aqueous PEO 45−Py solutions, we determined a weight fraction or loading density of 31 wt % for PEO45−Py in the capsule/PEO45−Py sample. This value contrasted with the low loading density of 1.3 wt% that we determined for a control sample that was treated identically but contained no hydrolyzed PtBA nanochannels, thus suggesting the necessity of the nanochannels for effective capsule loading. This capsular sample that has been loaded with PEO45−Py and rinsed was then redispersed into water, immediately aerosprayed onto a nitrocellulose-coated TEM grid, and stained with OsO4 vapor for TEM analysis. Figure 3b shows a TEM image of a specimen prepared in this manner. The TEM image of Figure 3b appears clearly different from that shown in Figure 3a. While block separation could be discerned on the particles in Figure 3a, the centers of the particles in Figure 3b were dark, suggesting that electrons encountered a long path length of organic matter while crossing these regions. This was possible because the capsules were heavily loaded with PEO45−Py. pH-Responsive PEO45−Py Release. The Py groups of the loaded PEO45−Py at a high local concentration should readily form excimers and exhibit a low monomeric emission.43−45 We further discovered that both the monomer and excimer fluorescence of nonencapsulated PEO45−Py was effectively quenched by PCEMA in the THF solution (Supporting Information).40 Therefore, this dual action due to excimer formation and fluorescence quenching by the PCEMA wall should result in a low quantum yield in monomeric Py fluorescence for the encapsulated PEO45−Py chains. However, the Py monomeric fluorescence intensity I(t) should increase after PEO45−Py had been released from the capsules provided

and quantitative nature of this chemistry under our reaction conditions have been demonstrated previously for other systems and were confirmed in this case by our Fourier transfer infrared analysis of the capsules before and after their treatment by trifluoroacetic acid.40 The PtBA-hydrolyzed capsules were then aero-sprayed from water onto a freshly cleft mica plate and characterized by AFM. Figure 4c shows an AFM height image of the capsules. While the PtBA domains were barely noticeable in the height image of the cross-linked vesicles shown in Figure 4a, dimples were clearly visible on the PtBA-hydrolyzed capsules and especially on the capsules marked by the red arrows in Figure 4c. These dimples had a similar size and packing symmetry to the circular domains seen in Figure 4b. Therefore, the dimples must have been due to the formation of nanochannels after PtBA hydrolysis. It is also noteworthy that the capsules in Figure 4c were not as round as the cross-linked vesicles seen in Figure 4a. This difference may have been because the nanochannel-bearing capsules were more prone to deformation than their precursor bearing solid walls. PEO chains consisting of 45 repeat units and bearing one terminal hydroxyl group were end-tagged with pyrene butyric acid to yield PEO45−Py, which was then loaded into the nanochannel-bearing capsules (Supporting Information). To load the capsules, methanol was slowly evaporated over 5 days from a concentrated PEO45−Py solution that was equilibrated with these capsules. We speculated that PEO45−Py entered the capsules in order to even out the PEO45−Py concentration across the capsular wall. To remove PEO45−Py that was not loaded into the capsules, we vortexed the clay-like dye/capsule mixture for 20 s with an aqueous HCl solution at pH = 2.85 and then centrifuged the mixture to settle the capsules before decanting the supernatant containing solubilized PEO45−Py chains. An acidic solution was used for this separation because the PAA chains are known to be less soluble and assume compact conformations in acidic media.35,41 Furthermore, we have previously tested reagent permeation across PAA-lined nanochannels in diblock copolymer films that were micrometers thick and discovered that reagent permeation rate was the lowest at pH ≈ 3.42 The effectiveness of the rinsing protocol was monitored by measuring the UV absorbance of PEO45−Py in the separated supernatant after each rinsing step. In one experiment, 5100

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Figure 4. AFM (a) topography and (b) phase images of cross-linked μ-(PtBA)(PCEMA)(PEO)1.14 vesicles and (c) an AFM topography image of μ(PtBA)(PCEMA)(PEO)1.14 nanocapsules after PtBA hydrolysis. The samples were aero-sprayed onto mica surfaces and dried before viewing.

that the released PEO45−Py amount was low to avoid Py excimer formation or PEO45−Py micellization in the bulk phase. Therefore, monitoring changes in I(t) should allow us to follow the PEO45−Py release. We performed a control experiment to demonstrate that the PEO45−Py monomeric fluorescence intensity of a dilute aqueous PEO45−Py solution was independent of pH. We next excited PEO45−Py at 342 nm and monitored I(t) variation at 375 nm as a function of time for several PEO45−Py-loaded capsular samples after they had been dispersed into dilute HCl or NaOH solutions that gave the final pH values of 2.85, 6.76, and 9.98. These results are shown in Figure 5. In every case, the PEO45−Py monomeric fluorescence intensity initially increased rapidly with time and then plateaued. We fitted the I(t) data of Figure 5 using a phenomenological equation: I(t ) = I∞ − I1 exp( −k1t ) − I2 exp( −k 2t )

where I∞ denotes the plateaued fluorescence intensity, while k1 and k2 are the rate constants at which the corresponding fluorescence intensity components I1 and I2 grow. The resultant k1, I1, k2, I2, and I∞ values were then employed to calculate the average rate constant ⟨k⟩ using eq 2: ⟨k⟩ = (I1 × k1 + I2 × k 2)/(I1 + I2)

(2)

and the final to initial fluorescence intensity ratio using I∞/(I∞ − I1 − I2). While the ⟨k⟩ values were 2.37 × 10−3, 10.3 × 10−3, and 16.7 × 10−3 s−1 at pH = 2.85, 6.76, and 9.98, respectively, the corresponding I∞/(I∞ − I1 − I2) values were 4.5, 13.4, and 13.6. Thus, both the rate and extent of PEO45−Py release increased with increasing pH. In another experiment, a PEO45−Py-loaded capsule sample was initially dispersed into water at pH = 2.85 to trigger an initial I(t) increase. After the I(t) had plateaued, NaOH was added to increase the solution pH to 11.23. This triggered another increase in I(t). This set of results provided further

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ASSOCIATED CONTENT

S Supporting Information *

Experimental details; characterization results for PEO45−Py; absorbance and fluorescence intensity increase with PEO45−Py concentration. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (G.L.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS NSERC of Canada is gratefully acknowledged for financially sponsoring this research. Dr. Ian Wyman is thanked for proofreading the manuscript. G.L. thanks the CRC program of Canada for a Tier I Canada Research Chair in Materials Science.

Figure 5. Variations in the Py monomeric fluorescence intensity as a function of time after PEO45−Py-loaded capsules had been dispersed into HCl or NaOH solutions that reached final solution pH values of 2.85, 6.76, and 9.98. Also shown are the data for a sample with an initial pH of 2.85 that was adjusted to a final value of 11.23 via the addition of NaOH. The green solid curves represent the best fits by eq 1 to the experimental data.

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confirmation that base addition enhanced the release of PEO45−Py from the capsules. The higher rate and extent of PEO45−Py release under more basic conditions were presumably due to the reduced gating effect of the PAA chains under these conditions. At low pH values, the PAA chains were H-bonded41,45 and formed a compact structure that apparently guarded or partially blocked the nanochannels. Such a structure could, for example, be the “gelled PAA rings” depicted as structure 4′ in Scheme 1b. Partial blockage of the channels should impede PEO45−Py release in general. More importantly, it might completely stop the release of the high-molecular-weight fraction of the PEO45− Py chains, reducing the extent of PEO45−Py release. These gates were more widely opened in basic media, leading to faster and more complete release of PEO45−Py.

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CONCLUSIONS In summary, we have prepared vesicles via a double assembly strategy. At the tier I level, we assembled PtBA-b-PCOOH-bPCEMA and PEO-b-PNH2 together through the binding of their PCOOH and PNH2 blocks and performed amidation to the assembled molecular architectures to yield μ-(PtBA)(PCEMA)(PEO)1.14. The resultant architectural copolymer was then used as a building block to form vesicles as the product of a tier II assembly. In the vesicles, PCEMA formed the walls, which were permeated by PtBA cylinders. The PCEMA phase in the vesicular walls was then photo-cross-linked, and the PtBA domains were hydrolyzed to yield an unprecedented nanostructure, capsules that were permeated by regularly sized PAAgated nanochannels. The nanochannels allowed the loading of the capsules by PEO45−Py up to 31 wt %. The loaded PEO45− Py chains exhibited a low Py monomer fluorescence emission intensity. After they had been released, their emission intensity increased. This increase in the pyrene monomer fluorescence intensity with time allowed us to monitor the PEO45−Py release under different conditions. The rate and extent of PEO45−Py release could be regulated by changing the pH of the surrounding aqueous solution, and this release was enhanced under basic conditions. Future generations of this type of novel capsules may have applications for pH-controlled release or size-selective release of drugs or reagents. 5102

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dx.doi.org/10.1021/ma501099f | Macromolecules 2014, 47, 5096−5103