Article pubs.acs.org/Macromolecules
Autocatalytic Self-Sorting in Biomimetic Polymer Kaiyi Zhou, Hui Cao, Pan Gao, Zhigang Cui, Yi Ding, and Yuanli Cai* State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China S Supporting Information *
ABSTRACT: Autocatalytic self-sorting in the biomimetic poly(cystamine methacrylamide hydrochloride) (PCysMA) is presented, whose units comprise lysine-mimetic alkylammonium ions and cystine-mimetic alkyl disulfide spacers. The block copolymer with poly(2-hydroxypropylmethacrylamide) was synthesized directly by RAFT in acidic water under visible light irradiation at 25 °C. Disulfide exchange can be initiated by the terminal thiolates as generated by alkalization-induced aminolysis. 65−67% CysMA units sort into hydrophobic polymer disulfides and water-soluble cystamine at pH 10.5. Moreover, intermediate reactions occur in the presence of copper ions, i.e., Cu(II)−NH2 coordination, aminolysis, NH2-to-SH substitution, and cupric-to-cuprous reduction in metal centers, thus autocatalytic self-sorting with essentially 100% conversion at pH 8.8. UV−vis spectroscopy, 1H NMR, atomic absorption spectroscopy, and elemental analysis confirmed this ideal self-sorting. Dynamic light scattering and atomic force microscopy identified supramolecular-to-supracolloidal self-assembly with concomitant release of cystamine molecules and intermediate cuprous complexes. Such a self-sorting underlines an amazing prospect for the use of a single polymer to achieve artificial reaction complexity, hierarchy, and metabolic process, with minimal synthetic efforts.
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INTRODUCTION Hierarchical supramolecular-to-supracolloidal (using colloids as building blocks)1−4 assembly is of considerable interest in the nanotechnology and synthetic biology fields.5,6 Substantial breakthroughs have been made with the aid of dynamic covalent chemistry (DCC)7,8 based on molecular recognition.9,10 Various architectures were achieved in the multicomponent systems known as dynamic combinatorial libraries (DCLs).11−14 Nitschke15−19 and other research groups20 illustrated that simple compounds could sort into exquisite architectures by subcomponent self-assembly via dynamic covalent bonds and metal coordination. Nanocages, capsules, and knots that are inaccessible via traditional organic synthesis can be achieved by self-sorting from multicomponent systems.21,22 Huang23−26 and Zhang27 demonstrated the effectiveness of self-sorting organization to prepare supramolecular polymers. Weck28 and Sijbesma29,30 proposed selfsorting in synthetic polymers based on competitive hydrogen bonding. However, self-sorting organization in polymeric reaction systems in aqueous media is far from understood in particular for those akin to hierarchical self-sorting functions in natural polymers such as proteins. Recent research attention has been paid to reversible (non)covalent chemistry of polypeptides and the analogues, through which a range of nanostructures with adaptive and selfhealing properties were achieved.31−33 Giuseppone34 reported the facile access to dynamic covalent peptides via reversible native chemical ligation. Wu35 used orthogonal cysteine− © XXXX American Chemical Society
penicillamine disulfide pairing to direct the oxidative folding of peptides. As recognition subunits in proteins, amino acid residues mediate physicochemical properties with the aids of dynamic covalent bonds. Actually, self-sorting via dynamic covalent bonds is ubiquitous in natural proteins. Therefore, it is likely to be a good starting point to use peptide-mimetics to achieve hierarchical self-sorting in aqueous medium. Herein, we report autocatalytic self-sorting in a biomimetic polymer in aqueous medium. To this end, poly(2-hydroxypropylmethacrylamide)-block-poly(cystamine methacrylamide hydrochloride) (PHPMA-b-PCysMA) was synthesized by RAFT36,37 in acidic water under visible light irradiation at 25 °C.38 The hydrophilic PHPMA block39,40 served as steric stabilizer of the reaction domains. The CysMA units comprises lysine-mimetic alkylammonium ions and cystine-mimetic alkyl disulfide spacers (Scheme 1). Disulfide reaction is highly popular in DCLs, as pioneered by Lehn,9 Sanders,11 Ott,10,13,14 Scheme 1. Biomimetic CysMA Unit in Combination of Peptide Cysteine and Lysine Residues
Received: January 22, 2016 Revised: February 22, 2016
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DOI: 10.1021/acs.macromol.6b00152 Macromolecules XXXX, XXX, XXX−XXX
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Figure 1. (a) UV−vis spectra of the solutions after stirred at different pH values at 25 °C for 24 h. (b) Time-dependent evolution of UV−vis spectrum at pH 6.6. λCEP is characteristic absorption wavelength of 4-cyano-4-ethylsulfanylthiocarbonylsulfanylpentanoic acid (CEP) chain-ends.
Rowan,7 and other research teams.8,12 Alkalization in the presence of copper ions can induce the NH3+-to-NH2 transition and Cu(II)−NH2 coordination.41−43 Moreover, the terminal thiolates can be achieved by aminolysis of RAFT chainends,44−46 which promote the NH2-to-SH substitution and cupric-to-cuprous reduction in metal binding sites, thus bringing about autocatalytic disulfide exchange.47,48 Most recently, we38 accomplished thiol-functionalization of PCysMA in acidic water in argon by means of reduction with dithiothreitol, which could assemble into various nanostructures through ionization/oxidization upon alkalization in air. According to above-mentioned reactivity, we anticipated that the reaction complexity, hierarchy, and metabolism could be achieved by self-sorting in this reactive block. The reaction and self-sorting organization in the absence and presence of copper ions were studied using UV−vis spectroscopy, 1H NMR, elemental analysis, atomic absorption spectroscopy, aqueous electrophoresis, dynamic light scattering (DLS), and atomic force microscopy (AFM).
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hydrodynamic diameter (Dh) and the dispersity (μ2/Γ2) of nanoparticles were determined using cumulants analysis in CONTIN routine. These results were averaged over three runs, and each was collected for 30 min. Atomic force microscopy (AFM) was performed on a Bruker Multimode 8 microscope using a SCANASYST-AIR probe in a peak force quantitative nanomechanical scan mode. Silicon wafer was immersed into the mixture of 98% H2SO4 and 35% H2O2 (7:3, v/v) for 1 h and rinsed with deionized water. The reaction solution was diluted to 0.10 mg mL−1, cast on silicon wafer, frozen immediately in liquid nitrogen, and lyophilized under reduced pressure for AFM. Aqueous electrophoresis was used to determine zeta potential (ξ) parameter of nanoparticles, which was performed on a Malvern Zetasizer Nano-ZS90 instrument. UV−vis spectroscopy was conducted on a Shimadzu UV-3600 UV− vis spectrometer. Elemental analysis was conducted on ELEMENTAR Analysensysteme elemental analyzer. Atomic absorption spectroscopy of the samples before and after reaction was carried out using an AA-Duo 220FS 220Z atomic absorption spectrometer. Acid−base titration was conducted using a TOLEDO FE-20 digital pH-meter.
EXPERIMENTAL SECTION
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Materials. Details for synthesis and characterization of PHPMA107b-PCysMA80 are described in the Supporting Information and Figure S1. CuCl2·2H2O (99.999%) was obtained from Aladdin; deuterium oxide (D2O, 99.8% D), deutero-chloric acid (DCl, 99.5% D, 20% in D2O), and sodium deuteroxide (NaOD, 99.5% D, 40% in D2O) were purchased from J&K; these agents were used as received. Deionized water (R > 18.2 MΩ/cm) was used for the synthesis and characterization. Methods. 1H NMR spectroscopy was conducted on an INOVA 400 MHz NMR instrument at 25 °C. The copolymer (25.0 mg, 55.76 μmol of CysMA units) was dissolved in D2O (25 mL) in a 25 mL flask. The solution was divided into 10 aliquots. Each was adjusted to the predetermined pH using DCl and NaOD, stirred at 25 °C for 24 h, and shifted to a NMR tube for 1H NMR analysis. Typically, the effect of coordination on reaction was studied as follows. CuCl2·2H2O (2.4 mg in 5.0 mL of D2O, 13.94 μmol) was dissolved in copolymer solution (25.0 mg in 20.0 mL of D2O, 55.76 μmol of CysMA units). This solution was divided into 10 aliquots and adjusted to different pH values. Each solution was stirred at 25 °C for 24 h and then shifted to a NMR tube for 1H NMR analysis. Dynamic light scattering (DLS) was conducted on a Brookhaven BI-200SM setup fitted with 22 mW He−Ne laser (λem = 633 nm), BI200SM goniometer, and BI-Turbocorr digital correlator. The solution (1.0 mg mL−1 polymer in water) was filtered using a 0.45 μm filter and adjusted to the predetermined pH. The reaction solution was shifted to a DLS cuvette and maintained at 25 ± 0.02 °C using a BI-TCD controller. Phase transition was monitored by tracking the variation of light scattering intensity at an angle of 90°. The intensity-average
RESULTS AND DISCUSSION Synthesis of PHPMA-b-PCysMA. This block copolymer was synthesized directly via RAFT in acidic water at pH 3.5 under visible light irradiation at 25 °C.38 Our previous results demonstrated that weak visible light irradiation (I420 nm = 0.2 mW/cm2) was sufficient to induce ultrafast aqueous RAFT at 25 °C.49 Moreover, reaction can be started up and suspended immediately by switching on−off visible light.50,51 Therefore, the chain length can be controlled by light-off suspending the reaction at the predetermined time points.51,52 1H NMR and elemental analysis (Supporting Information) confirmed the intactness of as-achieved PHPMA107-b-PCysMA80 sample. SEC results indicated the well-defined molecular structure with a number-average molecular weight (Mn) of 33.4 kDa and a polydispersity index (PDI, Mw/Mn) of 1.11 (Figure S1). Aminolysis of RAFT Chain-Ends. These chain-ends are fairly stable in acidic media at pH 3.0, as indicated by invariable UV−vis bands at λCEP = 308 nm44,50 in ambient air for 7 days (Figure 1a). However, the band at λCEP = 308 nm decreased and a new band at λthiol = 242 nm47,53 appeared at pH 5.6, in which traces of NH2 motifs existed as judged by the acid−base titration. These results indicate that the chain-ends were decomposed into thiolates due to aminolysis.44−46 The aminolysis was completed in the solutions above pH 6.6. As B
DOI: 10.1021/acs.macromol.6b00152 Macromolecules XXXX, XXX, XXX−XXX
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Figure 2. 1H NMR spectra (inset) and dehydration of CysMA units at different pH at 25 °C for 24 h (a) and those after adjusted to pH 3.0 (b).
Figure 3. (a) Light scattering intensity and hydrodynamic diameter of particles (1.0 mg mL−1 in water) at different pH values at 25 °C for 24 h. (b) DLS profile at pH 10.5 (black) and those after acidified to pH 3.0 (red).
⎛ I(b + k , t ) − 2Id , t Id ,0 ⎞ ⎟⎟ × 100% dehydration = ⎜⎜1 − I(b + k ,0) − 2Id ,0 Id , t ⎠ ⎝
shown in Figure 1b, the band at λthiol = 242 nm reached a maximum and the band at λCEP = 308 nm disappeared at pH 6.6 shortly in 20 min. This catalytic amount of terminal thiolates can initiate dynamic disulfide exchange.54−56 Self-Sorting Behavior. The perfect stability at pH 3.0 was confirmed by the invariable 1H NMR spectra in ambient air for 7 days. However, as shown in the inset of Figure 2a, signals l, m, n, p in CysMA units (arrows) decreased with an increase in the reaction pH and disappeared at pH 10.5 due to the dehydration of PCysMA block. Meanwhile, signals in new species (stars) appeared over pH 7.4−10.5. Signals x, y in cystamine molecules (Figure S2) are discernible at pH 10.5. These results demonstrate that CysMA units have been converted into hydrophobic polymeric disulfides and hydrophilic cystamine molecules in alkali solutions, which is a typical character of selfsorting as occurred in the multicomponent systems,21,22 and in agreement with the principle of self-sorting in polymer via hydrogen-bonding recognition.28−30 In terms of the driving force, however, this self-sorting is governed by the hydrophilic− hydrophobic diversity of as-generated disulfide species.
(1)
The dehydration of PCysMA block was determined according to eq 1 using integral signal b as an indicative of PCysMA and integral signal d in PHPMA as a standard. As shown in Figure 2a, PCysMA block was dissolved in water at pH < 5.7 but dehydrated from pH 6.5 to 8.7. To identify the amino-containing species, the reaction solutions were acidified back to pH 3.0. As shown in the inset of Figure 2b, CysMA signals (arrows) decreased with an increase in reaction pH and disappeared at pH 10.5 due to hydrophobic cross-linking of polymeric disulfides. Moreover, cystamine molecules at pH 10.5 was constant after adjusted back to pH 3.0, as judged by Iy/Id = Ix′/Id′. 1H NMR analysis indicates that 67% CysMA units sorted into the polymeric disulfides and cystamine molecules at pH 10.5, with 33% inaccessible to aqueous medium (Figure S3). Elemental analysis indicates that 65% units participated in self-sorting at pH 10.5 (Supporting Information). C
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Figure 4. AFM height images and representative cross sections of micelles in reaction solution at pH 10.5 (a) and those adjusted back to pH 3.0 (b).
Figure 5. (a) Acid−base titration plots in the absence (black) and presence (red) of copper ions. (b) UV−vis spectrum evolution of copolymer solution in the presence of copper ions at pH 7.0.
Figure 6. (a) 1H NMR spectra after reaction in the presence of copper ions for 24 h. (b) 1H NMR spectra of reaction solution at pH 8.8 after adjusted back to pH 3.0 (red) and dialyzed (blue).
disappearing of the band at λCEP = 277 nm shortly in 12 min (Figure 5b). Cu(II)−NH2 coordination occurred immediately as judged by a new band at λCu(II)−NH2 = 665 nm57 in 2 min. Subsequent NH2-to-SH substitution and cupric-to-cuprous reduction47,48,58 took place in the metal centers, leading to an absorbance decrease at λCu(II)−NH2 = 665 nm57 and increase at λCu(I)−S = 462 nm.59,60 These results provide unambiguous evidence of autocatalytic disulfide exchange.61 The reactions were inspected by 1H NMR after being maintained at predetermined pH values for 24 h. The CysMA units are fairly stable at pH 3.0 even in the presence of copper ions, as judged by the invariable integral signals (Figure 6a). However, signals in cystamine molecules (stars) and intermediate cuprous−(2-aminoethanethiol) complexes (1)58 are discernible at pH 5.6, in which traces of NH2 motifs existed as indicated by acid−base titration results (Figure 5a). CysMA signals (arrows) disappeared over pH 6.6−8.8 due to complete
Self-Assembly. The phase transition was monitored using dynamic light scattering (DLS). As shown in Figure 3a, light scattering intensity was fairly low in acidic solutions below pH 6.5. The intensity increased abruptly upon increase from pH 6.8 to 7.8, indicating that phase transition occurred. The particles shrank from Dh = 42 nm at pH 7.8 to 31 nm at pH 10.5 due to the dehydration. Moreover, the micelles at pH 10.5 are identical to those after acidified to pH 3.0 (Figure 3b). AFM results identified the spherical micelles with invariable rigidity upon acidified to pH 3.0, as judged by invariable height-to-diameter ratios (H/D = 0.45) of their cross sections (Figure 4). These results indicate inaccessible residual CysMA units; otherwise, micelles would have been softened by the ionization at pH 3.0. Self-Sorting in the Presence of Copper Ions. As shown in Figure 5a, the buffering effect was amplified in the presence of copper ions, and deionization of NH3+-motifs was essentially complete at pH 6.5. Moreover, the chain-ends were decomposed rapidly into thiolates at pH 7.0, as judged by D
DOI: 10.1021/acs.macromol.6b00152 Macromolecules XXXX, XXX, XXX−XXX
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Macromolecules Scheme 2. Schematic Illustration of Autocatalytic Self-Sorting Organization in PCysMA Block
Figure 7. (a) pH-dependent light scattering intensity and the zeta potential (ξ) of the solutions after maintained for 24 h. (b) Time-dependent variation of light scattering intensity in the absence of copper ions at pH 10.5 (black) and presence of copper ions at pH 7.0 (red).
Figure 8. AFM images (top) and representative cross sections (bottom) of as-lyophilized particles assembled upon reaction for 5, 25, and 60 min (from left to right) at pH 7.0.
clearly higher than 65−67% conversion as observed in the absence of copper ions at pH 10.5. In short, as illustrated in Scheme 2, in the presence of copper ions, the alkalization induced immediate Cu(II)−NH2 coordination and rapid aminolysis into the terminal thiolates, and thereby NH2-to-SH substitution and cupric-to-cuprous reduction in the metal binding sites, which led to the autocatalytic disulfide exchange with essentially complete conversion. This ideal self-sorting is capable in a single polymer in aqueous medium, which gave rise to programmable supramolecular-tosupracolloidal assembly as to be discussed below.
dehydration of the reactive block. In order to identify the asgenerated amino-containing species, reaction at pH 8.8 was acidified back to pH 3.0. As shown in Figure 6b, the signals in PCysMA are still undetectable owing to the irreversible crosslinking. However, signals in cystamine (x, y) and intermediate cuprous complexes (1′, 2′) are detected after acidification. These small species could be removed by dialysis, as judged by 1 H NMR (top spectrum in Figure 6b) and atomic absorption spectroscopy (Cu: initial 94 ppm; final 0.032 ppm). 1H NMR (Figure S4) indicates that all CysMA units participated in the self-sorting. Essentially complete conversion (>98%) was also confirmed by elemental analysis (Supporting Information). It is E
DOI: 10.1021/acs.macromol.6b00152 Macromolecules XXXX, XXX, XXX−XXX
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Figure 9. AFM images (top) and representative cross sections (bottom) of the as-lyophilized nanostructures of the reaction solutions at pH 7.0, 7.8, and 8.8 in the presence of copper ions.
Hierarchical Assembly in the Presence of Copper Ions. The pH-dependent phase transition was studied after maintained at 25 °C for 24 h. As shown in Figure 7a, phase transition occurred in the solutions above pH 5.5, as judged by the increase in light scattering intensity. The ξ value represents surface charge of particles in relation to the surrounding medium.62 Thus, inspection of the ξ-variation allows for convenient identification of NH3+ motifs on as-assembled particles.38,40,63−65 The ξ value dramatically decreases upon increase from pH 5.5 to 6.4 but moderately from pH 6.4 to 8.8 due to the deionization. Therefore, Cu(II)−NH2 coordination was enhanced and electrostatic repulsive interactions weakened in neutral solution at pH 7.0. The phase transition was tracked using DLS. The solution in the absence of copper ions was adjusted to pH 10.5 to ensure complete deionization. Light scattering intensity was recorded after rigorous shaking for 1 min at 25 °C. As shown in Figure 7b, sharp increase in light scattering intensity over 38−41 min indicates phase transition. Phase transition was also observed in the autocatalytic hydrolysis by Bachmann66 and dynamic imine conversion by Giuseppone67 and van Esch.68 However, this phase transition occurred more rapidly than those of asmentioned small molecule reaction systems.66−68 In contrast, in the presence of copper ions, NH3+ motifs deionized at pH 7.0 (Figure 5b). Thus, phase transition occurred immediately due to Cu(II)−NH2 coordination, as judged by an intensity at ∼36 kcps detected in 1 min. The intensity leveled off in initially 8 min and then increased up to 54 min (Δt = 46 min), which indicates a programmable supramolecular-to-supracolloidal assembly. The evolution of nanostructures at pH 7.0 was investigated using AFM. The solution was rapidly adjusted to pH 7.0 under rigorous shaking. Samples were taken at the time points of 5, 25, and 60 min, cast onto silica wafer, immediately frozen in liquid nitrogen, and lyophilized under reduced pressure before AFM studies. As shown in Figure 8, this polymer assembled into spherical micelles in 5 min. Thereafter, the micelles organized into chain-like hierarchical nanostructures in 25 and 60 min. The rigidity increased with reaction time, as indicated
by an increase in H/D ratios from 0.16−0.19 (5 min) to 0.18− 0.22 (25 min) and 0.21−0.23 (60 min). To illustrate the nanostructures, the polymer was reacted separately at pH 7.0, 7.8, and 8.8 in ambient air for 24 h. As shown in Figure 9, this polymer assembled into chain-like nanostructures with essentially constant rigidities around H/D of 0.22−0.25. This is a typical character of emergent supracolloidal self-assembly1−4 and the directional supracolloidal self-assembly via dynamic imine conversion and metal coordination as reported recently by our group.69 In this sense, this ideal self-sorting promoted programmable supramolecular-to-supracolloidal assembly into hierarchical nanostructures with concomitant release of cystamine and cuprous complexes in aqueous medium. Such a supramolecularto-supracolloidal self-sorting underlines an amazing prospect for the use of a single polymer to achieve artificial reaction complexity, hierarchy, and metabolic process.
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CONCLUSION This article described autocatalytic supramolecular-to-supracolloidal self-sorting in a single polymer in aqueous medium, using a reactive polymer whose units comprise lysine-mimetic alkylammonium ions and cystine-mimetic alkyl disulfide spacers. This reactive block is fairly stable in acidic water at pH 3.0. NH3+-to-NH2 transition on alkalization induced aminolysis into the terminal thiolates and thus initiated the disulfide exchange in the reactive block. 65−67% CysMA units sorted into hydrophobic polymeric disulfides and hydrophilic cystamine molecules at pH 10.5. In contrast, in the presence of copper ions, alkalization induced immediate Cu(II)−NH2 coordination, rapid aminolysis, and subsequent NH2-to-SH substitution and cupric-to-cuprous reduction in the metal centers, which induced autocatalytic self-sorting with essentially 100% conversion at pH 8.8 and a programmable supramolecular-to-supracolloidal assembly with concomitant release of cystamine molecules and intermediate cuprous complexes into aqueous medium. Such self-sorting underlines an amazing prospect for the use of a single polymer to achieve the reaction complexity, hierarchy, and also metabolic process, with minimal synthetic efforts. Intensive studies on stimuli-responsive F
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properties and structure−behavior correlation are ongoing and will be reported in a following paper.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b00152. Synthesis of PHPMA-b-PCysMA; 1H NMR spectra of cystamine and copolymer solutions; elemental analysis (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] (Y.C.). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21274097, 21474069, and 21334004) and the Priority Academic Program Development of Jiangsu Higher Education Institutions for the financial support of this research. Prof. Xinhua Lu at Soochow University is acknowledged for his kind assistance in AFM, DLS, and elemental analysis.
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Macromolecules
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DOI: 10.1021/acs.macromol.6b00152 Macromolecules XXXX, XXX, XXX−XXX
