Letter Cite This: ACS Macro Lett. 2019, 8, 629−633
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Diselenide-Containing Polymeric Vesicles with Osmotic Pressure Response Jiahao Xia, Peng Zhao, Shuojiong Pan, and Huaping Xu* Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China
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S Supporting Information *
ABSTRACT: Mechanophore is a kind of functional group that can undergo chemical reactions when given mechanical force stimuli. In this paper, osmotic pressure was used as an external force to trigger a diselenide exchange reaction. A diselenide bond containing block polymer capable of self-assembling to a vesicle structure and an ester bond containing a counterpart were synthesized in this study. When NaCl was added into the solution to generate the osmotic pressure difference inside and outside vesicles, diselenide containing vesicles were ruptured, while the ester bond counterpart stayed still. Further investigation into the chemical composition of both vesicles indicated the occurrence of the diselenide exchange reaction. The osmotic pressure response of the diselenide bond enriched the diselenide dynamic covalent chemistry and offers a potential application in a controlled release system.
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achieved between spheres and stomatocytes (a bowl style vesicle with an open mouth).19,20 Feringa et al. designed a vesicle-capped nanotube via coassembling of a soft phospholipid and a rigid amphiphilic molecule.21 Once altering the osmotic pressure by adding or removing sodium chloride (NaCl), the soft vesicle could be encapsulated or released from the nanotube. Weitz et al. constructed a polymeric capsule and used force-induced deformation as a model to investigate its mechanical properties.22 They demonstrated that adjusting osmotic pressure with NaCl and applying mechanical force with a microcantilever could both achieve the deformation of the capsule. To the best of our knowledge, osmotic pressure has not been used to trigger a chemical reaction. Dynamic covalent bonds are special chemical groups that can cleave, form, or exchange under external stimulus and have been extensively used in supramolecular chemistry and smart material fabrication.23−29 The diselenide bond has recently proven to be a dynamic covalent bond that can undergo metathesis reaction simply by visible light irradiation.30,31 In the meantime, the diselenide bond can also be cleaved by a very mild redox reagent like 0.01% v/v hydrogen peroxide or 0.01 mg/mL reduced glutathione.32,33 These features allow diselenide containing polymers to be used in both adaptive and biomedical materials.34−36 The essence of the sensitivity comes from a weak bond energy at 172 kJ/mol of diselenide bond.37 This enlightened us to investigate the possibility of using
he occurrence of a chemical reaction relies on overcoming the energy barrier. There are various sources of energy that can contribute to this process, including, light, heat, electricity, and so on. In recent years, mechanical force as a new approach has attracted much attention due to its simplicity and its wide applications in the field of material science.1 Moore et al. first put forward the idea of Mechanophore, which is defined as mechanically sensitive chemical groups.2 Those special groups can undergo chemical reactions when mechanical force is applied. Ultrasound was employed in solution and was found to accelerate and alter the course of certain ring-opening reactions.3 In 2009, a specific mechanophore spiropyran was incorporated into polymer chains.4 And when tensile stress was applied to the bulk material, an obvious color change was observed due to the electrocyclic ring-opening reaction of spiropyran. Sijbesma et al. developed a type of Mechanophore that can induce chemiluminescence under force stimuli.5−7 1,2-Dioxetane ring derivatives can be activated by mechanical force to produce two carbonyl moieties that can emit blue light. Those mechanophores act like force sensors that shed new insight into the study of bulk material breakage.8−13 Osmotic pressure is a common but important force that regulates the biological system.14,15 Yet, it has been largely neglected as a stimulus in the research of responsive polymers compared with heat, pH, redox, and light. A few examples in osmotic pressure response are mostly featured in the shape transformation of polymer assemblies.16−18 van Hest et al. synthesized poly(ethylene glycol)-block-polystyrene and found by adjusting the osmotic pressure of assembly solution, controllable morphology transition of polymersome could be © XXXX American Chemical Society
Received: April 5, 2019 Accepted: May 14, 2019
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DOI: 10.1021/acsmacrolett.9b00250 ACS Macro Lett. 2019, 8, 629−633
Letter
ACS Macro Letters
and deionized water (V/V = 3:1) were used as assembly solvents, and dioxane was later removed by dialysis to complete the assembly process. We first investigated the selfassembly behavior of two polymers. As shown in Figure 2,
osmotic pressure as an external force to trigger the diselenide exchange reaction. Herein, we demonstrated the osmotic pressure response of the diselenide bond (Scheme 1). A diselenide bond containing Scheme 1. Osmotic Pressure Response of Diselenide Bond
amphiphilic polymer was synthesized and further selfassembled into vesicles in water. Adding NaCl in solution could cause a concentration difference inside and outside the vesicles, and the osmotic pressure induced from different salt concentration led to the rupture of the vesicle structure. Morphological and chemical composition changes were investigated, and the results indicated the cleavage of the diselenide bond. Diselenide containing amphiphilic polymer mPEGSeSePS was first prepared by diselenide metathesis (Figure 1a).
Figure 2. DLS results of mPEGSeSePS (a) and mPEGCOOPS (b) assemblies; TEM images of mPEGSeSePS (c) and mPEGCOOPS (d) assemblies, the average sizes of both aggregates are around 600 nm; SEM images of mPEGSeSePS (e) and mPEGCOOPS (f) assemblies, hollow structures of vesicle identity were clearly observed.
Dynamic Light Scattering (DLS) experiment was first conducted, and the hydrodynamic diameter of the aggregates for mPEGSeSePS and mPEGCOOPS were at 563 and 572 nm, respectively. The morphologies of the aggregates were further studied by a Transmission Electron Microscope (TEM) and a Scanning Electron Microscope (SEM). From TEM images, both mPEGSeSePS and mPEGCOOPS formed spherical aggregates with an average size of 600 nm, with some of the larger aggregates reaching micrometer scale. SEM images confirmed that the aggregates were vesicles as the hollow structure of the sphere could be clearly observed. Both TEM and SEM results were in accordance with the DLS results. It should be noted that the similarity of assembly behavior of two samples was due to the similar structure and molecular weight of two block polymers, and thus, mPEGCOOPS should act as a suitable contrast. After confirming the vesicle structure, we sought to investigate the osmosis effect of the diselenide bond. Osmotic pressure was induced by adding NaCl, as there will be a concentration gradient inside and outside the vesicles. To maximize the effect, we started with saturated NaCl solution. The same amount of NaCl was added into both assembly solutions. As shown in Figure S4, before applying osmotic pressure, both solutions were homogeneously dispersed. After 24 h, an obvious aggregation and precipitation was found in
Figure 1. (a) Diselenide-containing amphiphilic polymer mPEGSeSePS was prepared by diselenide metathesis reaction of (mPEGSe)2 and (PSSe)2 in dioxane solution; (b) chemical structure of mPEGSeSePS; and (c) chemical structure of mPEGCOOPS.
Polyethylene glycol was selected as the hydrophilic block and the polystyrene was selected as the hydrophobic block. Di(poly(ethylene glycol) methyl ether) diselenide (mPEGSe)2 and di(polystyrene) diselenide (PSSe)2 were mixed in dioxane and irradiated by visible light for 3 h. After the reaction, there would be a mixture of exchange product mPEGSeSePS and the remaining reactant (mPEGSe)2 and (PSSe)2 due to the dynamic equilibrium of the diselenide metathesis reaction. In order to verify the effect of diselenide bond, a control sample poly(ethylene glycol) methyl ether-block (ester bond)polystyrene (mPEGCOOPS) was synthesized with similar structure and molecular weight but replacing diselenide bond with an ester bond (Figure 1c). The bond energy of C−O is 358 kJ/mol, which is much higher compared with 172 kJ/mol of diselenide bond.37 As a result, the ester bond is chemically more stable than diselenide bond. Since two polymers are both amphiphilic, they can selfassemble in water to form aggregates. The mixture of dioxane 630
DOI: 10.1021/acsmacrolett.9b00250 ACS Macro Lett. 2019, 8, 629−633
Letter
ACS Macro Letters
critical concentration was around 3% wt NaCl. It should be noted that NaCl is not a necessity. Apart from NaCl, NaBr and CaCl2 were also used as an osmotic pressure sauce, and the same phenomenon was seen as NaCl. This result demonstrated that neither Na+ nor Cl− is essential, and this response behavior is widely applicable for different ions. Although the morphology changes after applying osmotic pressure were confirmed, the mechanism behind it was not yet revealed. To do so, the chemical composition of the vesicles needs to be analyzed during the response period. Both polymer vesicle solutions were split into two equal amounts, with adding saturated NaCl to one sample and keeping the other sample blank. After 24 h, all four assembly solutions were dialyzed against deionized water (cutting off molecular weight 1000 kDa) to remove any water-soluble molecules within the cut-off range. After complete dialysis, the samples were then freeze-dried to obtain powders and were further characterized by Nuclear Magnetic Resonance (NMR) and Gel Permeation Chromatography (GPC). As shown in Figure S7A, for sample mPEGCOOPS, NMR results of the control group (no NaCl) and experimental group (NaCl) were identical, with PS and PEG signals both in existence, indicating that the chemical composition was unchanged when exposed to osmotic pressure. However, for sample mPEGSeSePS, for control group (no NaCl), the spectrum is very similar to mPEGCOOPS, but the experimental group (NaCl) only had a PS segment remaining and the PEG segment disappearing (Figure 4a). This result suggested that for mPEGSeSePS the diselenide bond may be ruptured and the PEG block was removed by dialysis. GPC results further confirmed this assumption. For mPEGCOOPS, for both the control group and the experimental group, there was only one peak in the spectrum (Figure S7B), indicating the molecular weight remained the same with or without osmotic pressure stimuli, and for mPEGSeSePS, the spectra were a bit complicated (Figure 4b). Without NaCl, there were three peaks in the spectra ascribing to exchanged product mPEGSeSePS and reactants (PSSe)2 and (mPEGSe)2. For the experimental group there was only the PSSeSe signal remaining, and the peaks for mPEGSeSePS and (mPEGSe)2 vanished. Furthermore, for the experimental group, the solution inside and outside the dialysis bag were collected and concentrated for the X-ray Photoelectron Spectroscopy (XPS) study. For the solution outside the dialysis bag, the XPS C 1s signal has two peaks corresponding to the C−C bond and C−O bond from PEG. And for solution inside the dialysis bag, only the C−C bond was detected, indicating the absence of the PEG segment. Combing the results from NMR, GPC, and XPS, we found that for mPEGSeSePS vesicles, after osmotic pressure stimuli, the mPEG−PS linkage was broken, while for mPEGCOOPS vesicles, the linkage was not. Osmotic pressure is proved to be able to generate force at the interface, weak as the diselenide bond, the generated force is strong enough to break the bond, while a tougher ester bond can tolerant this level of force. The breakage of the diselenide bond disrupted the vesicle structure, with the PS segment forming irregular aggregates and the PEG segment dissolved in water and further removed by dialysis. One of the biggest applications of a stimuli-responsive polymer is for delivery, so we seek to find out if it is possible to use osmotic pressure as an external stimuli for controlled release. Fluorescent molecule 8-hydroxypyrene-1,3,6-trisulfonic acid, trisodium salt (HPTS) was selected as the model compound due to its high water solubility and strong
mPEGSeSePS vesicle solution, while no significant changes could be observed for mPEGSCOOPS vesicle solution. We further employed SEM and TEM to study the insight of this phenomenon (Figure 3). From TEM results, mPEGSeSePS
Figure 3. SEM and TEM results after osmotic pressure stimuli for two assemblies. TEM images of mPEGSeSePS (a) and mPEGCOOPS (b) assemblies; SEM images of mPEGSeSePS (c) and mPEGCOOPS (d) assemblies; DIC images of mPEGSeSePS vesicles before adding NaCl (e) and after adding NaCl (f), vesicles are highlighted by red circles and after adding NaCl no vesicles could be observed at the focused plane. Microscope images showed that mPEGSeSePS structures were disrupted by osmotic pressure, while mPEGCOOPS assemblies were not much affected.
assemblies have changed into large irregular aggregates, indicating the rupture of the vesicle structure. In the meantime, the spherical structure of mPEGCOOPS assemblies remained unchanged. SEM images revealed the same result, with the morphology of mPEGSeSePS assemblies becoming irregular aggregates, while that of mPEGCOOPS stays the same. Microscope studies indicated that, in response to external osmotic pressure, the assembly of mPEGSeSePS was disrupted, while the assembly of mPEGCOOPS was not much affected. The fact that vesicle structure was reaching micrometer level made it possible for optical microscope observation. From Figure 3e, those tiny hollow dots were mPEGSeSePS vesicles in the solution state under differential interference contrast (DIC) microscope. We then applied an online observation to verify the time dependence of the response. The mPEGSeSePS vesicle solution was added with saturated NaCl and immediately put under the DIC microscope for observation. Photographs were taken at a 10 min time interval to monitor the changes. At the beginning, quite a few vesicles could be spotted, and as time went by, less and less vesicles could be seen. After 40 min, almost no vesicle could be observed under the microscope (Figure S5). This online observation illustrated that osmotic pressure response is quite efficient. Apart from the response speed, the critical NaCl concentration was also investigated. As shown in Figure S6, a series of NaCl concentration gradients were used, and once concentration is above 3% wt, a large precipitate was observed, indicating the 631
DOI: 10.1021/acsmacrolett.9b00250 ACS Macro Lett. 2019, 8, 629−633
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ACS Macro Letters
structures and the release of cargos inside the cavity. The in vitro cell toxicity experiment of the mPEGSeSePS assembly suggested it was almost nontoxic to A549 cells at the given concentrations (Figure S8). This model experiment illustrated that diselenide bond containing polymers could potentially serve as an alternative stimuli-responsive delivery vehicle. In conclusion, we discovered the osmotic pressure response of the diselenide bond. A diselenide bond containing a block polymer capable of self-assembling to a vesicle structure and an ester bond containing a counterpart were synthesized for this study. Osmotic pressure was manipulated by different concentrations of NaCl, and both the morphology and the chemical composition of vesicles were investigated. From TEM, SEM, and DIC microscope images it is found that osmotic pressure can cause the rupture of the vesicle structure. GPC, NMR, and XPS results further indicated that the mechanism involves the cleavage of the diselenide bond by osmotic pressure force. It is worth noting that this response is widely applicable for different ions, although a critical concentration is required (3% wt in the case of NaCl). Furthermore, this vesicle is proved to be able to release embedded cargos once triggered by osmotic pressure, thus, providing an alternative in the field of controlled release delivery.
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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/acsmacrolett.9b00250.
Figure 4. Chemical composition comparsion of mPEGSeSePS vesicles with and without osmotic pressure stimuli. (a) NMR spectra of mPEGSeSePS with and without NaCl. (b) GPC chromatograms of mPEGSeSePS with and without NaCl. (c) XPS C 1s peaks of dialysis solution outside (left) and inside (right) the dialysis bag.
Materials, instruments, experiments, and results, including NMR and GPC chromatograms of the polymers used in the research, and photographs of the assemblies (PDF)
fluorescence. The vesicle preparation method is the same, except HPTS aqueous solution was used to replace the deionized water. The mPEGSeSePS assembly was dialyzed against deionized water to remove HPTS not embedded. As shown in confocal images (Figure 5), before adding saturated
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Huaping Xu: 0000-0002-7530-7264 Author Contributions
J.X. and H.X. designed the experiments. J.X. and P.Z. performed the experiments. The manuscript was prepared by J.X. and H.X. All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
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Figure 5. Confocal images of mPEGSeSePS vesicles embedding HPTS before (left) and after (right) applying osmotic pressure. After adding NaCl the vesicle structure was destroyed and the embedded green fluorescent molecules were released.
ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grant 21734006), the National Science Foundation for Distinguished Young Scholars (Grant 21425416), the National Basic Research Plan of China (2018YFA0208900), and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (21821001). We thank professor Yan He (Tsinghua University) for the differential interference contrast microscope test.
NaCl, a fluorescent spherical structure could be seen with a bright dot in the center of the assembly, indicating that HPTS were trapped in both the shell and the cavity of the vesicles. After applying osmotic pressure for 24 h, only limited irregular aggregates could be observed, and the bright fluorescent dot in the center disappeared, indicating the rupture of vesicle 632
DOI: 10.1021/acsmacrolett.9b00250 ACS Macro Lett. 2019, 8, 629−633
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ACS Macro Letters
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DOI: 10.1021/acsmacrolett.9b00250 ACS Macro Lett. 2019, 8, 629−633
