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Hydrogen Bonding in Aprotic Solvents, a New Strategy for Gelation of Bioinspired Catecholic Copolymers with N-Isopropylamide Mohammad Vatankhah-Varnoosfaderani, Amin GhavamiNejad, Saud Hashmi, Florian J. Stadler* Copolymers of N-isopropylacrylamide (NIPAM) and dopamine methacrylate can establish a reversible, self-healing 3D network in aprotic solvents based on hydrogen bonding. The reactivity and hydrogen bonding formation of catechol groups in copolymer chains are studied by UV–vis and 1H NMR spectroscopy, while reversibility from sol to gel and inverse as well as self-healing properties are tested rheologically. The produced reversible organogel can self-encapsulate physically interacting or chemically bonded solutes such as drugs due to thermosensitivity of the used copolymer. This system offers dual-targeted and controlled drug delivery and release—by slowing down release kinetics by supramolecular bonding of the drug and by reducing diffusion rates due to modulus increase.
1. Introduction Existence of catechol group as a very active functionality in polymer chains induces some interesting properties and Dr. M. Vatankhah-Varnoosfaderani, Prof. F. J. Stadler College of Materials Science and Engineering, Shenzhen University, Shenzhen 518060, P.R. China E-mail: [email protected] Dr. M. Vatankhah-Varnoosfaderani, Dr. A. GhavamiNejad, Dr. S. Hashmi, Prof. F. J. Stadler Chonbuk National University, School of Semiconductor and Chemical Engineering, Baekjero 567, Deokjin-gu, Jeonju, Jeonbuk 561–756, Republic of Korea Dr. M. Vatankhah-Varnoosfaderani Islamic Azad University, Omidiyeh Branch, Department of Polymer, 63731–93719, Omidiyeh, Iran Dr. M. Vatankhah-Varnoosfaderani Department of Chemistry, University of North Carolina at Chapel Hill, North Carolina 27599-3290, USA Dr. A. GhavamiNejad Department of Bionanosystem Engineering, Graduate School, Chonbuk National University, Jeonju 561-756, Republic of Korea
consequently versatile application such as antimicrobial coatings,[1] drug delivery systems,[2] biosensors,[3] and adhesives[4–9] in wet environment,[10,11] which can Dr. S. Hashmi Department of Chemical Engineering, NED University of Engineering & Technology, University Road, Karachi 75270, Pakistan Prof. F. J. Stadler Nanshan District Key Lab for Biopolymers and Safety Evaluation, Shenzhen 518060, P.R. China Prof. F. J. Stadler Shenzhen Engineering Laboratory for Advanced Technology of Ceramics, Shenzhen 518060, P.R. China Prof. F. J. Stadler Shenzhen Key Laboratory of Special Functional Materials, Shenzhen 518060, P.R. China
Macromol. Rapid Commun. 2015, DOI: 10.1002/marc.201400501
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be clearly related to catechol moieties as blocking them leads to a loss of these properties.[10] There are several reports about irreversible 3D network formation of polymers containing catechol groups in presence of oxidizing reagents, e.g., sodium periodate.[12] Oxidizing agents convert catechols to highly reactive quinone leading to cross-linking.[9,13] Furthermore, there are also reversible interactions in systems containing catechols such as intra- and intermolecular hydrogen bonding between catecholic hydroxyl groups with each other and also with protic (H2O) or aprotic solvents dimethylsulfoxide (DMSO).[14,15] Also formation of metal–ligand complexes and stabilized quinhydrone complexes by π–π interactions as another possible catechol interactions were reported.[16,17] Finally, catecholic polymers can construct reversible 3D network by adding multivalent cat ions such in alkaline pH.[18–25] These gels formed due to above-mentioned interactions can be degelled to solution by decreasing pH to acidic state. Controlled drug release systems, as one of application field of smart gels, aim at improving drug efficiency and control release of drug over time, which remedies shortcomings of ordinary drug systems, releasing most of the drug immediately.[26] Nowadays, different methods increase drug efficiency and prevent side effects of high local concentration of drugs around cells.[27] This work introduces a new gelation mechanism in catechol containing polymers based on H-bonding between catechol groups and opens new doors of application for catecholic polymers. DMSO the “universal solvent” in pharmaceutical sciences, was chosen, and, thus, such organogels are suitable for drug and vaccine delivery.[28] However, in DMSO solution, poly(N-isopropylacrylamide) (PNIPAM)-based materials are not thermosensitive.[29] Hydrogen bonding catecholic OH-groups lead to a 3D polymer network and, consequently, gel formation. In this work, understanding the exact mechanism of crosslinking of N-isopropylacrylamide (NIPAM)-dopamine moieties in DMSO is studied by UV–vis spectroscopy, 1 H NMR, and rheology.[24,25]
2. Experimental Section The synthesis of the copolymer of NIPAM and dopamine methacrylamide (DMA) (NIPAM-co-DMA) with a DMA content of 5%, abbreviated as NIDO5% was published elsewhere.[24,25] The material has a molecular weight Mn of ≈2800 g mol−1 and Mw/ Mn ≈ 1.9.[24,25] 1 H NMR spectra were recorded in deuterated methanol (CD3OD), DMSO, or deuterium oxide (D2O) with a Bruker AM400 spectrometer (400 MHz). The mechanical/rheological properties of the hydrogels were evaluated using a Malvern Kinexus Pro with a parallel-plate
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geometry (20 mmØ). The frequency dependence of the gels was performed in linear viscoelastic regime (γ0 < 30%). Self-healing tests were performed by increasing the deformation stepwise from γ0 = 0.1 to 1000% (ω = 10 s−1, strain sweep), followed immediately by a time-sweep under linear conditions (γ0 = 2…5%, ω = 10 s−1) while monitoring the recovery. Drug delivery experiments were performed by loading a gel with Evans Blue. The loaded gel was then immersed in a vessel with PBS heated to 25 and 37 ± 0.5 °C.
3. Results While in alkaline H2O, gelation took several hours, the same conditions in DMSO lead to an organogel within 2–3 s upon mixing (movie 1, Supporting Information). Experimental details are provided in the Supporting Information. In alkaline NIDO5%-solution, intramolecular interactions exist between catecholic OH-groups with one acting as H-bond donor and the other as acceptor, forming intracatecholic hydrogen bonds (intra-CHB). The same interaction also takes place between catecholic OH groups belonging to different polymer molecules → intercatecholic hydrogen bonds (inter-CHB) (Figure 1, Supporting Information). The likeliness of inter-CHB is increased by the catecholic OH group, not involved in inter-CHB, both directly and via bridging DMSO molecules, acting as H-bond donor for the DMSO oxygen, which are strengthened by C H…π interactions, involving the DMSO methyls and both catecholic centroids. However, these interactions are insufficient for gelation. Adding sodium hydroxide (NaOH) in an aprotic solvent dissociates hydrogen from catecholic OH groups, thus, converting from donor to strong hydrogen bond acceptor ( O−). In contrast to protic solvents, aprotic solvents (e.g., DMSO) cannot stabilize anions through hydrogen bonding; so this increases the H-bonding strength,[30] giving rise to a 3D polymeric network and gel formation. As summarized in Figure 1a,b, the gel structure is, consequently based on reversible, noncovalent H-bonding ( OH… O−), which provide stimuli responsiveness and self-healing. While in NIDO5%-solution in DMSO H-bonding between catechol and DMSO exists, but the H-bond between catecholic OH groups and its conjugated base is stronger than the H-bond between catecholic OH groups and DMSO by 6.1 kcal mol−1, thus, leading to DMSO not interacting significantly with NIDO5% in alkaline conditions.[30] 3.1. 1H NMR and UV–Vis The gelation speed depends on dissociation rate of hydrogen from catecholic OH groups. H-bonding between OH groups and ( O−) groups form gradually to reach critical concentration making stable 3D network to withstand
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+NaOH
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hydroxyl protons are marked as a–c and d in Figure 1d,e, respectively, according to Figure 1a,b. Gelation leads to hydrogen dissociation of OH groups, shifting the catechol protons peaks (a–c) to lower ppm (a′-c′), which increase with time (Figure 1d,e). A decrease of surface area of the catecholic OH groups’ proton peak around 8.64 (d) and 8.78 ppm (d) with time until reaching equilibrium after 3 h (8–9 ppm, cf. Table 1, Supporting Information). The catecholic protons shift (b→b′) due to OH group dissociation within minutes, obvious as increasing peak intensity at 6.2 ppm confirms the macroscopic timescale of 3D network formation (gelation), which leads to gelation (Figure 2, Supporting Information). Addition of gaseous HCl (or any protic acid) to the gel, lead to degelling quickly (movie 2, Figure 2, Supporting Information), as protons on gel surface reduce O− back to catecholic OH groups and, consequently, H-bonding disappears, as can be seen from vanishing intensity at 6.2 ppm. The remaining Cl− anion can bind to bisphenols such as catechol and deoxidize, which manifests macroscopically as discoloring of alkaline state’s brown-red.[32] This process demonstrates the acid sensitivity of this interaction making them a valuable functionality for smart gels. Very similar information can also be obtained from UV–vis experiments, which are discussed in the Supporting Information. Both methods suggest that the organogels’ DOPA-groups are not oxidized significantly, as they would be after longer exposure to water.[25]
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Figure 1. Schematic of the reactions in a) solution and b) gel state and 1H NMR data, c) complete spectrum, d) 6.1–6.7 ppm, e) 8.6–9 ppm. Assignment of peaks according to Figure 2a,b.
flowing, which was followed by time-resolved 1H NMR experiments in deuterated DMSO before and after oxidizing agent addition (Figure 1c).[31] The aromatic and
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The frequency dependent, linear viscoelastic dynamicmechanical response in oscillation (Figure 2a) of 20% NIDO5% gel in DMSO with 1/2 eq. NaOH shows typical elastic gel behavior (G′ (ω) >> G″ (ω), dG′ (ω)/dω ≈ 0). The loss modulus G″ (ω) exhibits a clear frequency dependency, suggesting fast segmental relaxations typical of supramolecular polymers.[24,33] At low frequencies, G″ (ω) is low (δ = 1.2–1.5°), suggesting a quasi-permanent network within experimental range, supporting 1H NMR. Despite statistical network formation, very few slow processes occur, suggesting that the CHB are strong and numerous enough for macroscopic flow inhibition. When comparing to the theoretical value for this gel, it is compelling that only a fraction of about 0.5% of the CHB contribute to the network, signifying high levels of open bonds (unbound catechols and intra-CBH), “loops,” and chains with less than 2 catechols per chain.[34–36] At high ω, segmental motions, especially dangling ends, increase G″ (ω), being characteristic of supramolecularly bonded networks.[24,25,33,37] The nonlinear properties were assessed by first increasing the deformation γ0 = (0.1%–1000%) at
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G', G'' [Pa]
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constant ω = 10 s−1 followed by a time sweep experiment at constant low deformation to assess structural recovery (Figure 2b,c). The strain sweep, shows typical characteristics of polymer melts and associative systems,
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having a linear viscoelastic limit γ0 ≈ 30%, (Figure 2b).[38] After this a G″ (γ0) and δ(γ0) upturn as well as a halving of G′ (γ0) before reaching a plateau (γ0 ≈ 100%–250%) is obvious. Higher deformations (γ0 ≈ 500%) lead to structural collapse, signified by a sharp decrease of G′ (γ0).[24,33,39] Although the modulus is within the domain of comparable supramolecular systems,[24] the plateau G″ (γ0 ≈ 200%) differs from other supramolecular systems with metal–ligand interactions or multiple H-bonding,[40–42] where the G″ (γ0)-peak would be typically γ0 ≈ 100%.[24,33,38– 42] Recently, a comparable behavior for a system combining hydrophobic and metal–ligand interactions with a two-step network disassembly was found.[33,43] max After applying γ 0 = 1000%, an almost instantaneous recovery of the data is evident (Figure 2c), which means the damage inflicted on the gel for these conditions can recover within several seconds, while the recovery of G″ (t) takes ≈10 min. However, in total G′ (t) and G″ (t) increase by ≈10%, suggesting that sample damaging increases network density. A possible explanation for this is that clusters not contributing to the network open as well and when the functionalities form CHB again, some of these isolated clusters form network-integrated CHB. This mechanism is related to relaxation-inhibited orientations, as CHB along the oriented paths significantly increases the relaxation time for relaxation.[44]
While the loaded “drug” Evans blue (1 mg mL−1) makes the gel appear dark blue before immersion to the Krebs– Henseleit solution at 37 °C (Figure 3a), after 60 s immersion, it whitens (Figure 3b). Diffusive exchange of ion into and DMSO and Evans Blue out of the gel triggers the lower critical solution temperature (LCST), leading to gel collapse and an effective diffusion barrier formation. Figure 3c clearly shows an LCST layer of ≈0.5 mm thickness, while the remaining sample is unaffected. This can be explained by the broad LCST of NIDO5% in H2O (at pH 9, LCST = 30–45 °C).[25] Additionally, Hofmeister ions lower the LCST[45–47] and the solubility of a polymer solvent mixture (H2O/DMSO) is usually lowered further.[48] The encapsulation of the inner part and, thus, drug diffusion speed control is shown by Evans Blue release and shows good evidence for self-encapsulation (see movie 3, Supporting Information), which is supposedly caused by a mixture of phase separation due to induced thermosensitivity by H2O/DMSO[29] as well as by H-bonds in DMSOrich domains and metal–ligand interactions in water-rich domains.[25] In order to examine the potential use of the organogels in drug delivery closer, the release rate to phosphate buffer solution was studied at 25 °C and 37 °C, below and above the LCST, respectively. Figure 3D shows a dye
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Figure 3. DMSO gel (20 wt% NIDO5% in DMSO with ½eq. NaOH loaded with 1 mg mL−1 Evans Blue). a) as-prepared gel, b) gel after immersion in PBS for 60 s, c) section of the gel, showing the DMSO gel, encapsulated by LCST-layer, d) drug release performance at 25 °C and 37 °C.
release of ≈75% at T = 25 °C within 6 d, while at T = 37 °C, the release kinetics are slowed down significantly after 12 d and a dye release of ≈50%, no clear equilibrium has been found. This outcome supports the visual finding that above the LCST, self-encapsulation with a hydrophobic shell slow dye/drug release behavior. The properties, potentially, enable injection of copolymer solution into physiological environment directly after addition of NaOH, which then self-encapsulates and should give time for organogel formation inside. Furthermore, surgically implanting or applying prepared gels into or onto wounds, which then self-encapsulate upon contact. Moreover, this system can deliver drugs with two mechanisms. Drugs as a solute in the copolymer solution in DMSO can be delivered due to diffusion and temperature. Therefore, such system could find potential applications in slow drug release, where a distribution in small quantities over longer time is needed. Furthermore, targeted drug delivery is possible by transient metal– ligand bonds with some drugs such as Bortezomib.[2]
The mechanical data of this system are comparable to aqueous solution with H3BO3 of the same polymer in moduli and self-healing ability,[24,25] suggesting a transient supramolecular bonding situation for CHB and metal–ligand bonds. When assuming an equivalence of B3+-dicatechol bonds and the hydrogen-bonded species in DMSO, discussed in this article (this assumption is reasonable due to similar moduli), it is safe to assume that at any given time, only a certain fraction of the CHB is closed, making it truly supramolecular and not covalent. Furthermore, widely used DMSO in biomedical technology allows for potential applications as novel drug release systems. The special property of the gel–drug and DMSO release in aqueous environment coupled with selfencapsulation of the gel, leads to versatile possibilities to shape the gel according to patients’ need and then let the body conditions encapsulate the gel, regulating the release rate. The self-encapsulation also allows for generation of slow-releasing drug delivery systems, which can
4. Conclusion While the supramolecular cross-linking of catechols by polyvalent cations is well established for obtaining stimuli-responsive gels, it is a novel concept that solutions of such polymers in aprotic solvents such as DMSO yield stimuli-responsive gels based on H-bonding.[11] By different spectroscopic methods, the reaction and attraction pathways were clearly identified (see Figure 4).
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Figure 4. Scheme of the reactions.
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be easily shaped before implanting where the self-encapsulation will happen. We expect these abilities to lead to new applications for bioinspired and biocompatible materials with superior tunability.
Supporting Information Supporting Information is available from the Wiley Online Library or from the author. Acknowledgements: M.V.-V. and A.G. contributed equally to this work. The authors acknowledge financial aid from the National Research Foundation of Korea (110100713) and Nanshan District Key Lab for Biopolymers and Safety Evaluation (No. KC2014ZDZJ0001A). The authors thank the staff of the CBNU central lab for the help with the NMR-measurements. Received: September 3, 2014; Revised: November 9, 2014; Published online: ; DOI: 10.1002/marc.201400501 Keywords: catechol; drug release; hydrogen bonding; musselinspired; self-healing
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Communication
Hydrogen Bonding in Aprotic Solvents, a New Strategy for Gelation of Bioinspired Catecholic Copolymers with N-Isopropylamide Mohammad Vatankhah-Varnoosfaderani, Amin GhavamiNejad, Saud Hashmi, Florian J. Stadler* Copolymers of N-isopropylacrylamide (NIPAM) and dopamine methacrylate can establish a reversible, self-healing 3D network in aprotic solvents based on hydrogen bonding. The reactivity and hydrogen bonding formation of catechol groups in copolymer chains are studied by UV–vis and 1H NMR spectroscopy, while reversibility from sol to gel and inverse as well as self-healing properties are tested rheologically. The produced reversible organogel can self-encapsulate physically interacting or chemically bonded solutes such as drugs due to thermosensitivity of the used copolymer. This system offers dual-targeted and controlled drug delivery and release—by slowing down release kinetics by supramolecular bonding of the drug and by reducing diffusion rates due to modulus increase.
1. Introduction Existence of catechol group as a very active functionality in polymer chains induces some interesting properties and Dr. M. Vatankhah-Varnoosfaderani, Prof. F. J. Stadler College of Materials Science and Engineering, Shenzhen University, Shenzhen 518060, P.R. China E-mail: [email protected] Dr. M. Vatankhah-Varnoosfaderani, Dr. A. GhavamiNejad, Dr. S. Hashmi, Prof. F. J. Stadler Chonbuk National University, School of Semiconductor and Chemical Engineering, Baekjero 567, Deokjin-gu, Jeonju, Jeonbuk 561–756, Republic of Korea Dr. M. Vatankhah-Varnoosfaderani Islamic Azad University, Omidiyeh Branch, Department of Polymer, 63731–93719, Omidiyeh, Iran Dr. M. Vatankhah-Varnoosfaderani Department of Chemistry, University of North Carolina at Chapel Hill, North Carolina 27599-3290, USA Dr. A. GhavamiNejad Department of Bionanosystem Engineering, Graduate School, Chonbuk National University, Jeonju 561-756, Republic of Korea
consequently versatile application such as antimicrobial coatings,[1] drug delivery systems,[2] biosensors,[3] and adhesives[4–9] in wet environment,[10,11] which can Dr. S. Hashmi Department of Chemical Engineering, NED University of Engineering & Technology, University Road, Karachi 75270, Pakistan Prof. F. J. Stadler Nanshan District Key Lab for Biopolymers and Safety Evaluation, Shenzhen 518060, P.R. China Prof. F. J. Stadler Shenzhen Engineering Laboratory for Advanced Technology of Ceramics, Shenzhen 518060, P.R. China Prof. F. J. Stadler Shenzhen Key Laboratory of Special Functional Materials, Shenzhen 518060, P.R. China
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be clearly related to catechol moieties as blocking them leads to a loss of these properties.[10] There are several reports about irreversible 3D network formation of polymers containing catechol groups in presence of oxidizing reagents, e.g., sodium periodate.[12] Oxidizing agents convert catechols to highly reactive quinone leading to cross-linking.[9,13] Furthermore, there are also reversible interactions in systems containing catechols such as intra- and intermolecular hydrogen bonding between catecholic hydroxyl groups with each other and also with protic (H2O) or aprotic solvents dimethylsulfoxide (DMSO).[14,15] Also formation of metal–ligand complexes and stabilized quinhydrone complexes by π–π interactions as another possible catechol interactions were reported.[16,17] Finally, catecholic polymers can construct reversible 3D network by adding multivalent cat ions such in alkaline pH.[18–25] These gels formed due to above-mentioned interactions can be degelled to solution by decreasing pH to acidic state. Controlled drug release systems, as one of application field of smart gels, aim at improving drug efficiency and control release of drug over time, which remedies shortcomings of ordinary drug systems, releasing most of the drug immediately.[26] Nowadays, different methods increase drug efficiency and prevent side effects of high local concentration of drugs around cells.[27] This work introduces a new gelation mechanism in catechol containing polymers based on H-bonding between catechol groups and opens new doors of application for catecholic polymers. DMSO the “universal solvent” in pharmaceutical sciences, was chosen, and, thus, such organogels are suitable for drug and vaccine delivery.[28] However, in DMSO solution, poly(N-isopropylacrylamide) (PNIPAM)-based materials are not thermosensitive.[29] Hydrogen bonding catecholic OH-groups lead to a 3D polymer network and, consequently, gel formation. In this work, understanding the exact mechanism of crosslinking of N-isopropylacrylamide (NIPAM)-dopamine moieties in DMSO is studied by UV–vis spectroscopy, 1 H NMR, and rheology.[24,25]
2. Experimental Section The synthesis of the copolymer of NIPAM and dopamine methacrylamide (DMA) (NIPAM-co-DMA) with a DMA content of 5%, abbreviated as NIDO5% was published elsewhere.[24,25] The material has a molecular weight Mn of ≈2800 g mol−1 and Mw/ Mn ≈ 1.9.[24,25] 1 H NMR spectra were recorded in deuterated methanol (CD3OD), DMSO, or deuterium oxide (D2O) with a Bruker AM400 spectrometer (400 MHz). The mechanical/rheological properties of the hydrogels were evaluated using a Malvern Kinexus Pro with a parallel-plate
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geometry (20 mmØ). The frequency dependence of the gels was performed in linear viscoelastic regime (γ0 < 30%). Self-healing tests were performed by increasing the deformation stepwise from γ0 = 0.1 to 1000% (ω = 10 s−1, strain sweep), followed immediately by a time-sweep under linear conditions (γ0 = 2…5%, ω = 10 s−1) while monitoring the recovery. Drug delivery experiments were performed by loading a gel with Evans Blue. The loaded gel was then immersed in a vessel with PBS heated to 25 and 37 ± 0.5 °C.
3. Results While in alkaline H2O, gelation took several hours, the same conditions in DMSO lead to an organogel within 2–3 s upon mixing (movie 1, Supporting Information). Experimental details are provided in the Supporting Information. In alkaline NIDO5%-solution, intramolecular interactions exist between catecholic OH-groups with one acting as H-bond donor and the other as acceptor, forming intracatecholic hydrogen bonds (intra-CHB). The same interaction also takes place between catecholic OH groups belonging to different polymer molecules → intercatecholic hydrogen bonds (inter-CHB) (Figure 1, Supporting Information). The likeliness of inter-CHB is increased by the catecholic OH group, not involved in inter-CHB, both directly and via bridging DMSO molecules, acting as H-bond donor for the DMSO oxygen, which are strengthened by C H…π interactions, involving the DMSO methyls and both catecholic centroids. However, these interactions are insufficient for gelation. Adding sodium hydroxide (NaOH) in an aprotic solvent dissociates hydrogen from catecholic OH groups, thus, converting from donor to strong hydrogen bond acceptor ( O−). In contrast to protic solvents, aprotic solvents (e.g., DMSO) cannot stabilize anions through hydrogen bonding; so this increases the H-bonding strength,[30] giving rise to a 3D polymeric network and gel formation. As summarized in Figure 1a,b, the gel structure is, consequently based on reversible, noncovalent H-bonding ( OH… O−), which provide stimuli responsiveness and self-healing. While in NIDO5%-solution in DMSO H-bonding between catechol and DMSO exists, but the H-bond between catecholic OH groups and its conjugated base is stronger than the H-bond between catecholic OH groups and DMSO by 6.1 kcal mol−1, thus, leading to DMSO not interacting significantly with NIDO5% in alkaline conditions.[30] 3.1. 1H NMR and UV–Vis The gelation speed depends on dissociation rate of hydrogen from catecholic OH groups. H-bonding between OH groups and ( O−) groups form gradually to reach critical concentration making stable 3D network to withstand
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+NaOH
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hydroxyl protons are marked as a–c and d in Figure 1d,e, respectively, according to Figure 1a,b. Gelation leads to hydrogen dissociation of OH groups, shifting the catechol protons peaks (a–c) to lower ppm (a′-c′), which increase with time (Figure 1d,e). A decrease of surface area of the catecholic OH groups’ proton peak around 8.64 (d) and 8.78 ppm (d) with time until reaching equilibrium after 3 h (8–9 ppm, cf. Table 1, Supporting Information). The catecholic protons shift (b→b′) due to OH group dissociation within minutes, obvious as increasing peak intensity at 6.2 ppm confirms the macroscopic timescale of 3D network formation (gelation), which leads to gelation (Figure 2, Supporting Information). Addition of gaseous HCl (or any protic acid) to the gel, lead to degelling quickly (movie 2, Figure 2, Supporting Information), as protons on gel surface reduce O− back to catecholic OH groups and, consequently, H-bonding disappears, as can be seen from vanishing intensity at 6.2 ppm. The remaining Cl− anion can bind to bisphenols such as catechol and deoxidize, which manifests macroscopically as discoloring of alkaline state’s brown-red.[32] This process demonstrates the acid sensitivity of this interaction making them a valuable functionality for smart gels. Very similar information can also be obtained from UV–vis experiments, which are discussed in the Supporting Information. Both methods suggest that the organogels’ DOPA-groups are not oxidized significantly, as they would be after longer exposure to water.[25]
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Figure 1. Schematic of the reactions in a) solution and b) gel state and 1H NMR data, c) complete spectrum, d) 6.1–6.7 ppm, e) 8.6–9 ppm. Assignment of peaks according to Figure 2a,b.
flowing, which was followed by time-resolved 1H NMR experiments in deuterated DMSO before and after oxidizing agent addition (Figure 1c).[31] The aromatic and
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The frequency dependent, linear viscoelastic dynamicmechanical response in oscillation (Figure 2a) of 20% NIDO5% gel in DMSO with 1/2 eq. NaOH shows typical elastic gel behavior (G′ (ω) >> G″ (ω), dG′ (ω)/dω ≈ 0). The loss modulus G″ (ω) exhibits a clear frequency dependency, suggesting fast segmental relaxations typical of supramolecular polymers.[24,33] At low frequencies, G″ (ω) is low (δ = 1.2–1.5°), suggesting a quasi-permanent network within experimental range, supporting 1H NMR. Despite statistical network formation, very few slow processes occur, suggesting that the CHB are strong and numerous enough for macroscopic flow inhibition. When comparing to the theoretical value for this gel, it is compelling that only a fraction of about 0.5% of the CHB contribute to the network, signifying high levels of open bonds (unbound catechols and intra-CBH), “loops,” and chains with less than 2 catechols per chain.[34–36] At high ω, segmental motions, especially dangling ends, increase G″ (ω), being characteristic of supramolecularly bonded networks.[24,25,33,37] The nonlinear properties were assessed by first increasing the deformation γ0 = (0.1%–1000%) at
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G', G'' [Pa]
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constant ω = 10 s−1 followed by a time sweep experiment at constant low deformation to assess structural recovery (Figure 2b,c). The strain sweep, shows typical characteristics of polymer melts and associative systems,
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having a linear viscoelastic limit γ0 ≈ 30%, (Figure 2b).[38] After this a G″ (γ0) and δ(γ0) upturn as well as a halving of G′ (γ0) before reaching a plateau (γ0 ≈ 100%–250%) is obvious. Higher deformations (γ0 ≈ 500%) lead to structural collapse, signified by a sharp decrease of G′ (γ0).[24,33,39] Although the modulus is within the domain of comparable supramolecular systems,[24] the plateau G″ (γ0 ≈ 200%) differs from other supramolecular systems with metal–ligand interactions or multiple H-bonding,[40–42] where the G″ (γ0)-peak would be typically γ0 ≈ 100%.[24,33,38– 42] Recently, a comparable behavior for a system combining hydrophobic and metal–ligand interactions with a two-step network disassembly was found.[33,43] max After applying γ 0 = 1000%, an almost instantaneous recovery of the data is evident (Figure 2c), which means the damage inflicted on the gel for these conditions can recover within several seconds, while the recovery of G″ (t) takes ≈10 min. However, in total G′ (t) and G″ (t) increase by ≈10%, suggesting that sample damaging increases network density. A possible explanation for this is that clusters not contributing to the network open as well and when the functionalities form CHB again, some of these isolated clusters form network-integrated CHB. This mechanism is related to relaxation-inhibited orientations, as CHB along the oriented paths significantly increases the relaxation time for relaxation.[44]
While the loaded “drug” Evans blue (1 mg mL−1) makes the gel appear dark blue before immersion to the Krebs– Henseleit solution at 37 °C (Figure 3a), after 60 s immersion, it whitens (Figure 3b). Diffusive exchange of ion into and DMSO and Evans Blue out of the gel triggers the lower critical solution temperature (LCST), leading to gel collapse and an effective diffusion barrier formation. Figure 3c clearly shows an LCST layer of ≈0.5 mm thickness, while the remaining sample is unaffected. This can be explained by the broad LCST of NIDO5% in H2O (at pH 9, LCST = 30–45 °C).[25] Additionally, Hofmeister ions lower the LCST[45–47] and the solubility of a polymer solvent mixture (H2O/DMSO) is usually lowered further.[48] The encapsulation of the inner part and, thus, drug diffusion speed control is shown by Evans Blue release and shows good evidence for self-encapsulation (see movie 3, Supporting Information), which is supposedly caused by a mixture of phase separation due to induced thermosensitivity by H2O/DMSO[29] as well as by H-bonds in DMSOrich domains and metal–ligand interactions in water-rich domains.[25] In order to examine the potential use of the organogels in drug delivery closer, the release rate to phosphate buffer solution was studied at 25 °C and 37 °C, below and above the LCST, respectively. Figure 3D shows a dye
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Figure 3. DMSO gel (20 wt% NIDO5% in DMSO with ½eq. NaOH loaded with 1 mg mL−1 Evans Blue). a) as-prepared gel, b) gel after immersion in PBS for 60 s, c) section of the gel, showing the DMSO gel, encapsulated by LCST-layer, d) drug release performance at 25 °C and 37 °C.
release of ≈75% at T = 25 °C within 6 d, while at T = 37 °C, the release kinetics are slowed down significantly after 12 d and a dye release of ≈50%, no clear equilibrium has been found. This outcome supports the visual finding that above the LCST, self-encapsulation with a hydrophobic shell slow dye/drug release behavior. The properties, potentially, enable injection of copolymer solution into physiological environment directly after addition of NaOH, which then self-encapsulates and should give time for organogel formation inside. Furthermore, surgically implanting or applying prepared gels into or onto wounds, which then self-encapsulate upon contact. Moreover, this system can deliver drugs with two mechanisms. Drugs as a solute in the copolymer solution in DMSO can be delivered due to diffusion and temperature. Therefore, such system could find potential applications in slow drug release, where a distribution in small quantities over longer time is needed. Furthermore, targeted drug delivery is possible by transient metal– ligand bonds with some drugs such as Bortezomib.[2]
The mechanical data of this system are comparable to aqueous solution with H3BO3 of the same polymer in moduli and self-healing ability,[24,25] suggesting a transient supramolecular bonding situation for CHB and metal–ligand bonds. When assuming an equivalence of B3+-dicatechol bonds and the hydrogen-bonded species in DMSO, discussed in this article (this assumption is reasonable due to similar moduli), it is safe to assume that at any given time, only a certain fraction of the CHB is closed, making it truly supramolecular and not covalent. Furthermore, widely used DMSO in biomedical technology allows for potential applications as novel drug release systems. The special property of the gel–drug and DMSO release in aqueous environment coupled with selfencapsulation of the gel, leads to versatile possibilities to shape the gel according to patients’ need and then let the body conditions encapsulate the gel, regulating the release rate. The self-encapsulation also allows for generation of slow-releasing drug delivery systems, which can
4. Conclusion While the supramolecular cross-linking of catechols by polyvalent cations is well established for obtaining stimuli-responsive gels, it is a novel concept that solutions of such polymers in aprotic solvents such as DMSO yield stimuli-responsive gels based on H-bonding.[11] By different spectroscopic methods, the reaction and attraction pathways were clearly identified (see Figure 4).
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Figure 4. Scheme of the reactions.
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be easily shaped before implanting where the self-encapsulation will happen. We expect these abilities to lead to new applications for bioinspired and biocompatible materials with superior tunability.
Supporting Information Supporting Information is available from the Wiley Online Library or from the author. Acknowledgements: M.V.-V. and A.G. contributed equally to this work. The authors acknowledge financial aid from the National Research Foundation of Korea (110100713) and Nanshan District Key Lab for Biopolymers and Safety Evaluation (No. KC2014ZDZJ0001A). The authors thank the staff of the CBNU central lab for the help with the NMR-measurements. Received: September 3, 2014; Revised: November 9, 2014; Published online: ; DOI: 10.1002/marc.201400501 Keywords: catechol; drug release; hydrogen bonding; musselinspired; self-healing
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