Macromolecular Rapid Communications
Communication
Templateless Synthesis of PolyacrylamideBased Nanogels via RAFT Dispersion Polymerization Kai Ma, Yuanyuan Xu, Zesheng An* This paper reports on the synthesis of well-defined polyacrylamide-based nanogels via reversible addition–fragmentation chain transfer (RAFT) dispersion polymerization, highlighting a templateless route for the efficient synthesis of nanogels based on water-soluble polymers. RAFT dispersion polymerization of acrylamide in co-nonsolvents of water–tert-butanol mixtures by chain extension from poly(dimethylacrylamide) shows well-controlled polymerization process, uniform nanogel size, and excellent colloidal stability. The versatility of this approach is further demonstrated by introducing a hydrophobic comonomer (butyl acrylate) without disturbing the dispersion polymerization process.
1. Introduction Nanogels with diameters of less than 200 nm are physically or chemically cross-linked polymeric particles swollen with a high water content.[1–5] Their distinct properties including permeable structure, high water content, excellent stability, and multiple functionality have attracted broad interest across multidisciplinary areas of nanotechnology and biotechnology.[6–20] Recently, several sophisticated strategies have been developed to address the challenges for use of nanogels as clinical multifunctional biomaterials.[21–23] From a synthetic point of view, nanogels have been prepared either by cross-linking of functionalized
K. Ma, Y. Xu, Prof. Z. An Institute of Nanochemistry and Nanobiology, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444 , China E-mail: [email protected] K. Ma Department of Chemistry, Shanghai University, Shanghai 200444 , China
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macromolecular precursors or by direct polymerization of monomers. Regardless the starting materials being used, employing inverse emulsion, miniemulsion, and microemulsion as the template is a widely adopted method for the synthesis of nanogels composed of water-soluble polymers.[24–28] The main drawback of this approach is the involvement of volatile organic solvents and labile surfactants. Recently, several approaches for templateless synthesis of nanogels have been developed. For example, Thayumanavan and co-workers have developed a self-cross-linking approach to prepare nanogels from reactive macromolecular precursors directly in water.[29–32] We and others have developed reversible addition–fragmentation chain transfer (RAFT) dispersion polymerization to synthesize well-defined core–shell nanogels in water or water–ethanol mixtures.[33–40] However, it should be noted that the current RAFT dispersion polymerization approach relies on core-forming polymers that are thermally responsive, e.g., poly(isopropylacrylamide)[33,38] and poly(oligo(ethyleneglycol) methyl ether (meth)acrylate).[35,36] While this is an advantage because it provides responsive nanogels directly in one step, on the other hand, water-soluble polymers other than
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DOI: 10.1002/marc.201400730
Templateless Synthesis of Polyacrylamide-Based Nanogels via RAFT Dispersion Polymerization
Macromolecular Rapid Communications www.mrc-journal.de
responsive ones cannot be used for nanogel synthesis, thus limiting the choice of constituent polymers for nanogels. Effective addressing this problem would enhance the capability for tailoring the properties of the nanogels to be synthesized using the elegant RAFT dispersion polymerization, which in turn would allow for more flexible choice of nanogel compositions and functionalities for biomedical applications. Water-soluble polyacrylamide (PAM) has long been used for constructing nanogels in inverse mini-, microemulsions.[25,41–43] Given the popularity of PAM nanogels in various materials applications, the development of a templateless method capitalizing on the power of controlled radical polymerization and the benefits of aqueousbased media are highly appealing. Here, we report the synthesis of PAM-based nanogels employing the cononsolvency property of PAM in solvent mixtures of water and tert-butanol via RAFT dispersion polymerization of acrylamide (AM), in the presence of a cross-linker N,N′methylenebis(acrylamide) (BIS) (for cross-linked nanogels) and 2,2′-azobis(2-methylpropionamidine) dihydrochloride (V-50) as the radical initiator (Scheme 1).
2. Results and Discussion Dispersion polymerization requires that the starting components prior to polymerization should be soluble in the solvent and post-polymerization the generated polymer should be insoluble. Previous work on traditional free radical polymerization of AM in solvent mixtures of water with methanol or tert-butanol pointed to a cononsolvency property of PAM,[44,45] that is PAM becomes less soluble in the mixtures of water with methanol or tert-butanol. We found that more than 60 vol% tert-butanol in the mixture was needed to achieve successful RAFT dispersion polymerization, and optimal results were typically obtained with 70 vol% for PAM-based nanogels (Table S1, Supporting
Information) and 80 vol% tert-butanol for P(AM-co-BA)based nanogels (BA refers to butyl acrylate). A poly(dimethylacrylamide) (PDMA64) macromolecular chain transfer agent (macro-CTA) (Mn,GPC = 7600 g mol−1 and Ð = 1.08) was synthesized by the RAFT process, and was then used as the stabilizing block for chain extension of AM in mixtures of water–tert-butanol to synthesize the nanogels. As shown in Figure 1, polymerization of AM was very fast with 95% conversion being achieved in 3 h, and the polymerization showed pseudo first-order kinetics, indicative of RAFT-controlled polymerization process. Having demonstrated that the dispersion polymerization was under RAFT control, nanogel synthesis was then investigated with different molar ratios of AM/ PDMA, BIS/PDMA, and solids content. The results are summarized in Table 1. When the molar ratio of AM/ PDMA was 100, soluble polymers instead of nanogels were formed, suggesting that effective polymerizationinduced self-assemble[46–48] of the in situ-formed PDMA– PAM was only feasible for longer PAM (Entry 4, Table 1). Well-defined nanogels with Dh, measured by dynamic light scattering (DLS) in the original water–tert-butanol dispersant, smaller than 100 nm were obtained for the molar ratio of AM/PDMA being 200 and larger (Entries 1–3, Table 1). The diameter of a dried nanogel sample (Entry 3, Table 1) by transmission electron microscopy (TEM) (Figure 2A) is 19 ± 10 nm (averaged over 1790 particles), which is much smaller than the Dh (64 nm) measured in water–tert-butanol, suggesting solvation of the PDMA shell as well as partial solvation or plasticization of the PAM core in water–tert-butanol. The D′h (79 nm) measured in water by DLS is larger than Dh (64 nm) measured in water–tert-butanol, suggesting nanogel expansion from a co-nonsolvent to a good solvent. Under the synthetic conditions studied in this work, nanogels could be synthesized up to 10% solids; further increase in solids resulted in the formation of macrogels.
Scheme 1. RAFT dispersion polymerization of AM for the synthesis of nanogels.
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Figure 1. RAFT dispersion polymerization of AM in 30:70 (v:v) water–tert-butanol solution using PDMA64. AM conversion vs reaction time (A), ln ([M]0/[M]) vs reaction time (B). Polymerization conditions: [PDMA64]:[AM]:[V-50] = 1:200:0.4, solids content = 6%, w/v, 70 °C.
Since the size of the synthesized nanogels was within a small range, detailed elucidation of the effect of the molar ratios of AM/PDMA, BIS/PDMA, and V-50/PDMA was not appropriate. Manipulation of nanogel compositions and thus microstructures allows for tailoring of nanogel properties aiming for specific applications. We envisioned that RAFT dispersion polymerization in water–tert-butanol mixtures could ensure reliable incorporation of hydrophobic components into hydrophilic nanogels, which may be useful for the nanogels to encapsulate hydrophobic actives, for instance. To illustrate this important advantage, BA was used as a co-monomer to copolymerize with AM under dispersion polymerization conditions (Table S2, Supporting Information), and the DLS results are presented in Figure 2B. For the synthesis of P(AM-co-BA) nangels, the volume fraction of tert-butanol was increased to
80% in order to allow solubilization of sufficient amount of hydrophobic BA in the formulation. 1H NMR analysis (Supporting Information) suggested that up to 28 mol% of BA could be incorporated into the nanogels with similar sizes being obtained in the co-nonsolvent (Figure 2B), suggesting that introducing BA in the formulation did not disturb the dispersion polymerization process.
3. Conclusion We have developed a RAFT dispersion polymerization in co-nonsolvents for the synthesis of PAM-based nanogels. This approach exhibits excellent pseudo first-order kinetics under RAFT control. Well-defined nanogels composed of either PAM or P(AM-co-BA) with diameters of ≈100 nm or less have been efficiently synthesized under a
Table 1. Summary of RAFT dispersion polymerization for the synthesis of PDMA64-b-P(AM-co-BIS) nanogels.a)
Solid [%]b)
Feeding ratioc)
Dh [nm] (PDI)d)
D′h [nm] (PDI′)e)
Monomer conv.f) [%]
1
6
1:400:5:0.4
71 (0.08)
111 (0.11)
95
2
6
1:300:5:0.4
72 (0.10)
135 (0.24)
87
3
6
1:200:5:0.4
64 (0.01)
79 (0.07)
95
4
6
1:100:5:0.4
–
–
93
5
6
1:200:8:0.4
89 (0.10)
114 (0.26)
93
6
6
1:200:10:0.4
80 (0.07)
100 (0.09)
92
7
6
1:200:13:0.4
–
–
GEL
8
6
1:200:5:1
61 (0.05)
62 (0.19)
99
9
10
1:200:5:0.4
77 (0.04)
93 (0.11)
95
10
15
1:200:5:0.4
–
–
GEL
Entry
conditions: water–tert-butanol (30:70, v, v), 70 °C, 4 h; b)solids content (%, w/v) = mass(PDMA 64+ AM +BIS)/volume(water + tert-butanol); c)Molar ratios of [PDMA64]:[AM]:[BIS]:[V-50]; d)DLS results measured in water–tert-butanol (30:70, v:v) at 25 °C; e)DLS results measured in water at 25 °C; f)Monomer conversion determined by 1H NMR in D2O.
a)Synthetic
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Templateless Synthesis of Polyacrylamide-Based Nanogels via RAFT Dispersion Polymerization
Macromolecular Rapid Communications www.mrc-journal.de
Figure 2. TEM image of a representative nanogel (Entry 3, Table 1) (A) and DLS results for nanogels with different molar fractions of BA, measured in water–tert-butanol (20:80, v:v) at 25 °C (the number in the parenthesis represents the hydrodynamic diameter and PDI) (B).
broad range of conditions. Given that nanogels composed of water-soluble polymers are generally synthesized in inverse emulsion, miniemulsion, and microemulsion using volatile organic solvents and labile surfactants, such dispersion polymerization method has the advantages of having low toxicity, easily tunable size, high solid contents, and controllable architecture and composition. We expect that this approach may be extended to the synthesis of nanogels based on other water-soluble polymers and may find applications in various biomedical fields.
Supporting Information Supporting Information is available from the Wiley Online Library or from the author. Acknowledgements: The authors are grateful for financial support by National Natural Science Foundation of China (21274084) and Program for Innovative Research Team in University (IRT13078), and for assistance of Instrumental Analysis and Research Center, Shanghai University. Received: December 19, 2014; Revised: January 22, 2015; Published online: February 14, 2015; DOI: 10.1002/marc.201400730
Keywords: co-nonsolvents; dispersion polymerization; nanogels; polyacrylamide; RAFT
[1] J. K. Oh, R. Drumright, D. J. Siegwart, K. Matyjaszewski, Prog. Polym. Sci. 2008, 33, 448. [2] A. V. Kabanov, S. V. Vinogradov, Angew. Chem. Int. Ed. 2009, 48, 5418. [3] K. Raemdonck, J. Demeester, S. De Smedt, Soft Matter 2009, 5, 707. [4] R. T. Chacko, J. Ventura, J. M. Zhuang, S. Thayumanavan, Adv. Drug Delivery Rev. 2012, 64, 836.
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[39] J. Rieger, C. Grazon, B. Charleux, D. Alaimo, C. Jerome, J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 2373. [40] C. Grazon, J. Rieger, N. Sanson, B. Charleux, Soft Matter 2011, 7, 3482. [41] D. Gao, H. Xu, M. A. Philbert, R. Kopelman, Nano Lett. 2008, 8, 3320. [42] S. Wang, G. Kim, Y.-E. K. Lee, H. J. Hah, M. Ethirajan, R. K. Pandey, R. Kopelman, ACS Nano 2012, 6, 6843. [43] F. Giuntini, F. Dumoulin, R. Daly, V. Ahsen, E. M. Scanlan, A. S. P. Lavado, J. W. Aylott, G. A. Rosser, A. Beeby, R. W. Boyle, Nanoscale 2012, 4, 2034. [44] K.-C. Lee, S.-E. Lee, B.-K. Song, Macromol. Res. 2002, 10, 140. [45] K.-C. Lee, S.-E. Lee, Y.-J. Choi, B.-K. Song, Macromol. Res. 2004, 12, 213. [46] B. Charleux, G. Delaittre, J. Rieger, F. D’Agosto, Macromolecules 2012, 45, 6753. [47] J.-T. Sun, C.-Y. Hong, C.-Y. Pan, Polym. Chem. 2013, 4, 873. [48] N. J. Warren, S. P. Armes, J. Am. Chem. Soc. 2014, 136, 10174.
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Communication
Templateless Synthesis of PolyacrylamideBased Nanogels via RAFT Dispersion Polymerization Kai Ma, Yuanyuan Xu, Zesheng An* This paper reports on the synthesis of well-defined polyacrylamide-based nanogels via reversible addition–fragmentation chain transfer (RAFT) dispersion polymerization, highlighting a templateless route for the efficient synthesis of nanogels based on water-soluble polymers. RAFT dispersion polymerization of acrylamide in co-nonsolvents of water–tert-butanol mixtures by chain extension from poly(dimethylacrylamide) shows well-controlled polymerization process, uniform nanogel size, and excellent colloidal stability. The versatility of this approach is further demonstrated by introducing a hydrophobic comonomer (butyl acrylate) without disturbing the dispersion polymerization process.
1. Introduction Nanogels with diameters of less than 200 nm are physically or chemically cross-linked polymeric particles swollen with a high water content.[1–5] Their distinct properties including permeable structure, high water content, excellent stability, and multiple functionality have attracted broad interest across multidisciplinary areas of nanotechnology and biotechnology.[6–20] Recently, several sophisticated strategies have been developed to address the challenges for use of nanogels as clinical multifunctional biomaterials.[21–23] From a synthetic point of view, nanogels have been prepared either by cross-linking of functionalized
K. Ma, Y. Xu, Prof. Z. An Institute of Nanochemistry and Nanobiology, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444 , China E-mail: [email protected] K. Ma Department of Chemistry, Shanghai University, Shanghai 200444 , China
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macromolecular precursors or by direct polymerization of monomers. Regardless the starting materials being used, employing inverse emulsion, miniemulsion, and microemulsion as the template is a widely adopted method for the synthesis of nanogels composed of water-soluble polymers.[24–28] The main drawback of this approach is the involvement of volatile organic solvents and labile surfactants. Recently, several approaches for templateless synthesis of nanogels have been developed. For example, Thayumanavan and co-workers have developed a self-cross-linking approach to prepare nanogels from reactive macromolecular precursors directly in water.[29–32] We and others have developed reversible addition–fragmentation chain transfer (RAFT) dispersion polymerization to synthesize well-defined core–shell nanogels in water or water–ethanol mixtures.[33–40] However, it should be noted that the current RAFT dispersion polymerization approach relies on core-forming polymers that are thermally responsive, e.g., poly(isopropylacrylamide)[33,38] and poly(oligo(ethyleneglycol) methyl ether (meth)acrylate).[35,36] While this is an advantage because it provides responsive nanogels directly in one step, on the other hand, water-soluble polymers other than
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DOI: 10.1002/marc.201400730
Templateless Synthesis of Polyacrylamide-Based Nanogels via RAFT Dispersion Polymerization
Macromolecular Rapid Communications www.mrc-journal.de
responsive ones cannot be used for nanogel synthesis, thus limiting the choice of constituent polymers for nanogels. Effective addressing this problem would enhance the capability for tailoring the properties of the nanogels to be synthesized using the elegant RAFT dispersion polymerization, which in turn would allow for more flexible choice of nanogel compositions and functionalities for biomedical applications. Water-soluble polyacrylamide (PAM) has long been used for constructing nanogels in inverse mini-, microemulsions.[25,41–43] Given the popularity of PAM nanogels in various materials applications, the development of a templateless method capitalizing on the power of controlled radical polymerization and the benefits of aqueousbased media are highly appealing. Here, we report the synthesis of PAM-based nanogels employing the cononsolvency property of PAM in solvent mixtures of water and tert-butanol via RAFT dispersion polymerization of acrylamide (AM), in the presence of a cross-linker N,N′methylenebis(acrylamide) (BIS) (for cross-linked nanogels) and 2,2′-azobis(2-methylpropionamidine) dihydrochloride (V-50) as the radical initiator (Scheme 1).
2. Results and Discussion Dispersion polymerization requires that the starting components prior to polymerization should be soluble in the solvent and post-polymerization the generated polymer should be insoluble. Previous work on traditional free radical polymerization of AM in solvent mixtures of water with methanol or tert-butanol pointed to a cononsolvency property of PAM,[44,45] that is PAM becomes less soluble in the mixtures of water with methanol or tert-butanol. We found that more than 60 vol% tert-butanol in the mixture was needed to achieve successful RAFT dispersion polymerization, and optimal results were typically obtained with 70 vol% for PAM-based nanogels (Table S1, Supporting
Information) and 80 vol% tert-butanol for P(AM-co-BA)based nanogels (BA refers to butyl acrylate). A poly(dimethylacrylamide) (PDMA64) macromolecular chain transfer agent (macro-CTA) (Mn,GPC = 7600 g mol−1 and Ð = 1.08) was synthesized by the RAFT process, and was then used as the stabilizing block for chain extension of AM in mixtures of water–tert-butanol to synthesize the nanogels. As shown in Figure 1, polymerization of AM was very fast with 95% conversion being achieved in 3 h, and the polymerization showed pseudo first-order kinetics, indicative of RAFT-controlled polymerization process. Having demonstrated that the dispersion polymerization was under RAFT control, nanogel synthesis was then investigated with different molar ratios of AM/ PDMA, BIS/PDMA, and solids content. The results are summarized in Table 1. When the molar ratio of AM/ PDMA was 100, soluble polymers instead of nanogels were formed, suggesting that effective polymerizationinduced self-assemble[46–48] of the in situ-formed PDMA– PAM was only feasible for longer PAM (Entry 4, Table 1). Well-defined nanogels with Dh, measured by dynamic light scattering (DLS) in the original water–tert-butanol dispersant, smaller than 100 nm were obtained for the molar ratio of AM/PDMA being 200 and larger (Entries 1–3, Table 1). The diameter of a dried nanogel sample (Entry 3, Table 1) by transmission electron microscopy (TEM) (Figure 2A) is 19 ± 10 nm (averaged over 1790 particles), which is much smaller than the Dh (64 nm) measured in water–tert-butanol, suggesting solvation of the PDMA shell as well as partial solvation or plasticization of the PAM core in water–tert-butanol. The D′h (79 nm) measured in water by DLS is larger than Dh (64 nm) measured in water–tert-butanol, suggesting nanogel expansion from a co-nonsolvent to a good solvent. Under the synthetic conditions studied in this work, nanogels could be synthesized up to 10% solids; further increase in solids resulted in the formation of macrogels.
Scheme 1. RAFT dispersion polymerization of AM for the synthesis of nanogels.
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Figure 1. RAFT dispersion polymerization of AM in 30:70 (v:v) water–tert-butanol solution using PDMA64. AM conversion vs reaction time (A), ln ([M]0/[M]) vs reaction time (B). Polymerization conditions: [PDMA64]:[AM]:[V-50] = 1:200:0.4, solids content = 6%, w/v, 70 °C.
Since the size of the synthesized nanogels was within a small range, detailed elucidation of the effect of the molar ratios of AM/PDMA, BIS/PDMA, and V-50/PDMA was not appropriate. Manipulation of nanogel compositions and thus microstructures allows for tailoring of nanogel properties aiming for specific applications. We envisioned that RAFT dispersion polymerization in water–tert-butanol mixtures could ensure reliable incorporation of hydrophobic components into hydrophilic nanogels, which may be useful for the nanogels to encapsulate hydrophobic actives, for instance. To illustrate this important advantage, BA was used as a co-monomer to copolymerize with AM under dispersion polymerization conditions (Table S2, Supporting Information), and the DLS results are presented in Figure 2B. For the synthesis of P(AM-co-BA) nangels, the volume fraction of tert-butanol was increased to
80% in order to allow solubilization of sufficient amount of hydrophobic BA in the formulation. 1H NMR analysis (Supporting Information) suggested that up to 28 mol% of BA could be incorporated into the nanogels with similar sizes being obtained in the co-nonsolvent (Figure 2B), suggesting that introducing BA in the formulation did not disturb the dispersion polymerization process.
3. Conclusion We have developed a RAFT dispersion polymerization in co-nonsolvents for the synthesis of PAM-based nanogels. This approach exhibits excellent pseudo first-order kinetics under RAFT control. Well-defined nanogels composed of either PAM or P(AM-co-BA) with diameters of ≈100 nm or less have been efficiently synthesized under a
Table 1. Summary of RAFT dispersion polymerization for the synthesis of PDMA64-b-P(AM-co-BIS) nanogels.a)
Solid [%]b)
Feeding ratioc)
Dh [nm] (PDI)d)
D′h [nm] (PDI′)e)
Monomer conv.f) [%]
1
6
1:400:5:0.4
71 (0.08)
111 (0.11)
95
2
6
1:300:5:0.4
72 (0.10)
135 (0.24)
87
3
6
1:200:5:0.4
64 (0.01)
79 (0.07)
95
4
6
1:100:5:0.4
–
–
93
5
6
1:200:8:0.4
89 (0.10)
114 (0.26)
93
6
6
1:200:10:0.4
80 (0.07)
100 (0.09)
92
7
6
1:200:13:0.4
–
–
GEL
8
6
1:200:5:1
61 (0.05)
62 (0.19)
99
9
10
1:200:5:0.4
77 (0.04)
93 (0.11)
95
10
15
1:200:5:0.4
–
–
GEL
Entry
conditions: water–tert-butanol (30:70, v, v), 70 °C, 4 h; b)solids content (%, w/v) = mass(PDMA 64+ AM +BIS)/volume(water + tert-butanol); c)Molar ratios of [PDMA64]:[AM]:[BIS]:[V-50]; d)DLS results measured in water–tert-butanol (30:70, v:v) at 25 °C; e)DLS results measured in water at 25 °C; f)Monomer conversion determined by 1H NMR in D2O.
a)Synthetic
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Templateless Synthesis of Polyacrylamide-Based Nanogels via RAFT Dispersion Polymerization
Macromolecular Rapid Communications www.mrc-journal.de
Figure 2. TEM image of a representative nanogel (Entry 3, Table 1) (A) and DLS results for nanogels with different molar fractions of BA, measured in water–tert-butanol (20:80, v:v) at 25 °C (the number in the parenthesis represents the hydrodynamic diameter and PDI) (B).
broad range of conditions. Given that nanogels composed of water-soluble polymers are generally synthesized in inverse emulsion, miniemulsion, and microemulsion using volatile organic solvents and labile surfactants, such dispersion polymerization method has the advantages of having low toxicity, easily tunable size, high solid contents, and controllable architecture and composition. We expect that this approach may be extended to the synthesis of nanogels based on other water-soluble polymers and may find applications in various biomedical fields.
Supporting Information Supporting Information is available from the Wiley Online Library or from the author. Acknowledgements: The authors are grateful for financial support by National Natural Science Foundation of China (21274084) and Program for Innovative Research Team in University (IRT13078), and for assistance of Instrumental Analysis and Research Center, Shanghai University. Received: December 19, 2014; Revised: January 22, 2015; Published online: February 14, 2015; DOI: 10.1002/marc.201400730
Keywords: co-nonsolvents; dispersion polymerization; nanogels; polyacrylamide; RAFT
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