Article Cite This: Macromolecules XXXX, XXX, XXX−XXX
Visible Light-Mediated Polymerization-Induced Self-Assembly Using Continuous Flow Reactors Neomy Zaquen,†,‡,§ Jonathan Yeow,†,‡ Tanja Junkers,*,§,∥ Cyrille Boyer,*,†,‡ and Per B. Zetterlund*,† Centre for Advanced Macromolecular Design (CAMD) and ‡Australian Center for Nanomedicine, The University of New South Wales, High Street Gate 2, 2033 Kensington, Sydney, Australia § Organic and Bio-Polymer Chemistry (OBPC), Universiteit Hasselt, Agoralaan Building D, 3590 Diepenbeek, Belgium ∥ Polymer Reaction Design Group, School of Chemistry, 19 Rainforest Walk, Monash University, VIC 3800, Melbourne, Australia Downloaded via TUFTS UNIV on July 7, 2018 at 00:51:23 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
S Supporting Information *
ABSTRACT: We present the synthesis of polymeric nanoparticles of targeted morphology in a continuous process via visible light-mediated aqueous RAFT polymerization-induced self-assembly (PISA). A trithiocarbonate-derived poly(ethylene glycol) (PEG) macroRAFT was activated in the presence of hydroxypropyl methacrylate (HPMA) at 37 °C under blue light irradiation (460 nm), leading to the formation of PEG-b-P(HPMA) nanoparticles. The method is attractive in its simplicityspheres, worms, and vesicles can easily be obtained in a continuous fashion with higher control in comparison to conventional batch procedures. This allows for more accurate production of particle morphologies and scalable synthesis of these nano-objects. The versatility of this process was demonstrated by the in situ encapsulation of an active compound.
1. INTRODUCTION RAFT dispersion polymerization-induced self-assembly (PISA)1−4 has grown to become one of the most useful methods for synthesis of nanoparticles with a wide range of morphologies in aqueous media,5−11 alcoholic systems,12−16 organic solvents,17−21 ionic liquids,22,23 and supercritical carbon dioxide.24 The most common method to conduct controlled/living radical polymerization techniques such as RAFT PISA is via thermal activation. Over the past few years, photoinitiated RAFT PISA has emerged as a rapid and environmentally friendly way of accessing different morphologies under mild conditions.11,15,25,26 The use of visible light has the advantage of allowing spatiotemporal control and enables synthesis of pure morphologies over a broad range of conditions.27−31 In addition, excellent control over the polymerization is obtained due to the occurrence of less side reactions. While significant advances have been made for optimizing these processese.g., synthesis in the absence of photocatalyst/initiator11,15 and circumventing the need for degassing32,33 allowing PISA to be conducted in small volumes34,35there are still major issues concerning the scalability of PISA processes. Virtually any morphology in a solvent of choice is accessible nowadays, but most of the reactions are typically carried out on the milligram scale. As a result, materials are only available in small quantities with batch-to-batch variations, and thus commercialization of new complex materials is hampered.36−39 Microreactor technology © XXXX American Chemical Society
(MRT) has emerged as an attractive tool to bridge this gap.36−42 In recent years, MRT has established itself as a reliable and widely available technique for synthesis of complex materials. The high surface-to-volume ratio enables excellent thermal control over the reaction, leading to less side reactions and improved reproducibility and control over the polymerization.36−42 In general, the flow rates in microreactors are small (Reynolds number 60 min). Visual inspection and DLS results revealed the formation of stable dispersions of nanoparticles in the range of 245−300 nm and polydispersity (PDI) values between 0.23 and 0.35 (Figure S8). TEM (Figure 2, Figures S9 and S10) micrographs demonstrated the successful production of spheres, worms, and vesicles or a mixture of morphologies. These results demonstrated how the morphology can be conveniently dialed-in via the flow rate by adjusting the residence time and thus the monomer conversion which changes the length of the solvophobic block (F1−F8, Table S1). It has to be mentioned that the first trials for these reactions were performed using a syringe pump (New Era 1000 series). In those cases, conversion measurements never reached high values (99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99
7300 21700 28900 36100 43300 50600 57800 65000 21700 28900 36100 43300 50600 57800 65000
8500 26000 32400 48100 49000 56600 65000 77100 24500 27300 33400 38200 45300 52200 58000
11800 29000 35300 49400 57400 61900 70700 74300 24800 27700 38300 42100 44800 53600 65700
1.16 1.17 1.19 1.17 1.29 1.47 1.23 1.27 1.17 1.18 1.25 1.32 1.49 1.54 1.62
100 150 200 250 300 350 400 100 150 200 250 300 350 400
46 83 88 88 114 315 313 70 50 52 163 199 131 111
± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.41 0.27 0.27 0.13 0.32 0.21 0.18 0.42 0.37 0.31 0.32 0.39 0.25 0.22
S+W W W+V W+V V V V W W W W+V V V V
2 1 3 1 3 2 2 1 2 1 13 13 1 2
Experimental conditions: solvent, water; light source, blue LED light (λmax = 460 nm) with an intensity of 1.6 mW cm−2 and a solid content of 20 wt %. bBatch reactions are coded with the letter “B” and flow reactions with the letter “F”. cMonomer conversions were determined via 1H NMR spectroscopy (CD3OD). dTheoretical molecular weight was calculated using the following equation: Mn,th = [M]0/[PEG-CDTPA] × MWM × α + MWPEG‑CDTPA, where [M]0, [PEG-CDTPA], MWM, α, and MWPEG‑CDTPA correspond to the initial monomer concentration, initial macroRAFT concentration, molar mass of the monomer, conversion determined by 1H NMR, and the molar mass of the macroRAFT, respectively. eMolecular weight and polydispersity (Đ) were determined by SEC analysis calibrated to poly(methyl methacrylate) standards. fParticle diameter and polydispersity index (PDI) were determined by DLS analysis in water. gMorphology as observed by TEM analysis; S = spheres, W = worms, V = vesicles. a
Figure 3. Representative TEM images for aqueous RAFT dispersion PISA in batch (top) and flow (bottom) for targeted degrees of polymerization. Corresponding polymerization data can be found in Table 1. Assignment of the morphology for DP 200 (batch) was based on the literature.11
formation of worm-like particles is accompanied by an increase in viscosity as compared to the formation of spherical particles. As such, a switch to ASIA syringe pumps was made, as these
pumps were capable of pressures up to 20 bar, in comparison to the 5 bar for the New Era syringe pumps. D
DOI: 10.1021/acs.macromol.8b00887 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Figure 4. Reactor setup for the synthesis of PEG-b-P(HPMA) nanoparticles enabling monitoring of particle morphology.
results indicated formation of stable particles between 50 and 200 nm in size (Figure S15). TEM micrographs showed the morphology evolution from worms to vesicles (Figure 3) upon targeting DP100 to DP400. Small differences in morphology were observed when comparing batch and flow results at similar reaction conditions. It seemed that worm-like particles could be obtained over a larger targeted DP-range than in flow. Although flow reactions performed in millireactors are mostly limited to laminar flow, flow gives access to more defined conditions for nano-object formation, minimizing random effects from stirring in batch. This effect is mostly pronounced upon increasing viscosity of the reaction mixture, as is the case upon the formation of worm-like particles. However, by comparing the Mn values of batch and flow (Table 1), the large targeted DP range to obtain worms could be related to the actual molecular weights obtained via SEC measurements (although full conversion was observed via 1H NMR for each sample). Nevertheless, for the first time a protocol was developed in which particles of different morphology (spheres, worms, and vesicles) can be obtained in a continuous process. Further increasing the DP to 400 led to the formation of patchy vesicles. Vesicles are commonly reported morphologies in RAFT dispersion PISA;59,60 however, patchy vesicles have to the best of our knowledge so far only been observed when synthesizing multicompartment particles using two different macro-RAFT agents.61,62 Further examination of these patchy vesicles using SEM indicated that these structures are hollow (F24, Figure S17). Thus, morphology analysis convincingly shows that photoinitiated RAFT PISA in flow leads to morphologies which are inaccessible in batch under similar reaction conditions. Because of more defined reaction conditions in flow, small PEG domains might form leading to patchy vesicles. Further research to elucidate the exact structure of these particles and their formation process is currently ongoing. The robustness of the process was subsequently demonstrated by conducting the flow process for a prolonged period of 8 h. Performing reactions in flow enables continuous input of material into the reactor, thereby continuously generating product. However, prolonged polymerization may cause disruption of the continuous flow (due to e.g. fouling leading to clogging) which might influence the particle morphology.63,64 Experiment F16 (Table S1) was thus repeated for 8 h, yielding 20 g of polymeric nanoparticles exhibiting the same morphology as obtained after 1 h (F16A, Figure S13). The
After demonstrating that an increase in light intensity enabled full monomer conversion in 90 min, higher solid contents of 17.5 (F9−F12; Table S1) and 20 wt % (F13−F17) were targeted at varying residence times. All reactions reached full monomer conversion within 90 min of residence time. The higher dispersity values (Đ > 1.5) at high conversion were caused by the increased viscosity, which is typically observed for RAFT PISA (Table S1 and Figure S7).57,58 However, in all cases the increased viscosity did not result in blockage of the reactor. TEM micrographs (Figure S11) showed similar morphology changes for 17.5 wt % solid content as was previously observed for 15 wt % solid content with increasing conversion. A further increase to 20 wt % solid content (Figure S12) ultimately led to vesicle formation above 88% monomer conversion. These results showed that spheres, worms, and vesicles can be readily obtained by simply varying the solid content. As an increase in solid content up to 20 wt % gave access to pure vesiclesin contrast to the mixed phases obtained at lower solid contentsthis solid content (combined with a light intensity of 1.6 mW cm−2) was chosen as a standard recipe and used for the continuation of this work. While variation of the residence time is a convenient tool to preselect the morphology, targeting different morphologies at full conversion is more desirable. Hence, batch and flow reactions were conducted to full monomer conversion for a variety of targeted DPs of the second block (DP100 to DP400, Table 1). To compare batch and flow experiment outcomes, all reaction conditions were kept equal, with the type of reactionbatch or flowbeing the only variable. In this way, the possible effect of the flow characteristics on the particle morphology could be highlighted. SEC chromatograms of the batch polymerizations clearly showed the expected shift toward higher molecular weights upon increasing DP from 100 to 400 (B1−B7, Table 1, and Figure S16). Mn values up to 77 000 g mol−1 with Đ = 1.27 were easily reached within 6 h of reaction time. The corresponding DLS data indicated stable particles with a size range of 46−315 nm and PDI between 0.21 and 0.41 (Figure S15). TEM micrographs showed the expected transition from spheres/worms (DP100) to worms (DP150) and finally vesicles (DP ≥ 300, Figure 2).11 SEC results upon targeting DPs in flow showed a similar shift toward high molecular weights with increasing DP (F18−F24, Table 1). In 75 min, full monomer conversion and Mn values of 58 000 g mol−1 with Đ = 1.62 were reached as compared with the 6 h required in batch to obtain similar results. DLS E
DOI: 10.1021/acs.macromol.8b00887 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Table 2. Polymerization Conditions for Aqueous RAFT Dispersion PISA in Flow Generating PEG113-b-P(HPMA)x Particles via the Photoiniferter Route under Blue LED Irradiation at Varying Tube Lengthsa codeb A F28g F29g F27g
intensity (mW cm−2) 1.6 1.6 1.6
flow rate (mL h−1) 3 3 3
time (min)
αb (%)
Mn,thc (g mol−1)
Mnd (g mol−1)
Đd
DP
Dne (nm)
PDIe
morphology
60 60 60
58 25 67 97
7500 23200 45600 63300
9100 15400 41800 67100
1.06 1.12 1.40 1.62
100 270 390
77 ± 1 171 ± 6 97 ± 3
0.16 0.33 0.18
S W+V V
a
Experimental conditions: solvent, water; light source, blue LED light (λmax = 460 nm). bMonomer conversions were determined via 1H NMR spectroscopy (CD3OD). cTheoretical molecular weight was calculated using the following equation: Mn,th = [M]0/[PEG-CDTPA] × MWM × α + MWPEG‑CDTPA, where [M]0, [PEG-CDTPA], MWM, α, and MWPEG‑CDTPA correspond to the initial monomer concentration, initial macroRAFT concentration, molar mass of the monomer, conversion determined by 1H NMR, and the molar mass of the macroRAFT, respectively. dMolecular weight and polydispersity (Đ) were determined by SEC analysis calibrated to poly(methyl methacrylate) standards. eParticle diameter and polydispersity index (PDI) were determined by DLS analysis in water. fMorphology as observed by TEM analysis; S = spheres, W = worms, V = vesicles. gA 3 mL tube was used with dedicated T-pieces to collect material at dedicated volumes 1 mL (F28), 2 mL (F29), and 3 mL (F27).
proceeded rapidly, reaching full monomer conversion in only 75 min as compared to 6 h in batch. A protocol was developed by optimizing the light intensity, solid content, and residence time in the reactor, leading to the formation of a wide range of morphologies (spheres, worms, and vesicles). By doing so, a continuous process was developed in which 60 g of polymeric material per day can be produced, as compared to the milligram scale obtained via batch reactions. Importantly, once steady state conditions have been reached in the reactor, the particle morphology remains constant with time, allowing continuously producing the desired nano-objects with high precision. This opens the door for biomedical application as materials are made available in larger quantities while avoiding batch-to-batch variations. Finally, a potential application of this process was demonstrated by the in situ encapsulation of an active compound.
particle size was estimated from TEM micrographs and showed uniformity of the particles (size mean = 392 nm and STDEV = 26 nm, Figure S14 and Table S2). Importantly, this procedure allows production of 60 g of polymeric nanoparticles per day in a continuous process, as compared to the milligram scale typically accessible via RAFT photo-PISA batch reactions. The effect of flow rate on the morphology was subsequently explored by increasing the flow rate from 1 mL h−1 (1 mL reactor, F19, F22, and F24, Table 1) to 3 mL h−1 (3 mL reactor, F25, F26, and F27, Table S3). Equal reaction conditions were tested in which DPs of 150, 300, and 400 were targeted for both flow rates. TEM micrographs indicated the formation of worms (F19, F25), vesicles (F22, F26), or patchy vesicles (F24 and F27, Figure S20). The morphology was thus not significantly affected by increasing the flow rate from 1 to 3 mL h−1 under similar reaction conditions. One of the advantages of performing reactions in a tubular reactor is the possibility of tuning the monomer conversion along the reactor. To demonstrate this concept, a T-piece was positioned after each 1 mL volume increment, so that material at designated volumes could be collected (1, 2, and 3 mL, Figure 4). 1H NMR results clearly showed an increase in conversion upon sampling at these different points. These results were consistent with SEC and DLS data (Table 2, Figures S18 and S19). TEM images showed the evolution of the morphology from spheres (1 mL, F28, Figure S20) to a mixture of worms and vesicles (2 mL, F29) and finally patchy vesicles (3 mL, F27). Finally, the in situ encapsulation of an active compound (doxorubicin) was realized to demonstrate the potential of this PISA photo flow process. Experiment F16 (Table S1) was thus repeated with a drugdoxorubicinencapsulated in situ (F30 Table S4) and subsequently dialyzed against water (F31). TEM imaging showed the formation of vesicles (Figure S23). Successful encapsulation was confirmed by UV−vis measurements with an encapsulation efficiency of approximately 6.5 wt %similar to values obtained in the literature65 (Figures S21 and S22)corresponding to a doxorubicin loading of 0.5 wt % relative to polymer.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b00887. Details of the materials and characterization methods used, reactor setup, synthesis protocols, analysis results (1H NMR, SEC, DLS, TEM) for both batch and flow reactions (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail
[email protected] (T.J.). *E-mail
[email protected] (C.B.). *E-mail
[email protected] (P.B.Z.). ORCID
Tanja Junkers: 0000-0002-6825-5777 Cyrille Boyer: 0000-0002-4564-4702 Per B. Zetterlund: 0000-0003-3149-4464 Funding
MCSC-IF-GF applicant no. 12U1717N. Notes
The authors declare no competing financial interest.
4. CONCLUSIONS In summary, a process for the continuous synthesis of welldefined polymeric nanoparticles by aqueous photoiniferter RAFT PISA has been developed using flow reactor technology. Polymerizations of HPMA employing a PEG-based macroRAFT were induced using blue LED light. Reactions
■
ACKNOWLEDGMENTS The European Union Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 665501 with the research Foundation Flanders (FWO) F
DOI: 10.1021/acs.macromol.8b00887 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
formation of nano-objects via dispersion polymerization in alcoholic medium. Polym. Chem. 2014, 5 (24), 6990−7003. (14) Garrett, E. T.; Pei, Y.; Lowe, A. B. Microwave-assisted synthesis of block copolymer nanoparticles via RAFT with polymerizationinduced self-assembly in methanol. Polym. Chem. 2016, 7 (2), 297− 301. (15) Yeow, J.; Sugita, O. R.; Boyer, C. Visible Light-Mediated Polymerization-Induced Self-Assembly in the Absence of External Catalyst or Initiator. ACS Macro Lett. 2016, 5 (5), 558−564. (16) Zhu, A.; Lv, X.; Shen, L.; Zhang, B.; An, Z. PolymerizationInduced Cooperative Assembly of Block Copolymer and Homopolymer via RAFT Dispersion Polymerization. ACS Macro Lett. 2017, 6 (3), 304−309. (17) Derry, M. J.; Fielding, L. A.; Armes, S. P. Industrially-relevant polymerization-induced self-assembly formulations in non-polar solvents: RAFT dispersion polymerization of benzyl methacrylate. Prog. Polym. Sci. 2016, 52, 1−18. (18) Fielding, L. A.; Derry, M. J.; Ladmiral, V.; Rosselgong, J.; Rodrigues, A. M.; Ratcliffe, L. P. D.; Sugihara, S.; Armes, S. P. RAFT dispersion polymerization in non-polar solvents: facile production of block copolymer spheres, worms and vesicles in n-alkanes. Chem. Sci. 2013, 4 (5), 2081−2087. (19) Derry, M. J.; Mykhaylyk, O. O.; Armes, S. P. A vesicle-to- worm transition provides a new high-temperature oil thickening mechanism. Angew. Chem., Int. Ed. 2017, 56 (7), 1746−1750. (20) Kang, Y.; Pitto-Barry, A.; Maitland, A.; O’Reilly, R. K. RAFT dispersion polymerization: a method to tune the morphology of thymine-containing self-assemblies. Polym. Chem. 2015, 6 (27), 4984−4992. (21) Ratcliffe, L. P. D.; McKenzie, B. E.; Le Bouëdec, G. M. D.; Williams, C. N.; Brown, S. L.; Armes, S. P. Polymerization-Induced Self-Assembly of All-Acrylic Diblock Copolymers via RAFT Dispersion Polymerization in Alkanes. Macromolecules 2015, 48 (23), 8594−8607. (22) Zhou, H.; Liu, C.; Gao, C.; Qu, Y.; Shi, K.; Zhang, W. Polymerization-induced self-assembly of block copolymer through dispersion RAFT polymerization in ionic liquid. J. Polym. Sci., Part A: Polym. Chem. 2016, 54 (11), 1517−1525. (23) Zhang, B.; Yan, X.; Alcouffe, P.; Charlot, A.; Fleury, E.; Bernard, J. Aqueous RAFT Polymerization of Imidazolium-Type Ionic Liquid Monomers: En Route to Poly(ionic liquid)-Based Nanoparticles through RAFT Polymerization-Induced Self-Assembly. ACS Macro Lett. 2015, 4 (9), 1008−1011. (24) Jennings, J.; Beija, M.; Richez, A. P.; Cooper, S. D.; Mignot, P. E.; Thurecht, K. J.; Jack, K. S.; Howdle, S. M. One-pot synthesis of block copolymers in supercritical carbon dioxide: a simple versatile route to nanostructured microparticles. J. Am. Chem. Soc. 2012, 134 (10), 4772−4781. (25) Jiang, Y.; Xu, N.; Han, J.; Yu, Q.; Guo, L.; Gao, P.; Lu, X.; Cai, Y. The direct synthesis of interface-decorated reactive block copolymer nanoparticles via polymerisation-induced self-assembly. Polym. Chem. 2015, 6, 4955−4965. (26) Tan, J.; Sun, H.; Yu, M.; Sumerlin, B. S.; Zhang, L. Photo-PISA: Shedding Light on Polymerization-Induced Self-Assembly. ACS Macro Lett. 2015, 4 (11), 1249−1253. (27) Rieger, J. Guidelines for the Synthesis of Block Copolymer Particles of Various Morphologies by RAFT Dispersion Polymerization. Macromol. Rapid Commun. 2015, 36 (16), 1458−1471. (28) Charleux, B.; Delaittre, G.; Rieger, J.; D’Agosto, G. Polymerization-Induced Self-Assembly: From Soluble Macromolecules to Block Copolymer Nano-Objects in One Step. Macromolecules 2012, 45 (17), 6753−6765. (29) Pan, X.; Tasdelen, M. A.; Laun, J.; Junkers, T.; Yagci, Y.; Matyjaszewski, K. Photomediated controlled radical polymerization. Prog. Polym. Sci. 2016, 62, 73−125. (30) Chen, M.; Zhong, M.; Johnson, J. A. Light-Controlled Radical Polymerization: Mechanisms, Methods, and Applications. Chem. Rev. 2016, 116 (17), 10167−10211.
(N.Z). The authors thank Dr Rhiannon Kuchel for technical assistance and use of facilities at the Electron Microscope Unit at UNSW. Dr. Florent Jasinski is acknowledged for his support in this project.
■
ABBREVIATIONS CD 3 OD, deuterated methanol; CDTPA, 4-cyano-4[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid; DLS, dynamic light scattering; Dn, number-average diameter; Đ, dispersity; DP, degree of polymerization; HPMA, hydroxypropyl methacrylate; LED, light-emitting diode; Mn, numberaverage molecular weight; MRT, microreactor technoology; 1 H NMR, proton nuclear magnetic resonance; PDI, polydispersity index; PEG, poly(ethylene glycol); PFA, perfluoroalkoxy; PISA, polymerization-induced self-assembly; RAFT, reversible addition−fragmentation chain transfer polymerization; S, spheres; SEC, size exclusion chromatography; TEM, transmission electron microscopy; UV−vis, ultraviolet−visible spectroscopy; V, vesicles; W, worms; wt %, mass-based weight percentage.
■
REFERENCES
(1) Zetterlund, P. B.; Thickett, S. C.; Perrier, S.; Bourgeat-Lami, E.; Lansalot, M. Controlled/Living Radical Polymerization in Dispersed Systems: An Update. Chem. Rev. 2015, 115 (18), 9745−9800. (2) Canning, S. L.; Smith, G. N.; Armes, S. P. A Critical Appraisal of RAFT-Mediated Polymerization-Induced Self-Assembly. Macromolecules 2016, 49 (6), 1985−2001. (3) Lowe, A. RAFT alcoholic dispersion polymerization with polymerization-induced self-assembly. Polymer 2016, 106, 161−181. (4) Yeow, J.; Boyer, C. Photoinitiated Polymerization-Induced SelfAssembly (Photo-PISA): New Insights and Opportunities. Adv. Sci. 2017, 4 (7), 1700137. (5) Li, Y.; Armes, S. P. RAFT synthesis of sterically stabilized methacrylic nanolatexes and vesicles by aqueous dispersion polymerization. Angew. Chem., Int. Ed. 2010, 49 (24), 4042−4046. (6) Blanazs, A.; Madsen, J.; Battaglia, G.; Ryan, A. J.; Armes, S. P. Mechanistic insights for block copolymer morphologies: how do worms form vesicles? J. Am. Chem. Soc. 2011, 133 (41), 16581− 16587. (7) Warren, N. J.; Armes, S. P. Polymerization-induced self-assembly of block copolymer nano-objects via RAFT aqueous dispersion polymerization. J. Am. Chem. Soc. 2014, 136 (29), 10174−10185. (8) Doncom, K. E. B.; Warren, N. J.; Armes, S. P. Polysulfobetainebased diblock copolymer nano-objects via polymerization-induced self-assembly. Polym. Chem. 2015, 6 (41), 7264−7273. (9) Warren, N. J.; Mykhaylyk, O. O.; Mahmood, D.; Ryan, A. J.; Armes, S. P. RAFT Aqueous Dispersion Polymerization Yields Poly(ethylene glycol)-Based Diblock Copolymer Nano-Objects with Predictable Single Phase Morphologies. J. Am. Chem. Soc. 2014, 136 (3), 1023−1033. (10) Zhou, W.; Qu, Q.; Xu, Y.; An, Z. Aqueous PolymerizationInduced Self-Assembly for the Synthesis of Ketone-Functionalized Nano-Objects with Low Polydispersity. ACS Macro Lett. 2015, 4 (5), 495−499. (11) Blackman, L. B.; Doncom, K. E. B.; Gibson, M. I.; O’Reilly, R. K. Comparison of photo- and thermally initiated polymerizationinduced self-assembly: a lack of end group fidelity drives the formation of higher order morphologies. Polym. Chem. 2017, 8 (18), 2860−2871. (12) Huo, M.; Ye, Q.; Che, H.; Wang, X.; Wei, Y.; Yuan, J. Polymer Assemblies with Nanostructure-Correlated Aggregation-Induced Emission. Macromolecules 2017, 50 (18), 1126−1133. (13) Zhao, W.; Gody, G.; Dong, S.; Zetterlund, P. B.; Perrier, S. Optimization of the RAFT polymerization conditions for the in situ G
DOI: 10.1021/acs.macromol.8b00887 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Polymeric Micro and Nanoparticles with Controlled Size, Morphology, and Composition. Macromol. React. Eng. 2013, 7 (9), 414−439. (52) Asua, J. M. Challenges and Opportunities in Continuous Production of Emulsion Polymers: a Review. Macromol. React. Eng. 2016, 10 (4), 311−323. (53) Chemtob, A.; Lobry, E.; Rannée, A.; Jasinski, F.; Penconi, M.; Oliveros, E.; Braun, A. M.; Criqui, A. Flash Latex Production in a Continuous Helical Photoreactor: Releasing the Brake Pedal on Acrylate Chain Radical Polymerization. Macromol. React. Eng. 2016, 10 (3), 261−268. (54) Peng, J.; Tian, C.; Zhang, L.; Cheng, Z.; Zhu, Z. The in situ formation of nanoparticles via RAFT polymerization-induced selfassembly in a continuous tubular reactor. Polym. Chem. 2017, 8 (9), 1495−1506. (55) Xu, J.; Shanmugan, S.; Corrigan, N. A.; Boyer, C. Catalyst- Free Visible Light-Induced RAFT Photopolymerization, ACS Symposium Series 1187; American Chemical Society: 2015; pp 247−267. (56) McKenzie, T. G.; Fu, Q.; Wong, E. H. H.; Dunstan, D. E.; Qiao, G. G. Visible Light Mediated Controlled Radical Polymerization in the Absence of Exogenous Radical Sources or Catalysts. Macromolecules 2015, 48 (12), 3864−3872. (57) Tan, J.; Liu, D.; Bai, Y.; Huang, C.; Li, X.; He, J.; Xu, Q.; Zhang, X.; Zhang, L. An insight into aqueous photoinitiated polymerization-induced self-assembly (photo-PISA) for the preparation of diblock copolymer nano-objects. Polym. Chem. 2017, 8 (8), 1315−1327. (58) Jones, E. R.; Mykhaylyk, O. O.; Semsarilar, M.; Boerakker, M.; Wyman, P.; Armes, S. P. How Do Spherical Diblock Copolymer Nanoparticles Grow during RAFT Alcoholic Dispersion Polymerization? Macromolecules 2016, 49 (22), 172−181. (59) Puig, J.; Ceolin, M.; Williams, R. J. J.; Schroeder, W. F.; Zucchi, I. A. Controlling the generation of bilayer and multilayer vesicles in block copolymer/epoxy blends by a slow photopolymerization process. Soft Matter 2017, 13 (40), 7341−7351. (60) Zhang, X.-Y.; Liu, D.-M.; Lv, X.-H.; Sun, M.; Sun, X.-L.; Wan, W.-M. RAFT-Polymerization-Induced Self-Assembly and Reorganizations: Ultrahigh-Molecular-Weight Polymer and Morphology-Tunable Micro-/Nanoparticles in One Pot. Macromol. Rapid Commun. 2016, 37 (21), 1735−1741. (61) Li, S.; He, X.; Li, Q.; Shi, P.; Zhang, W. Synthesis of Multicompartment Nanoparticles of Block Copolymer through Two Macro-RAFT Agents Co-Mediated Dispersion Polymerization. ACS Macro Lett. 2014, 3 (9), 916−921. (62) Lunn, D. J.; Finnegan, J. R.; Manners, I. Self-assembly of “patchy” nanoparticles: a versatile approach to functional hierarchical materials. Chem. Sci. 2015, 6 (7), 3663−3673. (63) Wilms, D.; Klos, J.; Frey, H. Microstructured Reactor for Polymer Synthesis: A Renaissance of Continuous Flow Processes for Tailor-Made Macromolecules. Macromol. Chem. Phys. 2008, 209 (4), 343−356. (64) Tomovska, R.; de la Cal, J. C.; Asua, J. M. Miniemulsion PhotoCopolymerization of Styrene/Butyl Acrylate in a Continuous Tubular Reactor. Ind. Eng. Chem. Res. 2014, 53 (2), 7313−7320. (65) Blackman, L. D.; Varlas, S.; Arno, M. C.; Fayter, A.; Gibson, M. I.; O’Reilly, R. K. Permeable Protein-Loaded Polymerosome Cascade Nanoreactors by Polymerization-Induced Self-Assembly. ACS Macro Lett. 2017, 6 (11), 1263−1267.
(31) Tan, J.; Huang, C.; Liu, D.; Zhang, X.; Bai, Y.; Zhang, L. Alcoholic Photoinitiated Polymerization-Induced Self-Assembly (Photo-PISA): A Fast Route toward Poly(isobornyl acrylate)-Based Diblock Copolymer Nano-Objects. ACS Macro Lett. 2016, 5 (8), 894−899. (32) Xu, S.; Ng, G.; Xu, J.; Kuchel, R. P.; Yeow, J.; Boyer, C. 2(Methylthio)ethyl methacrylate: A versatile monomer for stimuli responsiveness and polymerization-induced self-assembly in the presence of air. ACS Macro Lett. 2017, 6 (11), 1237−1244. (33) Ng, G.; Yeow, J.; Xu, J.; Boyer, C. Application of oxygen tolerant PET-RAFT to polymerization-induced self-assembly. Polym. Chem. 2017, 8 (18), 2841−2851. (34) Yeow, J.; Chapman, R.; Xu, J.; Boyer, C. Oxygen tolerant photopolymerization for ultralow volumes. Polym. Chem. 2017, 8 (34), 5012−5022. (35) Tan, J.; Liu, D.; Bai, Y.; Huang, C.; Li, X.; He, J.; Xu, Q.; Zhang, L. Enzyme-Assisted Photoinitiated Polymerization-Induced Self-Assembly: An Oxygen-Tolerant Method for Preparing Block Copolymer Nano-Objects in Open Vessels and Multiwell Plates. Macromolecules 2017, 50 (15), 5798−5806. (36) Junkers, T. Precision Polymer Design in Microstructured Flow Reactors: Improved Control and First Upscale at Once. Macromol. Chem. Phys. 2017, 218, 1600421. (37) Li, X.; Mastan, E.; Wang, W.-J.; Li, B.-G.; Zhu, S. Continuous Production of Multiblock Copolymers in a Loop Reactor: When Living Polymerization Meets Flow Chemistry. Macromolecules 2016, 1, 1250−1271. (38) Tonhauser, C.; Natalello, A.; Löwe, H.; Frey, H. Microflow Technology in Polymer Synthesis. Macromolecules 2012, 45 (24), 9551−9570. (39) Junkers, T. Precise macromolecular engineering via continuousflow synthesis techniques. J. Flow Chem. 2017, 7 (3), 106−110. (40) Cambie, D.; Bottecchia, C.; Straathof, N. J.; Hessel, V.; Noel, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116 (17), 10276−10341. (41) Britton, J.; Raston, C. L. Multi-step continuous-flow synthesis. Chem. Soc. Rev. 2017, 46 (5), 1250−1271. (42) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry parallel. Chem. Rev. 2017, 117 (18), 11796−11893. (43) Junkers, T.; Wenn, B. Continuous Microflow PhotoRAFT Polymerization. React. Chem. Eng. 2016, 1, 60−64. (44) Chen, M.; Johnson, J. A. Improving photo-controlled living radical polymerization from trithiocarbonates through the use of continuous-flow techniques. Chem. Commun. 2015, 51 (31), 6742− 6745. (45) Noël, T. A Perspective on the Future of Flow Photochemistry,. J. Flow Chem. 2017, 7 (3−4), 87−93. (46) Gong, H.; Zhao, Y.; Shen, X.; Lin, J.; Chen, M. Organocatalyzed Photocontrolled Radical Polymerization of Semifluorinated (Meth)acrylates Driven by Visible Light. Angew. Chem., Int. Ed. 2018, 57 (1), 333−337. (47) Rubens, M.; Latsrisaeng, P.; Junkers, T. Visible light-induced iniferter polymerization of methacrylates enhanced by continuous flow. Polym. Chem. 2017, 8 (42), 6496−6505. (48) Corrigan, N.; Almasri, A.; Taillades, W.; Xu, J.; Boyer, C. Controlling Molecular Weight Distributions through Photoinduced Flow Polymerization. Macromolecules 2017, 50 (21), 8438−8448. (49) Moad, G.; Rizzardo, E.; Thang, S. H. RAFT polymerization and some of its applications. Chem. - Asian J. 2013, 8 (8), 1634−1644. (50) Daniloska, V.; Carretero, P.; Tomovska, R.; Asua, J. M. High performance pressure sensitive adhesives by miniemulsion photopolymerization in a continuous tubular reactor. Polymer 2014, 55 (20), 5050−5056. (51) Serra, C. A.; Cortese, B.; Khan, I. U.; Anton, N.; de Croon, M. H. J. M.; Hessel, V.; Ono, T.; Vandamme, T. Coupling Microreaction Technologies, Polymer Chemistry, and Processing to Produce H
DOI: 10.1021/acs.macromol.8b00887 Macromolecules XXXX, XXX, XXX−XXX
