2-(Methylthio)ethyl Methacrylate: A Versatile Monomer for Stimuli

Oct 24, 2017 - (18) During RAFT polymerization, oxygen can be removed by a number of methods, including employing an excess of radical initiator to fo...
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Letter Cite This: ACS Macro Lett. 2017, 6, 1237-1244

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2‑(Methylthio)ethyl Methacrylate: A Versatile Monomer for Stimuli Responsiveness and Polymerization-Induced Self-Assembly in the Presence of Air Sihao Xu,† Gervase Ng,† Jiangtao Xu,† Rhiannon P. Kuchel,‡ Jonathan Yeow,*,† and Cyrille Boyer*,† †

Centre for Advanced Macromolecular Design and Australian Centre for NanoMedicine, School of Chemical Engineering, and Electron Microscope Unit, Mark Wainwright Analytical Centre, The University of New South Wales, Sydney NSW 2052, Australia

‡

S Supporting Information *

ABSTRACT: In this communication, we investigate the photoinduced electron/energy transfer−reversible addition− fragmentation chain transfer (PET-RAFT) polymerization of 2-(methylthio)ethyl methacrylate (MTEMA) using 5,10,15,20tetraphenylporphine zinc (ZnTPP) as a photocatalyst under visible red light (λmax = 635 nm). Interestingly, the polymerization kinetics were not affected by the presence of air as near identical polymerization kinetics were observed for nondeoxygenated and deoxygenated systems, which is attributed to the singlet oxygen quenching ability of MTEMA. In both cases, well-defined polymers were obtained with good control over the molecular weight and molecular weight distribution (MWD). Furthermore, we have demonstrated that MTEMA can undergo the polymerization-induced self-assembly (PISA) process from a poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) macromolecular chain transfer agent (macro-CTA) to yield well-defined polymeric nanoparticles of various morphologies. These nanoparticles were rapidly disassembled after exposure to visible light due to the formation of singlet oxygen by the encapsulated ZnTPP and subsequent rapid oxidation of the thioether group.

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RAFT polymerization, oxygen can be removed by a number of methods, including employing an excess of radical initiator to form unreactive peroxy radicals,19−21 employing oxidase enzymes to convert oxygen into hydrogen peroxide3,22−24 or reacting photosensitized oxygen species with suitable quenching species.4,25−28 Some of these approaches have also recently been implemented in RAFT dispersion polymerization for the synthesis of polymeric nanoparticles using a polymerizationinduced self-assembly (PISA) approach. The PISA approach is a highly versatile and robust approach for the synthesis of selfassembled nanoparticles of various morphologies and can be performed at high particle concentrations (10−50 wt %).29−32 Recently, our group4,26 and others33 have demonstrated that a PET-RAFT initiated PISA process can occur without deoxygenation due to the quenching of photosensitized oxygen by exogenous quenchers. Alternatively, Tan’s group34 building on previous works by Stevens 3,22 and Yagci, 35 have demonstrated that the addition of an oxidase enzyme (and oxidizable substrate) can be employed to allow for a photoinitiated PISA process to be conducted without prior deoxygenation.

t is well-known that free radical polymerizations can be hampered by the rapid quenching of initiating and propagating radicals by molecular oxygen.1,2 In controlled/ living radical polymerizations (CLRP), such as atom transfer radical polymerization (ATRP) or reversible addition− fragmentation chain transfer (RAFT) polymerization, oxygen quenching can be particularly problematic since oxygen can lead to not only inhibitory behavior, but also affect the livingness of the polymerization.1 To overcome this limitation, conventional CLRP is performed in the absence of oxygen by employing techniques such as inert gas sparging or freeze− pump−thaw cycling. However, these techniques require specialist equipment, such as vacuum pumps and an inert gas source, which may hinder the general applicability of CLRP. Alternatively, oxygen tolerant CLRP techniques have been proposed as a method to simplify a typical reaction setup and enable CLRP to be conducted under a broader range of conditions, such as in microtiter wellplates3,4 or even automated synthesizers.5,6 A number of mechanisms have been proposed to impart oxygen tolerance to CLRP. For example, Matyjaszewski,7−9 Percec,10−12 and others have demonstrated that ATRP/SETLRP can be performed with limited amounts of air due to the consumption of oxygen by oxidation of the transition metal catalyst and its subsequent regeneration by a reducing agent,13−15 light,16,17 or electrochemical means.18 During © XXXX American Chemical Society

Received: September 19, 2017 Accepted: October 17, 2017

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DOI: 10.1021/acsmacrolett.7b00731 ACS Macro Lett. 2017, 6, 1237−1244

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ACS Macro Letters

Figure 1. (A) Scheme demonstrating the PET-RAFT polymerization of MTEMA in the presence of ZnTPP and CDTPA as photocatalyst and RAFT agent, respectively. PET-RAFT homopolymerization kinetics were performed with and without deoxygenation in DMF and under red light (λmax = 635 nm, 3.0 mW/cm2) using a [MTEMA]/[CDTPA]/[ZnTPP] = 200:1:0.01. Variation of (B) ln([M]0/[M]t) with irradiation time and (C) GPC derived molecular weight and dispersity with conversion. Corresponding MWDs at different irradiation times for polymerizations conducted (D) with and (E) without prior deoxygenation.

1B). Furthermore, regardless of whether prior deoxygenation was applied, the GPC derived molecular weight values were observed to increase linearly with monomer conversion and the molecular weight distributions (MWDs) remained narrow (Đ < 1.4) and unimodal throughout the polymerization, suggesting the controlled/living nature of the polymerization (Figure 1C− E; SI, Table S1).45 However, in both cases, a slight deviation between the experimental and theoretical molecular weight values was observed at low monomer conversion, which we attributed to the slow addition/fragmentation process in RAFT mediated methacrylate polymerizations at low temperatures and monomer conversions (particularly for trithiocarbonates) (see SI, Figure S1).26,46,47 Nonetheless, the unusual kinetic behavior of MTEMA suggests the efficiency with which molecular oxygen is removed from the system, since the presence of oxygen in conventional RAFT polymerization generally leads to an increased inhibition period.19 To investigate whether this degree of oxygen tolerance was specific to MTEMA, we attempted to polymerize MMA under the same polymerization conditions (SI, Figure S1). In comparison with MTEMA, the PET-RAFT polymerization of MMA in DMF without deoxygenation exhibited a long inhibition period (>200 min) and slower polymerization rate compared to the deoxygenated polymerization which presented a minimal inhibition period (SI, Figure S1A). Previously, we have demonstrated that the observed tolerance to oxygen in PET-RAFT polymerization can be attributed to the photosensitization of molecular oxygen by ZnTPP into singlet oxygen which is then rapidly quenched by reaction with quenchers such as DMSO48 (as a solvent) or exogenous additives such as 9,10-dimethylanthracene.26 We hypothesized that the oxygen tolerance of MTEMA under PET-RAFT conditions (in the absence of exogenous quenchers) was due to the oxidation of the thioether functionality of MTEMA into the corresponding sulfoxide (or sulfone) which effectively removes molecular oxygen from the polymerization mixture. 1H NMR analysis confirmed the oxidation of the thioether moiety in the crude nondeoxygenated polymerization mixture with the presence of a minor population (94%) were obtained within 24 h and good evidence of controlled/living behavior was observed (Figure 3A,C), indicating the minimal impact of oxygen on the PET-RAFT dispersion polymerization process. It is well known that the thioether group can be readily oxidized by reactive oxygen species (ROS), such as singlet oxygen and hydrogen peroxide.36,58 In recent years, ROS reactive polymers have attracted increasing interest owing to the upregulation of ROS in certain diseases, including cancer, diabetes, and various cardiovascular and degenerative diseases.59-60 Although a range of stimuli responsive PISA-derived nanoparticles have been developed,56,61-72 to date there have been no reports of ROS responsive nanoparticles synthesized using the PISA approach. We hypothesized that these PMTEMA based nanoparticles could exhibit oxidation sensitive

We varied the target degree of polymerization (DP) of MTEMA to study the effect of block length on nanoparticle formation, while maintaining a [POEGMA]/[ZnTPP] = 1:0.01 and a total solids content of 15 wt %. To negate the potential effect of the oxidized (P)MTEMA on nanoparticle morphology, these polymerizations were performed after deoxygenation with nitrogen. Under red light irradiation (λmax = 635 nm, 1.7 mW/ cm2), high monomer conversions (>93%) were achieved within 24 h, and the observed polymer dispersities remained low in all cases (Đ < 1.32; Figure 3A,B). Importantly, as the polymerization was conducted under vigorous stirring, we observed that the dispersions remained colloidally stable. Using transmission electron microscopy (TEM), we observed the evolution of the nanoparticle morphology from spheres (DP = 30, PISA-1), to worms (DP = 50, PISA-2), and finally vesicles (DP = 120, PISA-3; Figure 3D). Interestingly, similar to other PISA systems, the formation of the worm morphology was also accompanied by a significant increase in the viscosity of the dispersion which is usually associated with the onset of interworm contacts.56,57 To investigate whether the presence of oxygen could affect the nanoparticle morphology, we conducted the same PISA process without prior deoxygenation. 1240

DOI: 10.1021/acsmacrolett.7b00731 ACS Macro Lett. 2017, 6, 1237−1244

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Figure 4. (A) 1H NMR spectra (acquired in DMSO-d6) of aqueous POEGMA-b-PMTEMA vesicles (PISA-7, 0.5 wt%) after irradiation with visible light (λmax = 560 nm, 9.7 mW/cm2) in the presence of oxygen. For clarity, only the range from 2.05 to 2.80 ppm is shown here, for the full 1H NMR spectrum see SI, Figure S8. (B) Conversion of thioether groups with irradiation time as quantified using the 1H NMR peak at 2.15 ppm. (C) Digital photographs showing the change in turbidity with increasing irradiation time.

completely transparent indicating disassembly of the polymeric vesicles (SI, Scheme S1). In order to investigate this disassembly process further, we monitored the transmittance of 500 nm light through a 0.05 wt % vesicle solution (PISA-7) during irradiation. Under visible light irradiation (λmax = 560 nm, 9.7 mW/cm2), the solution transmittance increased over a period of 3 h indicating the disassembly of these vesicles under visible light (SI, Figure S10A,B). Alternatively, the addition of a chemical stimulus, H2O2, could also be used to trigger disassembly of these thioether functionalized nanoparticles due to oxidation of the PMTEMA block to PMSEMA49,73 (SI, Figure S10C,D). After addition of H2O2 (30 wt%), the transmittance increased over a period of 3 h to ∼90 % indicating almost complete disassembly of the thioether functionalized vesicles. 1H NMR analysis after the addition of H2O2 revealed the presence of the same PMSEMA peaks that are observed under the action of singlet oxygen (SI, Figure S9). We have successfully demonstrated that PET-RAFT polymerization of MTEMA proceeds without the need for deoxygenation of the polymerization mixture due to the singlet oxygen quenching properties of the monomer itself. Furthermore, MTEMA was polymerized under PET-RAFT dispersion polymerization conditions in methanol allowing for the fabrication of nanoparticles with various morphologies according to a PISA approach. These nanoparticles were rapidly disassembled after exposure to visible light in the presence of air due to the singlet oxygen mediated oxidation of the thioether moiety to the corresponding hydrophilic sulfoxide. To the best of our knowledge, this process demonstrates, for the first time, ROS (and visible light) responsive nanoparticles synthesized using a PISA approach.

behavior due to the high water solubility of the corresponding polymeric sulfoxide, poly(methylsulfinyl)ethyl methacrylate (PMSEMA).42 To test this hypothesis, we first synthesized POEGMA-b-PMTEMA nanoparticles with a high concentration of ZnTPP ([POEGMA]/[ZnTPP = 1:0.06]; Figure 3A, PISA-7). To reduce the formation of dead polymer chains, a lower light intensity (λmax = 635 nm, 1.0 mW/cm2) was employed enabling a narrow MWD (Đ = 1.32) to be obtained. Importantly, TEM analysis indicated the formation of a pure vesicle morphology in accordance with the corresponding experiment performed with a lower concentration of photocatalyst (SI, Figure S6). Finally, the nanoparticles were dialyzed directly against water to obtain a 0.5 wt% vesicle dispersion. Furthermore, the resultant aqueous dispersion was colored, which suggests the encapsulation of the catalyst within the hydrophobic core of the nanoparticles due to its strong aqueous insolubility. UV−vis spectra obtained directly in water or after disassembly of the nanoparticles in DMSO confirmed the presence of the characteristic Soret (∼428 nm) and Q (500 650 nm) bands of ZnTPP (SI, Figure S7A,B) which was quantified by comparison with a calibration curve to give a ZnTPP loading of 0.15 wt% relative to polymer with an encapsulation efficiency of approximately 85 % (see SI, Experimental Section). To determine whether the encapsulated ZnTPP retained its ability to generate singlet oxygen, we irradiated a 0.5 wt% solution of ZnTPP loaded vesicles (Figure 3, PISA-7) with visible light (λmax = 560 nm, 9.7 mW/cm2) and monitored the solution via 1H NMR. As the irradiation time increased, we observed a decrease in the PMTEMA peaks at 2.15 and 2.75 ppm corresponding to the methyl (CH3-S-CH2) and methylene (CH3-S-CH2) protons adjacent to the sulfur atom, respectively (Figure 4A, SI, Figures S8 and S9). Simultaneously, downfield peaks at 2.8−3.2, 2.65, and 4.30 ppm appeared, indicating the formation of PMSEMA via the oxidation of the PMTEMA block. Monitoring of the thioether peak at 2.15 ppm revealed that more than 70 % of PMTEMA was converted to PMSEMA after 5 h of visible light irradiation (Figure 4B). In addition, visual inspection revealed a decreasing turbidity of the reaction mixture over time which was attributed to the increased water solubility of PMSEMA compared to PMTEMA (Figure 4C). After 5 h irradiation, the initially cloudy reaction mixture was

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.7b00731. Additional experimental and characterization data, as well as Figures S1−S10, Table S1, and Scheme S1 (PDF). 1241

DOI: 10.1021/acsmacrolett.7b00731 ACS Macro Lett. 2017, 6, 1237−1244

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jiangtao Xu: 0000-0002-9020-7018 Cyrille Boyer: 0000-0002-4564-4702 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS C.B. and J.X. acknowledge Australian Research Council (ARC) for their Future Fellowships (FT12010096 and FT160100095, respectively).

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DOI: 10.1021/acsmacrolett.7b00731 ACS Macro Lett. 2017, 6, 1237−1244

Letter

ACS Macro Letters Triblock Terpolymer Exhibiting On−Off Switchable Pores. ACS Macro Lett. 2016, 5 (1), 88−93. (73) Petitdemange, R.; Garanger, E.; Bataille, L.; Dieryck, W.; Bathany, K.; Garbay, B.; Deming, T. J.; Lecommandoux, S. Selective Tuning of Elastin-like Polypeptide Properties via Methionine Oxidation. Biomacromolecules 2017, 18 (2), 544−550.

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DOI: 10.1021/acsmacrolett.7b00731 ACS Macro Lett. 2017, 6, 1237−1244