A Polymerization-Induced Self-Assembly Approach to Nanoparticles

Article pubs.acs.org/Macromolecules

A Polymerization-Induced Self-Assembly Approach to Nanoparticles Loaded with Singlet Oxygen Generators Jonathan Yeow,† Sivaprakash Shanmugam,† Nathaniel Corrigan,† Rhiannon P. Kuchel,‡ Jiangtao Xu,† 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: We report a photoinduced electron/energy transfer−reversible addition-fragmentation chain transfer (PET-RAFT) dispersion polymerization mediated by 5,10,15,20-tetraphenyl21H,23H-porphine zinc (ZnTPP) under low energy red (λmax = 635 nm) or yellow light (λmax = 560 nm). By varying the degrees of polymerization for the hydrophobic block, nanoparticles of different morphologies (spheres, wormlike micelles, and vesicles) were formed at high monomer conversion (>98%) under visible light irradiation. Interestingly, encapsulation of the ZnTPP catalyst into the nanoparticle core was achieved by direct dialysis against water with no significant change in nanoparticle morphology. These aqueous ZnTPP-loaded nanoparticles were demonstrated to have potential applications in photodynamic therapy owing to their ability to generate singlet oxygen under visible light irradiation. Finally, the ability of ZnTPP to generate singlet oxygen was exploited to perform polymerization without traditional deoxygenation procedures by addition of a singlet oxygen quencher (ascorbic acid).

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materials such as continuous flow polymerization reactors.38 Furthermore, the ability to perform these polymerizations at room temperature can reduce side reactions often observed in thermal polymerizations.39 A number of groups have recently applied the facile conditions associated with visible light to dispersion polymerization yielding self-assembled polymer nanoparticles according to a polymerization-induced self-assembly (PISA) approach. 40−46 In contrast to conventional self-assembly techniques, the PISA approach avoids the need for purification of preformed block copolymers and can be conducted at significantly higher solids content (10−50 wt %).47−53 Jiang et al. demonstrated the first application of visible light to initiate a PISA process; however, only spherical nanoparticles were formed. 41 Recently, our group 40 and others 42,44 have demonstrated the synthesis of higher order morphologies (worm-like micelles and vesicles) in addition to a number of key advantages such as temporal control over nanoparticle formation. The use of PISA-derived nanoparticles as carriers for therapeutic compounds has been demonstrated by a number of groups by affecting encapsulation/conjugation either during or after the dispersion polymerization.29,42,54−61 For example, Armes et al. have explored the in situ encapsulation of silica

INTRODUCTION Photodynamic therapy (PDT) is an emerging field of research for the treatment of cancer and has demonstrated potential in a number of clinical applications.1−3 One of the benefits of PDT in comparison to conventional therapies such as chemotherapy is the possibility to exert spatiotemporal control over the treatment, which decreases side effects and improves treatment efficacy. In this approach, photoactivation of a suitable light harvesting molecule (for instance, 5,10,15,20-tetraphenyl21H,23H-porphine zinc (ZnTPP)) triggers the formation of highly reactive singlet oxygen (or other reactive oxygen species) which causes rapid oxidative damage to biological species such as proteins or DNA.4,5 However, current PDT suffers from some limitations, such as the poor water solubility of most photocatalysts (PCs) and nonspecific PC accumulation in vivo. To overcome these drawbacks, the encapsulation of PCs into polymeric nanoparticles has attracted intense interest in the field of PDT.6,7 In particular, such nanocarriers are useful in overcoming the poor water solubility of most PCs and can be used to enhance the accumulation of the PC at the desired site. Recently, our group8−12 and others13−34 have demonstrated that a number of PC compounds (some of which are currently used in applications such as PDT) can also be used to regulate a controlled/living radical polymerization (CLRP) under a visible light stimulus. These facile polymerizations can be conducted under room temperature conditions and provide a fine degree of control over the polymerization opening up a range of new applications10,35−37 and processes for polymeric © 2016 American Chemical Society

Received: July 23, 2016 Revised: September 1, 2016 Published: September 19, 2016 7277

DOI: 10.1021/acs.macromol.6b01581 Macromolecules 2016, 49, 7277−7285

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Macromolecules Scheme 1. Synthetic Approach toward Generating Self-Assembled POEGMA-b-PBzMA Nanoparticles via PET-RAFT Dispersion Polymerization

deoxygenation in the presence of a singlet oxygen quencher (ascorbic acid). As far as we are aware, this is also the first report of a PISA polymerization that proceeds without the need for conventional deoxygenation, which simplifies the current procedure and opens the field for nonspecialists to perform similar investigations.68

nanoparticles within the hydrophilic lumen of PISA-derived vesicles.58 In addition, bovine serum albumin (BSA) could be encapsulated in a similar fashion; however, a low temperature thermal initiator was required to prevent protein denaturing. As an alternative, others have demonstrated that mild photopolymerization techniques (using a photoinitiator) can also be used for the in situ encapsulation of BSA (or silica nanoparticles) without sacrificing protein activity. Apart from hydrophilic encapsulation (which can only be achieved in polymer vesicles), our group has demonstrated the hydrophobic encapsulation of Nile Red as a model drug using both thermal and light-mediated dispersion polymerization techniques under ethanolic conditions.45,55 Such an approach may be particularly useful for the synthesis of therapeutic carriers with different morphologies bearing poorly water-soluble cargo. Supplementing our previous work on photoinduced electron/energy transfer−reversible addition-fragmentation chain transfer (PET-RAFT)62 and light-mediated PISA,40,45 we hypothesized that the use of a hydrophobic photoredox catalyst (such as 5,10,15,20-tetraphenyl-21H,23H-porphine zinc (ZnTPP)) to mediate a PET-RAFT dispersion polymerization might result in encapsulation of the catalyst within the hydrophobic nanoparticle core. Because of the well-studied and rich photophysical behavior of ZnTPP, we envisioned that such catalyst-loaded nanoparticles might have promising applications in photodynamic therapy63,64 or other light harvesting applications, such as photon upconversion.63,65,66 To achieve this, we have developed a novel red light activated PET-RAFT dispersion polymerization system under ethanolic conditions (owing to the insolubility of ZnTPP in water) (Scheme 1), yielding nanoparticles of different morphologies such as spheres (S), worm-like micelles (WLM), and vesicles (V). To the best of our knowledge, this is the first report of a PISA polymerization conducted under long wavelength visible red light (λmax = 635 nm). In particular, the use of this low energy wavelength in comparison to UV or blue light results in less nanoparticle-induced scattering during the polymerization67 and may be favorable for the incorporation of lightsensitive compounds during the PISA process.39 Interestingly, upon dialysis into water, the ZnTPP catalyst is encapsulated into the hydrophobic core of the nanoparticle and can be further activated under visible light to generate singlet oxygen suggesting a dual role for ZnTPP as both a polymerization catalyst and light activated drug for photodynamic therapy. Using the favorable properties of ZnTPP for generating singlet oxygen, the PISA polymerization proceeded without prior

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RESULTS AND DISCUSSION ZnTPP-Mediated Dispersion Polymerization under Red Light. The steric stabilizers used in this study were initially synthesized using the thermally initiated RAFT polymerization of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) in the presence of 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid (CDTPA) as RAFT agent (Scheme 1). These poly(oligo (ethylene glycol) methyl ether methacrylate) (POEGMA) macromolecular chain transfer agents (macro-CTA) were characterized by GPC and NMR and used for subsequent chain extension experiments (Supporting Information, Figure S1). Our group has previously demonstrated the ability of ZnTPP to activate the PET-RAFT polymerization of a range of monomers under varying homogeneous conditions (different irradiation wavelength, intensity, etc.).62 In this work, we extend these studies to a heterogeneous dispersion type polymerization. To achieve this, different catalyst concentrations (reported relative to macroCTA concentration) were used to activate the polymerization of BzMA in ethanol (EtOH) by chain extension of a POEGMA29.5 macro-CTA under red light (λmax = 635 nm) with an initial [BzMA]:[macro-CTA] = 200:1 (Figure S2). As expected, as the ratio of [ZnTPP]:[macro-CTA] increased, an increase in monomer conversion was observed with Exp. iv reaching 97% after 24 h of irradiation (Figure S2, Exp. iv). Concomitantly, an increase in polymer dispersity was also observed with higher ZnTPP concentrations; however, in all cases the GPC derived molecular weight distributions remained fairly unimodal (Figure S2B). Importantly, the polymerizations became increasingly turbid under red light irradiation and DLS analysis confirmed the formation of nanoparticles with a relatively narrow size distribution (PDI < 0.08) (Figure S2C). Subsequent TEM imaging indicated the formation of large kinetically frustrated spheres up to 95 nm in diameter (Figure S2D) which Armes et al. have previously attributed to the inhibited mobility of the core-forming polymer chains.69 Kinetics of ZnTPP-Mediated Dispersion Polymerization. In order to investigate the kinetics of this ZnTPPmediated dispersion polymerization, Fourier transform near7278


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Figure 1. Polymerization kinetics of ZnTPP-mediated dispersion polymerization under red light (λmax = 635 nm, 0.7 mW/cm2) as determined by online FTNIR monitoring. Polymerizations were performed at 10 wt % with [BzMA]:[POEGMA29.5]:[ZnTPP] = 200:1:0.02 in (A) EtOH or (B) EtOH:MeCN (90/10 v/v). Inset: TEM micrographs and digital photographs corresponding to different stages of the dispersion polymerization.

high monomer conversions (>98%). Although strictly only valid for spherical particles, DLS is commonly used to give an indication of the stability of nanoparticle dispersions prepared by PISA.71,75,77 In our conditions, we found that our dispersion polymerizations are stable as indicated by unimodal particle size distributions (Figures 2A and 3B, Figures S2 and S3). With a view toward preparing ZnTPP loaded nanoparticles, we sought to determine whether higher concentrations of catalyst could be used to mediate the PISA process. Interestingly, the same formulation with varied [ZnTPP]:[macro-CTA] ratios (Figure 2, Exp. x vs Exp. xi) yielded different morphologies which was attributed to the differing levels of polymerization control. At a [ZnTPP]:[macro-CTA] = 0.03 (Exp. xi), the GPC trace revealed the formation of a significant population of low molecular weight dead chains (Figure S3C) which may be due to the relatively poor initiation of BzMA by the POEGMA macro-CTA. This presumably led to the favoring of a S morphology rather than the WLM isolated in Exp. x (Figure 2B) due to the differences in the packing parameter. Our group45 and others78−80 have previously observed similar behavior, whereby the molecular weight distribution of the amphiphilic block copolymer could strongly affect its selfassembly behavior. In order to overcome this loss of polymerization control, we lowered the red light intensity to 0.7 mW/cm2 to reduce the degree of catalyst activation (Exp. xii). This enabled better control over the polymerization (Đ = 1.15) and retention of the WLM morphology obtained in Exp. x (Figure 2B). This suggests that the spherical morphology observed in Exp. xi was due to a difference in molecular weight distribution rather than the effect of the higher ZnTPP concentration on the packing parameter. Finally, the ability of ZnTPP to absorb at a range of visible light wavelengths62 was exploited to also synthesize WLM under yellow light (λmax = 560 nm, 3.1 mW/cm2) (Figure 2A and Figure S4, Exp. xiii). These data demonstrate the utility of a ZnTPP-mediated dispersion polymerization in synthesizing nanoparticles of different morphologies under different wavelengths of visible light. Encapsulation of Singlet Oxygen Generators. In order to study the encapsulation of the ZnTPP catalyst into the nanoparticle core, we performed dialysis to generate aqueous nanoparticle dispersions. Interestingly, initial dialysis of ethanolic dispersions against ethanol followed by water yielded aqueous dispersions without the characteristic purple color

infrared (FTNIR) spectroscopy was used to measure the polymerization kinetics online. Initially, we examined the polymerization kinetics in pure EtOH using a [BzMA]: [macro-CTA] = 200:1 and a [ZnTPP]:[macro-CTA] = 0.02 in order to maintain an acceptable balance between polymerization rate and molecular weight control (Figure 1A). As in Exp. i−iv, the solution became turbid upon visible light irradiation (after ∼2 h); however, TEM indicated the formation of only large spherical nanoparticles (Figure 1A). In accordance with other studies,70−72 we observed two distinct phases of the PISA process associated with the homogeneous (kpapp = 0.122 h−1) and heterogeneous (kpapp = 0.345 h−1) polymerization phases which may be due to a combination of monomer and ZnTPP partitioning into the core of the growing nanoparticle. Interestingly, the addition of a small amount of acetonitrile (10% v/v) into the initial polymerization medium resulted in vastly different kinetic behavior (Figure 1B). This effect was attributed to the different degrees of solvation of the coreforming polymer as previously suggested by the groups of Armes69 and Charleux.73 In particular, the polymerization mixture became increasingly viscous forming a free-standing gel after 8.5 h of irradiation with TEM imaging revealing the formation of a highly pure WLM phase. In accordance with previous studies by us40,45 and others,60,74−77 this gel-like behavior was attributed to the presence of multiple interworm contacts. Furthermore, the polymerization could be continued through this viscous region (given sufficient agitation to prevent colloidal instability), leading to the formation of a milky, free-flowing solution. TEM imaging confirmed this macroscopic transition to be due to the formation of a vesicle phase, thus confirming the importance of solvent composition on the formation of higher order morphologies. Nanoparticle Synthesis at High Monomer Conversion. In order to synthesize nanoparticles of different morphologies, we systematically varied the [BzMA]:[macro-CTA] ratio and targeted high monomer conversions under red light using POEGMA23 as macro-CTA in EtOH:MeCN (90:10 v/v). As the targeted degree of polymerization was varied from 50 to 150, the dispersions underwent a transition from S (DP = 50, Exp. v) to WLM (DP = 75, Exp. vii) and finally to a pure vesicle phase (DP = 150, Exp. ix) (Figure 2A,B). In each case, a good correlation was observed between the theoretical and experimental molecular weights. More importantly, the polymer dispersities remained narrow (Đ < 1.24) despite the 7279


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Figure 2. (A) Characterization and (B) corresponding TEM micrographs of POEGMA23-b-PBzMA diblock copolymers formed at 10 wt % under visible red light (λmax = 635 nm, 2.1 mW/cm2) in EtOH:MeCN (90:10 v/v). †Polymerization performed under lower intensity red light (λmax = 635 nm, 0.7 mW/cm2). *Polymerization performed under yellow light (λmax = 560 nm, 3.1 mW/cm2). Note: DLS diameters are reported based on the intensity-based size distribution and are included as an indicator of nanoparticle stability only.

aqueous nanoparticles were gently centrifuged at 3000 rpm for 3 min without affecting the stability of ZnTPP-loaded nanoparticles. The loading of ZnTPP within the vesicles was determined by visible absorption spectroscopy to be 0.2 wt % relative to polymer, indicating an encapsulation efficiency of about 20%. It is likely that further optimization of the encapsulation process via dialysis against water could increase the encapsulation efficiency of the ZnTPP catalyst while also maintaining nanoparticle stability. Investigation of Singlet Oxygen Formation. Since ZnTPP is a well-known photosensitizer capable of transferring energy to molecular triplet oxygen to yield singlet oxygen,81,82 we sought to determine the ability of these aqueous vesicles to generate singlet oxygen via photosensitization of the encapsulated ZnTPP catalyst. Singlet oxygen formation can be readily monitored by observing decreases in the characteristic absorption of the water-soluble singlet oxygen quencher anthracene-9,10-dipropionic acid disodium salt (ADPA) (Figure 3A).83−87 ZnTPP loaded vesicles (Exp. xiv) were therefore irradiated at different times by yellow light (λmax = 560 nm, 9.7 mW/cm2) in the presence of ADPA before centrifugation at 14 000 rpm to collapse the nanoparticles. UV−vis spectroscopy of the supernatant revealed that increasing the irradiation time led to a concomitant decrease in the ADPA absorption at 378 nm with more than 90% ADPA bleaching occurring within 40 min (Figure 3B,C). Taken together, these data suggest the feasibility of applying the ZnTPP photocatalyst as both a polymerization mediator and singlet oxygen generator which may find application in the field of photodynamic therapy.88,89 Work is currently underway to

typically associated with ZnTPP. Indeed, visible absorption spectroscopy revealed the lack of ZnTPP’s characteristic Soret (400−450 nm) or Q-band (500−650 nm) absorptions. These results suggest that this dialysis method could be used to successfully purify the nanoparticles owing to the finite solubility of ZnTPP in ethanol (Figure S5A,B (red line)). However, when the crude ethanolic dispersions were instead directly dialyzed against water, stable pink to purple aqueous dispersions were obtained with retention of the characteristic absorption peaks of ZnTPP (Figure S5A,B (blue line)). These data suggest the successful encapsulation of the photoredox catalyst into the hydrophobic interior of these nanoparticles. Furthermore, when ethanolic dispersions of Exp. v (S), Exp. vii (WLM), and Exp. ix (V) were dialyzed into water, no change in the nanoparticle morphology was observed by TEM imaging before and after dialysis (in addition to ZnTPP encapsulation) (Figure S5C). In order to synthesize ZnTPP-loaded nanoparticles for potential bioapplications, we attempted to utilize a higher [ZnTPP]:[macro-CTA] ratio of 0.5. The light intensity was reduced (λmax = 635 nm, 0.45 mW/cm2) to lower the rate of photocatalyst activation (Exp. xiv, Figure S6A) and limit the formation of dead polymers. Interestingly, while some low molecular weight tailing was observed (Figure S6B, Đ = 1.56), the obtained dispersions remained stable and TEM confirmed the presence of a fairly uniform vesicle morphology. These particles could be easily transferred via direct dialysis into water without a change in morphology (Figure S6C), allowing simultaneous encapsulation of the photocatalyst. To ensure the removal of any unencapsulated ZnTPP (precipitate), the 7280


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Figure 3. (A) Scheme demonstrating the generation of singlet oxygen by ZnTPP under visible light and subsequent reaction with ADPA to form the corresponding endoperoxide. (B) UV−vis absorption spectrum of ADPA after irradiation with yellow light (λmax = 560 nm, 9.7 mW/cm2) in the presence of ZnTPP loaded nanoparticles (1 mg/mL, 0.2 μg/mL ZnTPP). (C) Change in ADPA absorbance at 378 nm with increasing irradiation time.

Figure 4. (A) Characterization and (B) corresponding GPC-derived molecular weight distributions of POEGMA-b-PBzMA diblock copolymers synthesized using [ZnTPP]:[macro-CTA] = 0.005 and without deoxygenation prior to red light (λmax = 635 nm, 2.1 mW/cm2) irradiation for 48 h. (C) Corresponding TEM micrographs of self-assembled nanoparticles synthesized without prior deoxygenation. *Polymerization performed for 60 h with a headspace of 1 mL.

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deoxygenation. This process provides a route to further simplify the synthesis of drug-loaded nanocarriers and allows nanoparticle synthesis to become more accessible to nonspecialists in the field.68

synthesize ZnTPP loaded nanoparticles with different morphologies in order to study the effect of morphology on singlet oxygen production and delivery in biological systems. Oxygen Tolerant RAFT Dispersion Polymerization. The relatively rapid and highly efficient production of singlet oxygen by ZnTPP prompted us to consider using this process as a mechanism to remove molecular triplet oxygen from our initial polymerization vessel, thereby circumventing the need for traditional deoxygenation procedures. For example, Decker90 and later others91,92 demonstrated that a singlet oxygen quencher could be used to consume photosensitized oxygen in a conventional free radical polymerization. We sought to take advantage of ZnTPP’s ability to yield singlet oxygen by irreversibly reacting singlet oxygen with ascorbic acid (AscA), an inexpensive singlet oxygen quencher.93,94 In this way, ZnTPP could be used to both remove molecular oxygen and mediate the polymerization process. We initially tested this hypothesis by using [BzMA]:[POEGMA25]:[ZnTPP]:[AscA] = 100:1:0.005:2.6 in a sealed 1.5 mL vial (with minimal headspace) and without nitrogen purging (Figure 4A). After 48 h of red light irradiation, the polymerization mixture was turbid, and NMR analysis indicated a high monomer conversion had been reached (α = 98%). In contrast, in the absence of ascorbic acid the polymerization of BzMA was not tolerant to molecular oxygen under the same irradiation conditions (α = 0%) (Table S1, Exp. xx). Interestingly, despite the lack of prior oxygen removal, characteristics of a controlled polymerization were still observed with a polymer dispersity of 1.24 and a good correlation between the theoretical and GPC derived molecular weight (Figure 4A,B, Exp. xv). Online FTNIR monitoring (in a 0.2 mm quartz cuvette with minimal headspace) revealed an induction period of approximately 14− 16 h which is due to the slow in situ consumption of molecular oxygen (Figure S7). In addition to a number of reaction parameters ([ZnTPP], [BzMA], etc.), it is likely that the length of this induction period is also highly sensitive to the amount of oxygen, volume of reactor, headspace volume present in the reactor, and the shape of the polymerization vessel itself. Interestingly, TEM imaging revealed that this oxygen tolerant approach was capable of forming stable spherical nanoparticles. Furthermore, by increasing the target DP (at a solids content and MeCN composition of 20 wt % and 30% v/v, respectively), we observed the formation of higher order morphologies from WLM (Exp. xvi) to V (Exp. xviii) (Figure 4A,C), although some low molecular weight tailing was clearly observed at higher target DPs (Figure 4B). Interestingly, when the polymerization vessel headspace was increased to ∼1 mL (Exp. xix), the polymerization remained oxygen tolerant; however, more AscA was required to ensure sufficient removal of molecular oxygen. TEM imaging revealed the formation of a predominately WLM phase (similar to Exp. xvi); however, a minor population of S was also observed which was attributed to the effect of AscA on the self-assembly packing parameter. We propose that the oxygen tolerant nature of these polymerizations is due to photosensitization of molecular oxygen by ZnTPP, yielding singlet oxygen which is then reduced by AscA. This process then yields hydrogen peroxide and dehydroascorbic acid (DHA) as byproducts (Figure 5).93,95 However, it is also possible that competing mechanisms of oxygen tolerance may exist within this polymerization system.96 To the best of our knowledge, the use of ascorbic acid to consume oxygen in the form of singlet oxygen is the first report of a PISA polymerization that proceeds without prior

Figure 5. Proposed reaction mechanism of ascorbic acid (AscA) with singlet oxygen yielding dehydroascorbic acid (DHA) and hydrogen peroxide as byproducts.

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CONCLUSION In conclusion, the synthesis of polymeric nanoparticles with different morphologies was demonstrated using a ZnTPPmediated PISA process under low energy red light. Transfer of these particles into water via dialysis yields ZnTPP loaded nanoparticles that can be further activated under visible light to generate singlet oxygen in an aqueous environment. Furthermore, this photosensitization by ZnTPP can be applied to the initial polymerization mixture, rendering it oxygen tolerant due to the action of AscA in quenching singlet oxygen. Together, these results demonstrate the utility of applying ZnTPP as both a photocatalyst for oxygen tolerant PET-RAFT dispersion polymerization and a visible light activated drug.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.6b01581. Experimental details, NMR spectra, DLS results (Figures S1−S7 and Table S1) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (C.B.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS C.B. acknowledges the Australian Research Council (ARC) for his Future Fellowship (FT12010096). REFERENCES

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A Polymerization-Induced Self-Assembly Approach to Nanoparticles

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