Dynamic Single Chain Polymeric Nanoparticles: From Structure to Function

Chapter 21

Dynamic Single Chain PolymericNanoparticles: From Structure to Function

Müge Artar, Elisa Huerta, E. W. Meijer, and Anja R. A. Palmans*

Institute for Complex Molecular Systems, Laboratory of Macromolecularand Organic Chemistry, Eindhoven University of Technology, P.O. Box 513,

5600 MB, Eindhoven, The Netherlands*E-mail: [email protected]

Achieving the perfection of Nature in forming orderedstructures in three dimensions is one of the great challengesfor supramolecular chemists. Recently, the merger ofsupramolecular and polymer chemistry resulted in thepreparation of polymers with pendant supramolecular motifsthat intramolecularly self-assemble in solution into structuresof defined size and shape. This review summarizes therecent progress made in preparing and characterizing suchcompartmentalized structures in solution in which the internalstructure arises from non-covalent bond formation, makingthe obtained particles dynamic and adaptable. In addition, thepotential of these so-called dynamic single-chain polymericnanoparticles (SCPNs) is explored. We highlight the potentialof SCPNs for catalysis in water and sensing, functions thatall arise as a result of the well-defined conformations that areattained by directional non-covalent interactions

Introduction

Polymer chemistry has made noteworthy steps towards the synthesis ofpolymers with a defined length. Controlled radical polymerizations nowadaysallow to control the polymer molecular weight and the molar mass disperitieswhile at the same time highly functionalized monomers are accepted duringthe polymerization procedure. However, synthetic polymers typically consistof a random sequence of monomers and form random coils in solution. In

© 2014 American Chemical Society

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In Sequence-Controlled Polymers: Synthesis, Self-Assembly, and Properties; Lutz, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

contrast, an important feature of biomacromolecules is that they consist of anexact number of monomers that are positioned in a highly specific way alongtheir backbone. Although the number of monomers that Nature uses is limited,biomacromolecules posses a much higher degree of complexity and functionality:secondary interactions confer a precisely defined three-dimensional (3D) structurein solution to biomacromolecules from which specific properties arise. Forexample, the compartmentalization present in enzymes is key for creating activesites in which substrates are readily and selectively activated and converted intoproducts.

Several approaches have been followed to attain compartmentalizedstructures in synthetic macromolecules, and with those, some of the functionalityproteins posses have become accessible (1). Star polymers and dendrimers affordcontainers of nanometer-sized dimensions in which embedded, site-isolatedcatalysts perform a variety of catalytic and cascade catalytic reactions (2–6).In addition, dendrimers have been actively explored for i.a. drug deliveryapplications (7). Alternatively, amphiphilic block copolymers self-assemble inwater into compartmentalized structures and when catalysts are attached to thehydrophobic interior, catalysis in water becomes accessible for catalysts that arenormally inactive in pure water (8). Finally, polymer chains have been trappedinto forming particles of defined size with restricted conformations by internalcrosslinking of pendant functional groups (9, 10). This crosslinking is typicallydone in ultradilute conditions to prevent intermolecular interactions.

In recent years, the potential of compartmentalized nanometer-sized particlesby using pendant supramolecular motifs to fold polymers into single chainpolymeric nanoparticles (SCPNs) has been explored by us and others. Theadvantage of reversible interactions to create SCPNs is that the system remainsadaptive and and can respond to external triggers. Such systems mimic inmany ways the functions of proteins. We here summarize recent progress madein the synthesis and characterization of these dynamic SCPNs, stabilized bynon-covalent interactions. In addition, we outline our view on the future of thisnovel and exciting field.

Synthetic Access to Dynamic SCPNs

Control in polymer composition, size, and molecular mass distribution playsa crucial role in the formation of SCPNs. Ring-opening metathesis polymerization(ROMP) (11) and a number of controlled radical polymerization (CRP) (12–15)techniques have allowed polymerization of a large range ofmonomers with variousfunctionalities to preparewell-defined polymers. These polymer chains possessingpendant groups can be triggered to induce an intramolecular collapse or foldingof the polymer to form SCPNs.

SCPNs have been designed both in a non-dynamic and a dynamic fashion.In non-dynamic SCPNs, intramolecular crosslinks are formed by covalent bondformation while in dynamic SCPNs the crosslinks consist of non-covalent ordynamic covalent bonds. In non-dynamic SCPNs, many different types ofcovalent bond formation have been applied successfully for the intramolecular

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crosslinking of the polymers (16–23). In dynamic SCPNs, reversible covalentbonds such as disulfides (24) or acyl hydrazones (25) have been utilized as well asnon-covalent bonds such as diamides (26), 2-ureido-pyrimidinones (UPys) (27),benzene-1,3,5-tricarboxamides (BTAs) (28), a combination of BTAs and UPys(29), BTA-bipyridines (30), cucurbit[8]uril (31), thymine-diaminopyridine (32),six-point cyanuric acid-Hamilton wedge interactions (33) and a combination ofthe last two (34).

In our group, the first examples of SCPNs were prepared by directpolymerization of norbornenes functionalized with either a protected UPy or adodecyl moiety, using ROMP with a second generation Grubbs catalyst (27).In a following approach, single-electron transfer living radical polymerization(SET-LRP) was utilized to synthesize alkyn-functionalized methacrylate-basedpolymers, followed by a post-modification to attach azide functionalized UPysto free alkynes on the methacrylate backbone via azide-alkyne 1,3-dipolarcycloaddition (35). In both cases, SCPNs were formed via incorporatingpendant 2-ureidopyrimidinone units to polymer backbone and using their strongdimerization as a driving force for crosslinking or collapse of the single polymerchain. To control the dimerization by an external trigger, the 2-ureidopyrimidinonemoieties on the polymers were functionalized with o-nitrobenzyl ether photolabileprotecting groups (phUPy) at the terminal carbonyl of the UPy (36). Thephotolabile protecting groups were cleaved off by photoirradiation and the UPymoieties were allowed to dimerize in dilute solutions, resulting in the formationof polymeric nanoparticles (Figure 1). SCPN formation was demostrated bythe change in apparent hydrodynamic volume, and thus the size differencebetween the free polymer and the collapsed nanoparticle via size exculsionchromatography (SEC). The size of the SCPNs could be tuned via varying themolecular weight of the polymer (37).

Figure 1. Folding and structure of UPy containing SCPN. (Reproduced withpermission from reference (27). Copyright (2009) American Chemical Society.)

Foillowing these first experiments, Mes et al. showed that benzene-1,3,5-tricarboxamides (BTAs) can also be utilized as a supramolecular unitto form SCPNs (28). In this example, a prepolymer was synthesized viaactivators regenerated by electron transfer atom transfer radical polymerization(ARGET-ATRP), using isobornyl methacrylate and silyl-protected propargylmethacrylate as the monomers. The obtained prepolymers were functionalised

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with azide substituted BTAs. The BTA moiety comprised one o-nitrobenzylgroup protected amide in order to trigger the threefold hydrogen bonding intoBTA aggregates via light. Later, both BTA and UPy moieties were utilized inone polymer chain by Hosono et al. by which orthogonal self-assembly wasintroduced into SCPNs (Figure 2) (29). An ABA triblock copolymer possessingdifferent pendant functional groups in the A and B blocks was prepared via ATRP,to which a complementary BTA and phUPy moiety were ligated in a modularpost-functionalization approach. The ABA block-copolymer formed bothBTA-based helical aggregates and UPy dimers within one SCPN upon a two-stepthermal/photoirradiation treatment under dilute conditions. The orthogonalityof the BTA and UPy self-assembly was corroborated via variable-temperatureNMR studies. The collapse of polymers after deprotection of the photolabileprotecting groups of phUPys into SCPNs was indicated by significant reductionsin the hydrodynamic volume by SEC and a decrease in the radius of gyration asevidenced by small-angle X-ray scattering (SAXS).

Figure 2. (a) Design of a triblock copolymer with BTA and UPy moieties thatfolds into a single chain polymeric nanoparticle cross-linked via orthogonalself-assembly. (b) Chemical structure of the triblock copolymers. (c) Helicalself-assembly of chiral BTAs via threefold, symmetric hydrogen bonding. (d)Photoinduced dimerization of o-nitrobenzyl protected UPys via quadruple

hydrogen bonding. (Reproduced with permission from reference (29). Copyright(2013) American Chemical Society.)

Water solubility was first introduced into BTA-based dynamic SCPNsby Terashima et al. (38). Ru-catalyzed living radical polymerizationwas used to prepare a segmented amphiphilic copolymer based on

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oligo(ethyleneglycol)methacrylate (oEGMA) and a BTA-functional methacrylate(BTAMA). When the content of BTAMA was smaller than 20%, the copolymerswere water-soluble. In addition, a combination of circular dichroism (CD)spectroscopy and scattering techniques showed that these copolymers foldinto a single chain polymeric nanoparticles (SCPNs) as a result of the helicalself-assembly of the pendant BTA units and/or hydrophilic-hydrophobic phaseseparation (39). Interestingly, their folding was reminiscent to the cooperativefolding observed in proteins.

Recently, Sawamoto and coworkers reported on the single-chain foldingof amphiphilic random copolymers prepared by the Ru-catalyzed living radicalcopolymerization of a pEG methacrylate (pEGMA) and an alkyl methacrylate(RMA) in water (40). In this system, folding of the single chains was achievedvia hydrophilic/hydrophobic phase separation as being one of the simplest modelsin self-folding polymers without any additional non-covalent interaction and/orchemical linking. Detailed structural and chain-folding characterization on theresulting dynamic and reversible SCPNs disclosed the design rule for singlechain folding as an alkyl methacrylate content between 20−40 mol% per chain.Notably, a sharp and reversible lower critical solution temperature (LCST) andphase separation in water was observed with these p(EGMA-co-RMA) randomcopolymers. Besides tunable hydrophobicity of the compartments depending onnature and content of the alkyl methacylate, a stimulus-responsive unfolding wasobserved via the addition of methanol.

Besides UPy and BTA motifs, the 3,3′-bis(acylamino)-2,2′-bipyridinesubstituted benzene-1,3,5-tricarboxamide (BiPy-BTA) unit was also utilized as astructure forming element in SCPN design by Gillissen et al. (30). Ring-openingmetathesis polymerizations were applied to prepare polynorbornene basedcopolymers with pendant BiPy-BTA units using a third generation Grubbscatalyst. The polymers formed SCPNs in mixtures of tetrahydrofuran andmethylcyclohexane via π−π interactions. In the self-assembled state, a strongfluorescence was observed due to the rigidification of the bipyridine moieties,which was utilized as a sensor by using metal binding affinity that enablesquenching of the emission (see below).

Characterization of Dynamic SCPNs

As summarized above, the broad synthetic scope of polymer chemistryin combination with the molecular recognition that supramolecular chemistryaffords, enables the design of various SCPNs. However, the verification ofthe single chain character and untangling the nature of the three dimensionalarchitectures of the SCPNs has been less straightforward. In fact, we foundthat a combination of characterization techniques is required in order to excludeartifacts arising when those techniques are applied separately. Direct visualizationusing (cryogenic) transmission electron microscopy (TEM) is possible but lowcontrast and the small sizes of the parcticles typically hamper the elucidation

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of the overall structure. Atomic force microscopy (AFM) images have alsobeen frequently applied to visualize the size and shape of SCPNs. However,the method of sample preparation may yield unclear and even misleadingimages due to solvent evaporation effects. In addition, polymer-surface contactshave a significant impact on the conformation of the polymer chain (41). Sizeexclusion chromatography (SEC) is used to circumvent these issues allowing thedetermination of the hydrodynamic volume. However, SEC does not providedetailed information on the global conformations that the polymers adoptin solution. Spectroscopic techniques (nuclear magnetic resonance (NMR),fluorescence, ultraviolet (UV) and circular dichroism (CD) spectroscopy) allare usefull to provide evidence on the aggregation state of the supramolecularrecognition motifs but they do not distinguish between intra and inter chaininteractions. The most revealing method until now has been the combinationof scattering techniques (dynamic light scattering (DLS), small angle X-rayscattering (SAXS) and small angle neutron scattering (SANS)) to analyzedynamic SCPNs. These techniques were recently added to our analysis repertoireas being the only label-free method to measure both the single chain characteras well as give information on the global conformation that the SCPNs adopt inspecific solvent conditions.

While the first studies on SCPNs relied strongly on the use of AFMand SEC to elucidate the single chain character of the particles obtained,Stals et al. monitored the polymer backbone collapse of UPy functionalizedSCPNs using a combination of DLS, NMR, SEC and AFM (42). Hereto, alibrary of polymers with varying backbone structures, molecular weights andlinking groups was prepared that contained between 5-10% of photoprotectedpendant UPy groups. All characterizations were done in 3 different solvents,tetrahydrofuran, chloroform and dimethylformamide to assess the importance ofsolvent-polymer interactions in SCPN formation. After photodeprotection, UPydimerization was observed by 1H-NMR in tetrahydrofuran and chloroform, butnot in dimethylformamide, a solvent that surpresses hydrogen bond formation.Moreover, changes in hydrodynamic radius were observed by DLS and SECbefore and after deprotection, which were very sensitive to the solvent applied.AFM showed the formation of well defined particles. By combining the resultsof all techniques, the solvent emerged as the only decisive parameter for theformation of well-defined SCPNs. Later, complex polymeric architecturesbased on a block copolymer with a cylindrical brush block and a single-chainpolymeric nanoparticle block with pendant UPy groups were investigated (43).The self-assembly of these constructs was studied with a similar combinationof techniques but in this case, only high resolution AFM images provided clearevidence of SCPN formation.

For the systems in which folding is governed by BTA self-assembly, CDspectroscopy is a powerfull technique as shown by Mes et al. (28). When theBTAs are non-racemic, helical aggregates of one helicity are biased and thisassembly process gives rise to a signature Cotton effect. Upon attaching BTAs tothe polymer chains, the Cotton effect was found to be sensitive to the loading ofBTAs per polymer chain and the length of the oligo(ethyleneglycol) side chain(38). In addition, the magnitude of the Cotton effect was only determined by the

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local BTA concentration (28, 39). However, the presence of a Cotton effect doesnot exclude interparticle interactions. Therefore, scattering techniques proved tobe crucial to elucidate the single chain character in the BTA-based water-solublesystems. In recent studies, Gillissen et al. combined spectroscopy and small-angleneutron scattering to unravel the relation between interchain self-assembly andthe polymer conformation (39, 44). For the first time, SANS experiments revealedthe asymmetric shape of these SCPNs with a constant cross section, Rcs, andvariable length, L, with L > Rcs (Figure 3). Detailed investigations corroboratedthe elongated and highly stretched structure at room temperature, which adopts aconstant cross section regardless of the increase in the degree of polymerization.

Figure 3. A tentative picture of a BTAMA/oEGMA based SCPN at 25 °C in H2O.The drawn ellipsoid has the aspect ratio determined from the SANS profile underthese conditions. (Reproduced with permission from reference (39). Copyright

(2013) American Chemical Society.)

As mentioned in the previous section, a series of ABA-type triblockcopolymers were synthesized and functionalized with phUPy and BTA groups(29). Following the significant reductions in the hydrodynamic volume in SECand the decrease in the radius of gyration in small-angle X-ray scattering, AFMwas performed to monitor the “partly” and “fully” folded states correspondingto before and after UV irradiation stages, respectively. The AFM imagesclearly showed a significant chain collapse after the UV irradiation due to UPydimerization at both ends confirming the orthogonality achieved via design of thepolymer chain (Figure 4). In a following investigation, the effect of the polymertopology on folding was studied via comparing ABA and BAB-type triblockcopolymers as means of the differences in the degree of chain collapse (45). CDanalysis results suggested that two different folded structures were adopted byABA and BAB type polymers as a more tightly packed structure due to strongUPy association over the end blocks and a more loose packing structure sinceBTAs self-assemble separately in both end blocks, respectively. However, thiscould not be visualized by AFM images, highlighting our limits in elucidating theinternal folded structure of SCPNs. Therefore, developing new methods, suchas single-molecule force spectroscopy, to characterize the inherent structure ofSCPNs may prove to be of crucial importance to gain further insights into the 3Dstructure of SCPNs.

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Figure 4. AFM height images of ABA copolymers capturinge two-steps of themolecular folding process (a) before and (b) after UV irradiation. The top-rightinsets show magnifications of the framed areas. (Reproduced with permission

from reference (29). Copyright (2013) American Chemical Society.)

Functions of Dynamic SCPNs

To date, only a limited number of examples exist in which a function has beenintroduced into dynamic SCPNs. The type of supramolecular recognition motif isimportant to fold the polymer, while the nature of the side chain attached to thepolymer determines in which medium the function can be exploited. Evidently,attaching water-soluble side chains are crucial to compatibilize SCPNs with water,which is imporant in view of future biomedical applications and catalysis in water.

The interest for catalysis in water intiated a number of examples of functionalSCPNs. Terashima et al. prepared water-soluble segmented copolymers usingthe benzene-1,3,5-tricarboxamide motif as the supramolecular recognition unitand triphenylphosphine pendants for complexing Ru (38). While the BTAunits folded the polymers in water into compact conformations, as evidencedby CD and SANS, complexation of the triphenylphosphine moieties with Ruafforded catalytically active SCPNs. Transfer hydrogenation reactions in waterproceeded with turnover frequencies that were among the best reported for thesetypes of Ru-based complexes in water. More detailed studies by Artar et al.revealed that the Ru metals crosslinked the middle segment of the polymerswhere the triphenylphosphine groups were located (Figure 5) (46). In fact, thecombination of two orthogonal supramolecular interactions, hydrogen bondingbetween the BTA units and metal-ligand coordination between Ru and pendanttriphenylphosphines, assisted in procuring active catalysts in water. Huerta etal. attached L-proline, a well-studied organocatalyst capable of catalyzing aldolreactions, to water-soluble BTA-based polymers (Figure 6) (47). The polymersfolded into SCPNs up to high concentrations, as revelaed by dynamic lightscattering. The obtained SCPNs were highly active in the aldol reaction ofcyclohexanone and p-nitrobenzaldehyde in water. For a series of copolymers, thediastereomeric excess ranged from 0 to 90% and the enantiomeric excess from 40

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to 70%. We concluded that the exact positioning of the catalyst inside the SCPNis crucial for improving the selectivity of the reactions.

Figure 5. Design of catalytically active SCPNs for transfer hydrogenation ofketones in water.

Figure 6. Chemical structure of L-proline-functionalized catalytic polymer (top)and schematic representation of the unfolded polymer and the formation of the

compartmentalized catalytic structure in water (bottom).

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Finally, preliminary explorations have been conducted to apply SCPNs assensors (30). Bipyridine-based benzene-1,3,5-tricarboxamides show strong greenfluorescence in the aggregated state, but are nonfluorescent when molecularlydissolved (48). Gillissen et al. showed that the attachment of a byridine-basedBTA motif to a polymer backbone results in highly fluorescent SCPNs (30).The polymers were shown to fold intramolecularly via π-π interactions intofluorescent, compartmentalized particles in mixtures of tetrahydrofuran andmethylcyclohexane. Light scattering analysis showed compact conformations ofthe folded polymers with hydrodynamic radii in the range of 10 nm. Due to theaffinity of the 2,2′-bipyridine units to copper, the fluorescence was effectivelyquenched when Cu(II) was added to the SCPNs. As a result, the SCPNs obtainedwere effective sensors for this metal.

Conclusions and Future Perspectives

Folding polymer chains via pendant supramolecular recognition motifs intosingle chain polymeric nanoparticles is an emerging field of research, crossingthe boundaries between polymer chemistry, supramolecular chemistry, catalysisand physical organic chemistry. It is clear that not only highly interesting,compartmentalized structures can be prepared, but also that these SCPNs arecapable of a variety of interesting functions such as catalysis and sensing. Currentchallenges to be addressed are the lack of perfect control over the molar massdistributions and the necessity to develop methods that allow exact positioningof functional monomers along the polymer chain. These two issues are byno means trivial and especially the latter is one of the current “holy grails” inpolymer chemistry (49). In addition, improving characterization techniques thatallow visualization of the 3D structure of the SCPNs as well as give access todetermining the internal structure of the functional particles are highly desirable.

We envisage that SCPNs will play an exciting role in the development of, forexample, cascade catalytic reactions, possibly even in cellular environments. Thesite isolation of the catalysts in the interior of the SCPN in combination with highactivity and selectivity are important prerequisites to obain this goal. We alsoforesee that novel applications, for example in the biomedical field, will soon beexplored. In fact, the first examples applying non-dynamic SCPNs have alreadybeen presented (50, 51). The crucial step, however, is to combine different fieldsof research in order to take the next step. Evidently, our ability to fold syntheticmacromolecules into defined, compartmentalized structures is still far from theperfection achieved in the folding of polypeptides into conformations that displayselected functions. To mimic these natural systems, our current ability to formcompartmentalized structures with an ordered interior is not enough. Preciselocation of self-assembling motifs within the polymer chain and enhanced controlover polydispersities are of crucial importance to improve the scope of syntheticanalogues. We believe that with these multidisciplinary studies, the frontiers inpolymer and supramolecular synthesis, molecular analysis and three-dimensionalarchitectures of polymers are pushed forward.

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AcknowledgmentsThis research was supported by The Netherlands Organization for Scientific

Research (NWO) by an ECHO grant (M.A.) and Marie Curie Actions SCPNANOPart FP7-PEOPLE-2010-IEF-274668 (E.H.).

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Dynamic Single Chain Polymeric Nanoparticles: From Structure to Function

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