Perspective pubs.acs.org/Macromolecules
Polypeptoid Materials: Current Status and Future Perspectives Donghui Zhang,* Samuel H. Lahasky, Li Guo, Chang-Uk Lee, and Monika Lavan Department of Chemistry and Macromolecular Studies Group, Louisiana State University, Baton Rouge, Louisiana 70803, United States ABSTRACT: Polypeptoids have recently emerged as a subject of scientific interest due to their structural resemblance to existing pseudo-peptidic polymers including poly(αpeptide)s, poly(β-peptide)s, poly(2-oxazoline)s, and poly(Nsubstituted acrylamide)s. With demonstrated backbone degradability, biocompatibility, and thermal processability, polypeptoids are potentially useful in a variety of biotechnological applications. Before those applications can be realized, it is important to develop their synthesis and understand their fundamental properties. In this Perspective, we will review recent advances in the synthesis and characterization of polypeptoids and their copolymers as well as the development of polypeptoid-based functional and structured materials. We will conclude by discussing the future prospects for this nascent class of pseudo-peptidic polymers.
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INTRODUCTION Polypeptoids represent a class of pseudo-peptidic polymers that feature an aliphatic polyamide backbone with substitution on the nitrogen atoms. Basic forms of polypeptoids are illustrated in Figure 1. Poly(α-peptoid)s (or polypeptoids), poly(β-peptoid)s,
similar to poly(n-amide)s, they are potentially backbonedegradable. Poly(α-peptoid)s are generally stable under acidic condition [except for α-substituted poly(α-peptoid)s]3 and can be degraded in alkaline solutions. While studies of oliogomeric αpeptoids reveal their enhanced proteolytic stability relative to the αpeptides,16,17 the enzymatic stability of the polymeric analogues have never been reported. The combination of these attributes (i.e., biocompatibility, degradability, and processability) makes polypeptoids potentially useful for certain biotechnological applications (e.g., smart coatings, drug delivery, bioseparation). In this Perspective, we will summarize the early research efforts in the area of peptoid oligomers and polypeptoids so as to set the stage for the discussion of more recent developments. We will then highlight recent advances in the synthesis and characterization of polypeptoids as well as the development of functional or structured polypeptoid materials. We will conclude the article by offering our perspective on future research of polypeptoid-based materials.
Figure 1. Chemical structures of polypeptides and pseudo-peptidic polymers.
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DEVELOPMENT OF SYNTHETIC STRATEGIES Stepwise Synthesis of α-Peptoid Oligomers. In contrast to polypeptoids, whose studies are still in their infancy, oligomeric α-peptoids with discrete chain length and controlled sequence have received extensive investigation in the past 20 years. Tremendous progress has been made in understanding the sequence−conformation relationship7 and in the development of α-peptoid-based therapeutics and diagnostics.18 The α-peptoid oligomers are synthesized in a stepwise fashion by alternating the attachment of bromoacetic acid and various primary amines to a solid support (Scheme 1). This can be
and poly(γ-peptoid)s have attracted recent attention due to (a) their attendant synthetic challenges1−5 and (b) their structural resemblance to polymers of biological origins [e.g., poly(αpeptide)s] or biomedical importance including poly(β-peptide)s, poly(2-oxazoline)s, and poly(N-substituted acrylamide) (Figure 1).6,7 In contrast to polypeptides, polypeptoids lack stereogenic centers on the backbone and do not have extensive hydrogenbonding interactions as a result of the N-substituents. As a result, polypeptoid conformations are mostly controlled by the steric and electronic properties of the side chains,8 giving rise to random coils1 or well-defined secondary structures (e.g., helices) in some cases.9−14 Without extensive hydrogen bonding along the backbone, polypeptoids are soluble in many common solvents and are also amenable to thermal processing in analogy to conventional thermal plastics.15 As the backbone structures of polypeptoids are © XXXX American Chemical Society
Received: October 16, 2011 Revised: May 8, 2012
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Scheme 1
Luxenhofer and co-workers were motivated by the potential utility of poly(α-peptoid)s for drug delivery application and recently investigated the polymerization of a series of R-NCAs with various alkyl side chains (R = Me, Et, Pr, Bu, iBu) using a primary amine initiator (Scheme 2).2 All polymerizations proceeded in a living manner, yielding poly(α-peptoid)s with controlled polymer molecular weight (MW) and Poisson distribution. Sequential polymerization of R-NCAs afforded well-defined linear amphiphilic block co-polypeptoids that can efficiently encapsulate hydrophobic molecules (e.g., Reichardt’s dye). Colorimetric analysis of dye-encapsulated diblock copolypeptoid solution reveals that the interaction between the encapsulated molecule and the hydrophobic block of the copolymers can be readily tuned by controlling the Nsubstituent structure, a useful feature for drug delivery applications. NHC-Mediated Zwitterionic Polymerization of R-NCA toward Poly(α-peptoid)s. While NCA is known to undergo activated monomer polymerization in the presence of various bases (e.g., tertiary amine, pyridine, alkaline metal hydride, etc.),38,39 yielding high-MW poly(α-peptide)s, polymerization of R-NCA cannot occur by this mechanism due to the N-substitution. However, R-NCAs have been shown to polymerize in the presence of pyridine.40 The control over polymer molecular weight in this case is limited, and the polymer product contains substantial cyclic polysarcosines. As a result, the reaction was proposed to proceed through a zwitterionic propagating intermediate.40,41 Recent reports by Kricheldorf and co-workers on the tertiary amine-initiated42 or thermally43/ solvent44-induced polymerizations of Me-NCA also revealed substantial formation of cyclic polysarcosines in the final product, consistent with a putative zwitterionic propagating intermediate. Significant progress has been made using organic catalysts/ initiators for polymer synthesis. Notable examples include Nheterocyclic carbene (NHC)-mediated polymerization of various heterocyclic monomers such as lactide,45,46 γ-caprolactone,47 βbutyrolactone,48 δ-valerolactone,49 and ethylene oxide,50,51 yielding polymers with controlled polymer molecular weights and molecular weight distributions (PDI). Inspired by these studies, we have recently investigated the synthesis of poly(α-peptoid)s by NHC-mediated polymerization of Bu-NCA monomers (Scheme 3).1,52 The polymer molecular weight and polymerization rate can be controlled by the choice of solvent. In solvents with low dielectric constants (e.g., THF or toluene), the reaction exhibits the characteristics of a quasi-living polymerization. The polypeptoid molecular weight, which can be readily adjusted by controlling the initial monomer to NHC ratio ([Bu-NCA]0:[NHC]0), agree well with the theoretical molecular weights based on single-site initiation by the NHC. Spectroscopic analysis and intrinsic viscosity measurements reveal that the polypeptoids prepared by the NHC-mediated polymerization of Bu-NCAs have cyclic architectures with one NHC moiety attached to each polymer chain. By contrast,
accomplished either manually or automatically using a synthesizer.19 As a variety of primary amines are readily available from commercial sources, the stepwise synthetic approach enables the access to α-peptoids with diverse structures and precise control of the sequence and the chain length (n < 30 typically). However, synthesis of longer αpeptoids becomes time-consuming and low yielding, limited by the efficiency of coupling chemistry. Primary Amine-Initiated Polymerization of R-NCA toward Poly(α-peptoid)s. Early efforts in the synthesis of poly(α-peptoid)s, in particular poly(N-methylglycine) (a.k.a. polysarcosine), have been primarily motivated by the need to understand the mechanism of the nucleophilic ring-opening polymerization of N-carboxyanhydride (NCA), a reaction that produces poly(α-peptide)s. It has been demonstrated that Nsubstituted N-carboxyanhydrides (e.g., Me-NCA) can undergo ring-opening polymerization in the same manner as amino acidbased NCA monomers using nucleophilic initiators such as primary amines (Scheme 2). In the case of N-substituted Scheme 2
N-carboxyanhydride (R-NCA, Scheme 2), the propagating species bears a neutral secondary amino chain end.20 As a result, the steric effect of substituents on the nitrogen (and in some cases α-carbon) strongly influences the reaction,21,22 and their polymerization rates can differ by several orders of magnitude.23 As this makes the synthesis of poly(α-peptoid)s with bulky side chains particularly challenging,24,25 reports of these polymers are scarce. Apart from polysarcosine, poly(Nethylglycine) and poly(N-propylglycine) are the other two poly(α-peptoid)s that have been prepared from primary amineinitiated polymerization of the corresponding R-NCA monomers.26,27 However, characterization of their physical properties has not been reported. By contrast, poly(N-methylglycine) (a.k.a. polysarcosine) has been studied in depth. Polysarcosine is a random coil polymer with a statistical segment length b = 4.8 Å.28 The backbone exhibits high conformational heterogeneity with amide bonds populating both cis and trans conformations.29−31 Because of its natural origin, biocompatibility, water solubility, and nonionic character, polysarcosine has been investigated as a hydrophilic building block for microcapsules, peptosomes, and nanotubes by Kimura and co-workers.32−37 The resulting materials exhibit “stealth-like” properties analogous to those of poly(ethylene glycol) (PEG) (i.e., long circulation times and limited nonspecific organ uptake). B
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Scheme 3
polypeptoids in good yield. In summary, the NHC-mediated polymerization of R-NCA not only provides an efficient and general route toward poly(α-peptoid)s but also enables control over the polymer architecture and end groups by facile postpolymerization modification. Metal-Mediated Polymerization toward Poly(αpeptoid)s. In addition to organo-mediated polymerization of R-NCA monomers, poly(α-peptoid)s have also been synthesized by the metal-mediated alternating copolymerization of CO and imines (Scheme 4A).3 In addition to offering high
when the polymerization is conducted in polar solvents such as DMF and DMSO, only low molecular weight polypeptoids are obtained regardless of the [Bu-NCA]0:[NHC]0 ratio. Kinetic studies in low dielectric solvents (using Bu-NCA as the model substrate) reveal zwitterionic/spirocyclic propagating intermediates 1/2 (Scheme 3) that maintain a cyclic topology where the chain ends are in close contact throughout the course of polymerization.52 The chain propagation occurs by monomer addition to the zwitterionic carbamate species 1, which is the rate-determining step, followed by skeletal rearrangement of a mixed anhydride intermediate to regenerate 1. The equilibrium between 1 and 2 is rapid and greatly biased toward 1, as evidenced by the negligible CO2 pressure effect on the polymerization rate. Apart from initiating the chain growth, the NHC moieties also mediate the addition of monomer to 1 as a counter-ion and modulate the basicity of the carbamate chain end of 1 through Coulombic interactions. This significantly suppresses side reactions such as deprotonation and transamidation, and thus the polymerization proceeds in a quasi-living manner. The interaction between the oppositely charged chain ends of the zwitterionic intermediates is strongly influenced by the dielectric properties of the solvent, resulting in vastly differing outcomes regarding polymer MW and polymerization kinetics.1,52 For example, for the polymerization of Bu-NCA conducted in high dielectric solvents such as DMSO, the charged chain ends of the zwitterionic intermediates are fully dissociated, in analogy to the anionic propagating intermediate when R-NCA is polymerized using metal alkoxide or phenoxide initiator. The naked carbamate chain ends have enhanced basicity and nucleophilicity in these solvents, resulting in enhanced side reactions and nonliving polymerization behavior. The controlled polymerization method is applicable to a variety of R-NCA substrates (Scheme 3), enabling access to polypeptoids with diverse structures.1,13,14,52−55 Furthermore, the low molecular weight zwitterionic/spirocyclic propagating intermediates can also be readily converted into their linear analogues by end-capping with electrophiles (e.g., acyl chloride and methyl triflate).52 By contrast, treatment of the zwitterions with NaN(TMS)2 results in the clean formation of the NHC-free cyclic polymeric analogues (Scheme 1). While the exact mechanism for this transformation is unclear, this method provides a reliable approach to access NHC-free cyclic
Scheme 4
atom efficiency, this method enables access toward poly(αpeptoid)s bearing bulky side chains that are difficult to synthesize by other means.21−25 While the reaction exhibits some characteristics of a living polymerization, attempts to prepare block co-polypeptoids by the addition of variable imine monomers were unsuccessful. This has been attributed to the instability of the catalytic propagating species once all the monomers have been consumed.3 Metal-Mediated Polymerization toward Poly(β/γpeptoid)s. Poly(β-peptoid) and poly(γ-peptoid) are homologues of poly(α-peptoid) and have been synthesized from copolymerization of CO and N-substituted aziridine4,56 or N-alkylazetidine (Scheme 4B).5,57 The alternating copolymerization of CO and N-substituted aziridines exhibits the characteristics of a living polymerization, affording poly(β-peptoid) having controlled chain length and well-defined chain-end structures.4,56 This allows for the installation of functional groups at the chain ends by postpolymerization modification.58 For example, water-soluble poly(β-peptoid)s (R = Me, Et) were end-functionalized with a mercapto group to enable their attachment to a gold substrate. C
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Figure 2. (A) Cartoon depiction of the formation of cyclic brush-like polymers from the reaction of azido-terminated PEG and cyclic P(NPgG-rNBG) co-polypeptoids bearing propargyl side chains. Representative AFM topographic (B) and amplitude (C) images of cyclic brush-like polymers [c-P(NPgG166-r-NBG33)-g-(PEG550)154] on mica (0001) and the cross-section (D) and histogram analysis (E) of selected ring polymers within the sample.
on the N-substituent structure. For example, DSC/WAX studies of α-peptoid oligomers (15-mer) revealed that as the N-substitution changes from butyl, hexyl to octyl, the melting temperature decreases systematically from 168 to 158 and 140 °C.15 This agrees with conventional understanding that long and flexible side chains inhibit the efficient crystalline packing of molecules (or polymer chains), resulting in depressed melting temperatures. Interestingly, α-peptoids with isoamyl or 1-phenylethyl side chains exhibit elevated melting transition temperatures (Tm = 178 and 225 °C, respectively) relative to their analogues with linear alkyl side chains. This has been tentatively ascribed to increased stiffness of the α-peptoid backbones due to the branched and bulky side chains. For polypeptoids with aliphatic side chains, as the chain length increases, the water solubility decrease systematically, with poly(N-methylglycine)s and poly(N-ethylglycine)s being highly water-soluble (>5 g L−1) and polypeptoid with longer alkyl chains (n > 3) water insoluble.2 Polypeptoids with aliphatic side chains have random coil conformations,1 whereas N-substitution with bulky chiral side chains (e.g., S(R)-2-phenylethyl or S(R)-2cyclohexylethyl) induces polyproline I (PPI) helical conformations.9−14 These helical conformations turned out to be very flexible, as indicated by their short persistent chain length.61 Nanostructures by Functionalization of Poly(αpeptoid)s. As the polymerization of R-NCAs involves the reaction of electrophilic substrates with nucleophilic propagating intermediates, the side chain structures of the polypeptoids have been mostly limited to aliphatic or aromatic groups. Functional side chains that are highly electrophilic or nucleophilic are likely to interfere with the chain propagation by causing termination or chain transfer, resulting in diminished control over polymer molecular weight. An alternative strategy to increase the structural diversity of polypeptoids is the postpolymerization modification of polypeptoids bearing functionalizable side chains.53,62,63 Cyclic and linear polypeptoids bearing propargyl side chains (c/l-PNPgG) with controlled polymer molecular weights have been synthesized by NHC or primary amine-initiated polymerization of Pg-NCA.53 Functionalization of the side chains has been demonstrated by the reactivity of azido-terminated poly(ethylene glycol) in CuAAC chemistry, resulting in the formation of nanoring structures (Figure 2). In common
The poly(β-peptoid)-coated substrates exhibit resistance toward protein adhesion at a level comparable to the PEGcoated substrate, a benchmark for antifouling materials.58 The alternating copolymerization of CO and N-substituted aziridines has been extended toward the controlled synthesis of block co-poly(β-peptoid)s by sequential monomer addition.59 As poly(β-peptoid) backbones are stable against degradation in refluxing trifluoroacetic acid (TFA), the block co-poly(βpeptoid) where one block bears acid-labile N-substituents can be selectively deprotected to yield a novel poly(β-peptide)-bpoly(β-peptoid) block copolymer. This polymer has been shown to self-assemble into soluble antiparallel sheet-like supramolecular aggregates, stabilized by intermolecular hydrogen bonding.59 In addition to diblock co-poly(β-peptoid)s, poly(β-peptoid)s-b-polyester heterodiblock copolymers were also synthesized by the one-pot copolymerization of Nalkylaziridine, ethylene oxide, and CO in the presence of a discrete acyl cobalt catalyst. The resulting microstructure has been attributed to the selective insertion of N-alkylaziridine into a metal acyl intermediate, which is preferred over ethylene oxide due to the enhanced nucleophilicity of the former over the latter.60 Copolymerization of CO and N-substituted azetidine also yields poly(γ-peptoid)s (Scheme 2C).5,57 As a result of competing side reactions, the polymer MW control and polymer microstructure are strongly dependent on the monomer structure and experimental conditions. For example, the sequential addition of N-alkylazetidine or the alternating addition of CO and THF (the reaction solvent) competes with the alternating addition of CO and N-alkylazetidine, resulting in copolymers containing poly(β-peptoid) and polyamine segments [poly(amide-co-amine)] or poly(β-peptoid) and polyester segments [poly(amide-co-ester)].5,57 Novel polymer microstructures [e.g., multiblock gradient poly(amide-co-amine) or poly(amide-coester)] can be accessed by controlling the experimental conditions.
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PHYSICAL PROPERTIES AND MATERIALS DEVELOPMENT Physical Properties of Poly(α-peptoid)s. The physical properties of poly(α-peptoid)s (e.g., crystallinity,13,15,54 solubility,2 and backbone conformation)1,13 are strongly dependent D
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Figure 3. Representative cryo-TEM images obtained from dilute methanol solutions of the cyclic PNMG105-b-PNDG10 block co-polypeptoid after 1 h (A), 2 h (B), and 15 days (C) and the linear PNMG112-b-PNDG16 block co-polypeptoid after 1 h (D), 2 h (E), and 7 days (F) in methanol.
Supramolecular Assembly of α-Peptoid Oligomers. Recent investigations into the self-assembly of selected αpeptoids have led to findings that are particularly inspiring or pertinent for the future development of structured polypeptoidbased materials.70−72 For example, mixing a 1:1 ratio of two oppositely charged amphiphilic peptoid 36-mers with alternating aromatic and carboxyl (or ammonium) N-substituents along the backbone, i.e., [N-(2-phenyethyl)glycine-N-(2carboxyethyl)glycine]18 (Npe-Nce)18 and [N-(2-phenyethyl)glycine-N-(2-aminoethyl)glycine]18 (Npe-Nae)18, resulted in the formation of free-floating two-dimensional bimolecular nanosheets in water (Figure 4).72 The nanosheets span up to millimeters in lateral dimension and have nanoscale thicknesses. The hydrophobic aromatic side chains are buried at the interior of the sheet and form a highly ordered structure, whereas the hydrophilic carboxyl and ammonium groups are pointed outward alternatingly in a layered structure (Figure 4). Mechanistic studies revealed that the formation of the nanosheets requires the initial organization of amphiphilic molecules into a monolayer at the water/air interface, followed by the irreversible collapse of the monolayer into the biomolecular structure under lateral compression above a critical pressure.73 It has also been demonstrated that sensing elements can be incorporated into bimolecular sheets, enabling their potential use as nanosensing platforms.69 The 2-fold amphiphilic sequence, charge complimentarity, and aromatic interaction are considered critical in driving the nanosheet formation in the binary system. This prompted the design of new polypeptoids that self-assemble into stable nanosheets as a single-component system. Indeed, amphiphilic polypeptoids (Nae-Npe-Nce-Npe)9 and (Nae-Npe)9-(Nce-Npe)9 where the opposite charges are arranged in an alternating or blocky fashion along a single chain were shown to self-assemble into bimolecular nanosheets similarly to the binary system.73 Another interesting finding involves an achiral amphiphilic block peptoid 30-mer [N-(2-phenethyl)glycine]15-[N-(2carboxyethyl)glycine]15 (Npe15-Nce15) which at an intermediate pH (6.8) underwent a morphological transition from intedigitated biomolecular nanosheets into micrometer long
solvents, the c/l-PNPgG has a strong tendency toward aggregation, forming fibrous structures, which limits the coupling efficiency of CuAAC chemistry. The aggregation can be significantly reduced by copolymerization with another R-NCA monomer, which drastically improves the side chain functionalization efficiency of the CuAAC method. Supramolecular Assembly of Poly(α-peptoid)s. Because of the quasi-living nature of the NHC-mediated polymerization of R-NCAs, cyclic block co-polypeptoids having coil−coil or coil−helix conformations can be prepared by sequential monomer addition.1,14,54 Amphiphilic cyclic diblock co-polypeptoids [poly(N-methylglycine)-b-poly(N-decylglycine) (c-PNMG-b-PNDG)] whose composition can be readily controlled by the initial monomer to initiator ratio and conversion have been synthesized via this method.54 Timelapsed light scattering and cryogenic transmission electron microscopic analysis of selected block co-polypeptoids [e.g., (c-PNMG105-b-PNDG10)] reveal that c-PNMG105-b-PNDG10 self-assemble into spherical micelles (having uniform diameters in room temperature methanol solution), which reorganize into micrometer-long cylindrical micelles of uniform diameter over a period of 15 days (Figure 3A−C). The cylindrical micelles were first observed within a couple of hours after sample preparation, suggesting the structural transition from spherical to cylindrical micelles was rapid. Over the course of 15 days, the density and length of the cylindrical micelles continued to grow at the expense of the spherical micelles. An identical morphological transition has been observed for the linear analogue in room temperature methanol (Figure 3D−F), except that the transition occurs more rapidly for the linear than the cyclic diblock co-polypeptoids, as evidenced by the time-lapsed light scattering studies. The morphological transformation from spherical into cylindrical micelles has been tentatively attributed to crystallization of the PNDG hydrophobic core, in analogy to several other reported amorphous-semicrystalline block copolymers [i.e., polyisoprene-b-polyferrocenylsilane,64−67 poly(3-hexylthiophene)-b-poly(dimethylsiloxane),68 poly(lactide)b-poly(acrylic acid)].69 E
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Figure 4. (A) Fluorescent optical microscope image of two-dimensional crystalline nanosheets assembled from the 1:1 mixture of (Npe-Nae)18 and (Npe-Nae)18 periodic amphiphilic polypeptoids. The sheets are free-floating in aqueous solution and stained with Nile Red. (B) Height-mode AFM image of a sheet. (C) Molecular model of the nanosheets. The modeled structures shows that hydrophobic groups face each other in the interior of the sheet and oppositely charged hydrophilic groups are alternating and surface-exposed (atomic color scheme: carbon, yellow; nitrogen, blue; oxygen, red). Adapted by permission from Macmillan Publishers Ltd.72
Figure 5. (A) AFM image and (B) the modeled structure of the nanosheets as well as (C) the AFM image of the homochiral superhelices assembled from the Npe15-Nce15 amphiphilic diblock co-polypeptoids in aqueous solution (pH = 6.8).71
Figure 6. (A) Representative plots of transmittance at λ = 450 nm versus temperature for the selected aqueous solutions of cyclic co-polypeptoids c-P(NEG70-r-NBG47) (■, □), c-P(NEG65-r-NBG30) (●, ○); c-P(NEG101-r-NBG34) (▲, △) (polymer concentration = 1.0 mg mL−1; heating and cooling cycles are symbolized by the filled and unfilled symbols, respectively). (B) Plots of Tcp versus the molar fraction of NEG segment in the cyclic and linear P(NEG-r-NBG) random copolymers bearing different end groups and their respective linearly fit curves [c-P(NEG-r-NBG) (●, ), l-Bu-P(NEG-r-NBG) (▲, ), and l-Bn-P(NEG-r-NBG) (■, )].
homochiral superhelices with 624(69) nm diameter and hierarchical interior ordering in high yield (Figure 5).74 While the origin of the homochirality is not entirely clear, a fine interplay of the electrostatic and hydrophobic interaction are considered critical for their formation. Thermoresponsive Poly(α-peptoid)s. Poly(N-methylglycine) (PNMG) and poly(N-ethylglycine) (PNEG) exhibit significant solubilities in water. In spite of their structure resemblance to poly(2-oxazoline)s and PNIPAM, both of
which are thermally responsive with cloud point temperatures (Tcp), neither of these polypeptoids exhibits Tcp detectable by turbidity measurements below 100 °C. However, NHCmediated batch-mode copolymerization of Et-NCA and BuNCA produces random cyclic co-polypeptoids [c-P(NEG-rNBG)] that exhibit Tcp with minimal hysteresis (Figure 6A).55 The cloud point transitions of the co-polypeptoids tend to be broader (ΔT = 11−18 °C) than those of poly(2-oxazoline) (ΔT < 5 °C)74,75 and PNIPAM, a benchmark thermoresponsive F
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polymer.76 This has been ascribed to polymer aggregation below TcpS, resulting in the broadening of the effective particle sizes. The cloud point temperature in the range of 20−60 °C is readily accessed by controlling the co-polypeptoid composition. As the hydrophobic content (NBG) is increased, the Tcp decreases systematically (Figure 6A). The linear random co-polypeptoid analogues [l-Bu-P(NEG-r-NBG) or l-Bn-P(NEG-r-NBG)] have also been independently synthesized by primary amine (i.e., BuNH2 or BnNH2)-initiated polymerization of Et-NCA and BuNCA. Their Tcps are ∼5 °C higher than those of the cyclic analogues regardless of the copolymer composition (Figure 3B). As the reactivity ratios of each monomer are comparable for NHC [r1 = 0.93(3), r2 = 0.92(7)] or primary amine-initiated polymerizations [r1 = 1.08(8), r2 = 0.98(17)], the difference of Tcp has been attributed to architectural disparities rather than microstructural incongruities. In comparison, several recent studies of cyclic and linear PNIPAM also reported significant difference in their Tcp behaviors.77−79 The Tcp transition window of cyclic PNIPAM was shown to be wider than that of the linear analogues,83 which was attributed to the reduced cooperativity of the phase transition in the former than the latter. The results regarding the relative magnitude of the Tcps are inconclusive: one study reported an elevated Tcp of the cyclic PNIPAM relative to that of the linear analogue by about 4 °C,83 whereas two other studies reported the opposite trend.84,85 The inconsistency may have arisen from the differing end-group structures of the linear and cyclic PNIPAMs used in these studies. In additional to the tunable Tcps, cell viability studies reveal that the co-poly(αpeptoid)s have low cytotoxicity, on par with low molecular weight poly(ethylene glycol)s (PEGs), enhancing their potential uses in biomedical applications.55
known attributes will potentially generate materials with unconventional properties. In the synthetic space of polypeptoid materials, peptoid oligomers have discrete chain length and well-defined sequence, whereas polypeptoids have a chain length distribution and less-defined microstructure. Several intellectually interesting questions arise: (1) Can polypeptoids with broad but controlled molecular weight distribution be synthesized? (2) How does the transition from discrete molecules into polymeric mixtures impact the materials properties and functions? (3) Can some level of sequence control be conferred to the polypeptoid materials? These questions are important in view of the tremendous progress that has been made in understanding the sequence effect on the oligomeric peptoid conformation, biological activity, and selfassembly properties. Supramolecular Structures with Variable Length Scale and Dynamic Range. Despite the fact that diverse side chain structures can be introduced into the polypeptoids, the polymer dimension is typically less than 10 nm, a result of the degree of polymerization achievable by the current synthetic methods. To access polypeptoid materials with hierarchical structure and variable length scale (from nanometer to micrometer), investigation of their self-assembly both in solution and the solid state represents a sensible strategy. One can envision the incorporation of noncovalent and directional forces such as hydrogen bonding or aromatic− aromatic interactions into the design of polypeptoid materials to promote their hierarchical assembly. For example, conjugation of conventional polymers with N-alkyl urea− peptoids, a class of peptidomimetics that are capable of hydrogen bonding, has recently been investigated.80−82 The water-soluble poly(ethylene glycol)-N-alkyl urea-peptoid linear conjugates was shown to self-assemble into micrometer-long ribbon-shaped fibers as directed by the hydrogen-bonding interaction of the N-alkyl urea−peptoid segment.82 Polypeptoid materials with ordered structures and well-defined chemistry will provide tremendous flexibility in their integration and interfacing with more complex biological or synthetic systems, ultimately leading to useful applications (e.g., sensor and smart drug delivery). Biomedical or Technological Relevancy. A variety of synthetic polymers are currently used in biomedical/biotechnological areas and can be synthesized at a lower cost than polypeptoids. Therefore, one critical impetus for the future development of polypeptoid materials resides on establishing their technological relevance. For example, polypeptoids may not be biologically inert, as they are structurally analogous to polypeptides. Investigation of their enzymatic stability, biological activity, immunogenicity, and biodistribution will be of significant interest. With tunable chemistry and adjustable conformations, biologically active polypeptoids or polypeptoidbased particles may be uncovered. Comparative studies with benchmark polymers will facilitate their transition into various niche applications.
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SUMMARY AND OUTLOOK Recent advances in polymerization catalysis have enabled the synthesis of polypeptoids in reasonable quantities and with controlled and tunable chemistry, architecture, and microstructure, setting the foundation for the further investigation of their physical properties and potential technical utility. Despite their structural resemblance to several relatively well-studied polymers such as polypeptide, poly(2-oxazoline), or poly(N-Racrylamide)s, initial investigations of polypeptoids have revealed appreciable differences in their physical properties (e.g., thermal properties, cloud point transition). Future efforts that aim to understand the fundamental structure−property relationships of polypeptoids will undoubtedly provide new insights into their physical behavior, providing guidance for the rational design of polypeptoid-based materials with unprecedented functions. We consider the following research topics to be of significant interest, deserving special attention due to their potential impact on the future development of polypeptoidbased materials and related research fields: Polymerization Catalysis Development. While the current polymerization methods provide access to a variety of polypeptoid materials, the synthetic efficiency and the chemical diversity can be further improved. One can envision the design and refinement of organocatalysts that can serve to activate R-NCA and exogenous nucleophilic initiator simultaneously, in analogy to some reports on cyclic ester ring-opening polymerization. This will provide access to chemically diverse polypeptoids and broaden their potential technical applications. Chemistry that enables the synthesis of polypeptoid-based hybrids will also have a significant impact on the field. The marriage of polypeptoids with other synthetic polymers of
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest. G
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From left to right: Donghui Zhang, Samuel H. Lahasky, Li Guo, Chang-Uk Lee, and Monika Lavan. Donghui Zhang is an assistant professor in the Department of Chemistry and the Macromolecular Studies Group at the Louisiana State University in Baton Rouge, LA. She was born and raised in Beijing, P. R. China. After obtaining a B.S. in chemistry from Peking University in 1998, she moved to the US and enrolled in the chemistry graduate program at Dartmouth College, where she completed her Ph.D. in 2003. She did postdoctoral research at the University of Minnesota on the synthesis and characterization of polymers from biorenewable feedstock. She joined LSU in 2007 after a two-year stint as a research professor at New Mexico State University where her research was focused on carbon nanotube composites. Her current research interests include polymerization catalysis toward pseudopeptidic polymers and the design and synthesis of polypeptoid-based functional materials. Samuel H. Lahasky received his B.S. in Chemistry at Tulane University in 2007. He worked on the elastomer formulation at Dow Chemicals for one year prior to joining the graduate program in the Department of Chemistry at LSU in 2008. His current research is focused on the design and synthesis of polypeptoids that exhibit stimuli-responsive behavior. Li Guo received her B.S. in Chemistry from Zhengzhou University, China. She earned her Ph.D. in Polymer Chemistry and Physics with Prof. Zhijie Zhang at Institute of Chemistry, Chinese Academy of Sciences, China, in 2007. She is currently a Research Associate with Prof. Donghui Zhang in the Department of Chemistry at the Louisiana State University. Her current research focuses on the synthesis and property study of polypeptoids and polypeptides. Chang-Uk Lee received his B.S. in Polymer Science and Engineering from Pusan National University in Korea and M.S. in Polymer Engineering from the University of Tennessee. He is currently a fourth year graduate student in the Department of Chemistry at Louisiana State University. His Ph.D. research focuses on the synthesis and selfassembly of cyclic block co-polypeptoids. Monika Lavan is an undergraduate student at the Louisiana State University. She is pursuing a major in biochemistry and a minor in chemistry and is expected to graduate in 2013. She is conducting research in Professor Donghui Zhang’s laboratory. Her research focuses on the synthesis and characterization of polypeptoid− polypeptide block copolymers.
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ACKNOWLEDGMENTS This work was supported by Louisiana State University, the National Science Foundation (CHE-0955820), and Louisiana State Board of Regents [LEQSF(2008-11)-RD-A-11]. H
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