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Keywords:

  • biopolymers;
  • NCA;
  • polypeptides;
  • ring-opening polymerization;
  • structure-property relations

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

Design and synthesis of biodegradable stimuli-responsive polypeptides are important areas considering their promising applications in biomedical fields. This article summarizes the most recent progresses in the development of stimuli-responsive polypeptide materials prepared via ring-opening polymerization of α-amino acid N-carboxyanhydrides. We discuss the design, synthesis and structure-property correlation of emerging materials including thermo-responsive, redox-responsive, photo-responsive and biomolecule responsive polypeptides. Considering the unique structural features of amino acids, we try to emphasize that the thermo-responsive properties not only depend on the amino acid structure but also rely on the secondary structures of polypeptides. © 2013 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2013


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

Environmentally stimuli-responsive polymers are termed smart materials because their properties can respond to external stimuli such as temperature, pH, light, ions and biomolecules. These smart materials and their derivatives have found extensive applications in bio- and nano-technology.1–4 In contrast to conventional polymers, stimuli-responsive biodegradable polymers are greatly desirable for biomedical applications considering the advantages of their biodegradability and biocompatibility.5–7

There have been extensive efforts to construct biodegradable stimuli-responsive polymers. Several systems based on degradable polyesters,8–10 poly(amino ester)s,11–13 poly(organo phosphazenes),14 and poly(amino acid)s have been investigated. Among them, polypeptides made from α-amino acid carboxyanhydrides (NCAs) have received extensive research interest for their promising applications.7 The synthesis of polypeptide from ring-opening polymerization (ROP) of NCAs has been studied for a few decades.15–17 Numerous functional polymers based on natural amino acids have been constructed. The rich variety of naturally available amino acid monomers allowed researchers to make various polypeptides with different functionalities. In addition, these synthetic polypeptides have specific secondary structures such as α-helix and β-sheet, which offer additional factors to tune their properties and functionalities. For example, well-defined block copolypeptides can easily form injectable hydrogels.18 The critical gelation concentration and gel strength can be easily tuned by polypeptide chain length and monomer hydrophobicity.19 Combining polypeptides with hydrophilic PEG can form thermo-responsive hydrogels.20–23

For those ionic polypeptides, they can undergo solubility and conformation change upon solution pH change. Representative examples include poly-L-lysine and poly-L-glutamic acid. Using this naturally responsive feature, researchers prepared pH responsive aggregates such as micelle and vesicles.24–28 Here, we will mainly focus on recent developments of design and responsive mechanism of stimuli-responsive polypeptides other than pH.

SYNTHETIC STRATEGY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

Regarding the synthesis of polypeptide materials via ROP of NCAs, it is out of the scope of this paper. Readers are referred to several excellent reviews.15, 16 But, it is worth pointing out that recent developments of controlled polymerization chemistry of NCAs have afforded researchers several versatile methodologies to make well-defined (co)polypeptide materials on a large scale.

As illustrated in Scheme 1, there are generally two methods to make stimuli-responsive polypeptides. In Route I, natural amino acids are firstly conjugated with target group to give new functional amino acids, which are then converted into corresponding NCAs. Then, appropriate initiator systems can be applied to make stimuli-responsive polypeptides or copolypeptides. Using this method, thermo-responsive,29, 30 redox-responsive,31 and lectin-recognition (co)polypeptides32, 33 have been prepared. In Route II, natural amino acids are firstly functionalized with reactive functional groups, which are dormant during subsequent synthesis of NCAs and ROP. These monomers are converted into NCAs and then to polypeptides. Subsequently, stimuli-responsive groups are conjugated to the polypeptide side chain on demand. Either graft-onto or graft-from strategy is applied as discussed below.

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Scheme 1. Schematic illustrations of making stimuli-responsive polypeptides via ROP and post-modification methods.

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THERMO-RESPONSIVE POLYPEPTIDES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

Temperature is the most widely investigated and used stimulus in stimuli-responsive polymer systems because of its convenience to control and easy application both in vivo and in vitro.34 Generally, thermo-responsive polymers undergo a reversible phase transition at a critical temperature including low critical solution temperature (LCST) and upper critical solution temperature (UCST). For the former, the polymers change from dissolution to precipitation above the cloud point (CP), and the polymer chains undergo a coil-to-globule phase transition at LCST. For UCST, the polymer becomes soluble in water above the phase transition temperature. Note that the LCST is a thermodynamic parameter and considered the lowest CP in its phase diagram. Usually, turbidity measurements are applied to determine the CP, at which the polymer solution changes from clear to cloudy. Two extensively studied thermo-responsive polymers are poly(N-isopropyl acryl amide)35–38 and poly(oligo(ethylene glycol) methacrylate) (POEGMA).39, 40 From the thermodynamic consideration, the thermo-responsive property is due to a delicate amphiphilic balance between different subunits within polymer chains, which contains hydrophobic and hydrophilic moieties. For LCST-type thermo-responsive polymers, the hydrophilic units tend to form hydrogen bonding with water molecules, which undergo dehydration upon temperature increase. For materials design, incorporation of suitable amphiphilicity to polymers is necessary to obtain thermo-responsive property. Previous studies indicated that conjugation of oligo (ethylene glycol) (OEG) to polymer side chains can produce thermo-responsive polymers,10, 40–42 and the corresponding LCST can be tuned by varying the length of OEG or copolymerization of different monomers.

Therefore, a natural emerging idea is to link OEG moieties to side chains of polypeptides. In the past decade, great efforts have been contributed towards this goal of making PEGylated polypeptides, which were firstly pioneered by Deming and coworkers. For example, they reported synthesis of PEGylated poly-L-lysine, poly-L-cysteine, and poly-L-serine via direct ROP of PEGylated NCAs.43, 44 The corresponding structures are given in Figure 1(a–c). Depending on the chain length of OEG side chains, these polypeptides displayed different solubility in water and common solvents. Poly(Nε-2-(2-(2-methoxyethoxy) ethoxy)acetyl-L-lysine) [Fig. 1(a)] showed great water solubility and adopted essentially 100% α-helix structure over wide pH range. Also, the helix structure kept stable in solutions containing up to 3 M NaCl, 1 M urea, 1 M guanidine hydrochloride. In contrast, poly(O-(2-(2-methoxyethoxy)ethyl)-L-serine) [Fig. 1(b)] adopted random conformation in water. For both of them, counterparts containing a less ethylene glycol unit were insoluble in water. For others, poly(S-(2-(2methoxyethoxy)ethoxy) carbonyl-L-cysteine) [Fig. 1(c)] was not soluble in water due to formation of β-sheet. However, none of them displayed thermo-responsive properties in aqueous solutions.

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Figure 1. Chemical structure of PEGylated polypeptides prepared via direct ROP of NCAs.29, 43, 44

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Recently, we reported the preparation of thermo-responsive PEGylated poly-L-glutamate via direct ROP of NCAs.9 The OEG functionalized glutamic acids were firstly prepared by selective esterification between (ethylene glycol)s monomethyl ether and L-glutamic acid. The modified glutamic acids were then converted to corresponding NCAs to allow subsequent polymerization. Depending on the chain length of side chain, these PEGylated poly(L-glutamate)s (poly-L-EGzGlu) [Fig. 1(d)] can display reversible thermo-responsive properties in solution. In particular, poly-L-EG1Glu is insoluble in water and most organic solvents because it forms stable β-sheet after ROP. In contrast, both poly-L-EG2Glu and poly-L-EG3Glu display thermo-responsive properties in water [Fig. 2(a)]. Given similar chain length, poly-L-EG3Glu has a higher CP than poly-L-EG2Glu due to longer OEG side chain. Poly-L-EG3Glu adopted complete α-helical conformation at high molecular weight (MW) and has completely reversible LCST transition in water. In contrast, poly-L-EG2Glu only adopted partial helical conformation. More interestingly, its conformation can slowly evolve into β-sheet. Because of this characteristic, poly-L-EG2Glu could display kinetically irreversible LCST transition. It is also worth noting that the CP of this type of polypeptide can be varied between 32 and 56 °C via copolymerization of different monomers [Fig. 2(b)].

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Figure 2. (a) Plots of transmittance as a function of temperature for aqueous solutions of poly-L-EG2Glu and poly-L-EG3Glu. Solid line: heating, dash line: cooling. (b) CP of poly(EG2Glu-EG3Glu) copolypeptides as function of sample composition (reproduced from Ref.29, with permission from American Chemical Society).

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CD measurements found that the secondary structure of poly-L-EG3Glu did not change with temperature. Temperature varied 1H NMR studies revealed that their thermo-responsive properties arise from the OEG side chain. As we know, the peptide amide bond can form strong hydrogen bonding with themselves as well as with water molecules. In aqueous solution, they will compete with each other. Such competition offers a unique property in that their thermo-responsive properties are not only determined by the chemical structure of monomers but also reply on the regularity of their conformations. Disruption of secondary structure will result in loss of thermo-responsive properties. For example, we prepared racemic poly(rac-EG3Glu) and poly(rac-EG2Glu) homopolypepides using equal amount of OEG functionalized D-glutamate and L-glutamate NCAs, and found both samples were readily soluble in water without showing thermo-responsive properties. CD characterization further demonstrated that both samples adopted random coil conformation in water regardless of temperature. This was presumably due to transformation of intramolecular hydrogen bonding to intermolecular hydrogen bonding as illustrated in Scheme 2. For enantiomerically pure poly(L-EG3Glu) or poly(D-EG3Glu), they adopt helical conformation. In this case, the amide bonds within polypeptide backbone form predominate intramolecular hydrogen bonding, and their interaction with water molecules is minimal. Conversely, any disruption of such structural regularity will increase the percentage of hydrogen bonding between amide bonds and water molecules. As a result, poly(rac-EG3Glu) has better solubility in water than enantiomerically pure poly(L-EG3Glu) or poly(D-EG3Glu). Loss of thermo-responsive property is thus expected. Similar results were also observed from racemic poly(rac-EG2Glu) homopolypeptides.

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Scheme 2. Illustration of intramolecular hydrogen bonding for α-helical polypeptide (Left) and intermolecular hydrogen bonding of random coil (Right).

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Such thermo-responsive properties of PEGylated polyglutamate contrast sharply to those of conventional polymers such as PNIPAM. In case of polypeptide, the competition of intermolecular and intramolecular hydrogen bonding can significantly affect the solution properties of materials. Another factor to consider is MW. It was known that poly(γ-benzyl L-glutamate) adopts α-helical conformation with 3.6 residues per pitch,45, 46 and its helical stability also depends on polypeptide chain length.47 Short polypeptide adopts partial helical structure. It would be expected that when the degree of polymerization (DP) of poly-L-EGzGlu is too low to destabilize the α-helical conformation, the poly-L-EGzGlu chain will contain more and more random coil conformation to become more and more hydrophilic. As a result, the CP increased significantly with decrease of MW. To demonstrate this, we prepared two series of poly-L-EG2Glu and poly-L-EG3Glu homopolypeptides with different MW.30 As shown in Figure 3, the CP of dilute poly-L-EG2Glu solution decreased monotonically with the increase of DP. In particular, the CP of the poly-L-EG2Glu34 (DP = 34) is 54 °C, while the CP of the poly-L-EG2Glu93 (DP = 93) has decreased to 36 °C. Further increase MW did not induce significant decrease of the CP as reported before. The CP of poly-L-EG2Glu299 (DP = 299) is about 32 °C. For poly-L-EG3Glu, which has a longer OEG side chain than that of poly-L-EG2Glu, higher MW is necessary to show thermo-responsive property. Only when DP is larger than 55, poly-L-EG3Glu homopolypeptides start to show well-defined LCST transitions. The corresponding CP for poly-L-EG3Glu55 (DP = 55) is about 72 °C. When increasing the DP to 160, we observed a CP close to 56 °C.

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Figure 3. Dependence of CP and helicity of poly-L-EG2Glu on the DP (reproduced from Ref.30, with permission from Springer).

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CD measurements revealed that the helicity of poly-L-EG2Glu and poly-L-EG3Glu increases with their chain length. Low MW polypeptides have more random coil component than helical component, which makes them more hydrophilic than high MW poly-L-EGzGlu from the secondary structure point-of-view. Conversely, increase of MW induces more amide bonds to transform from random coil conformation to ordered helical structure. So, the CP of poly-L-EGmGlu has stronger dependence on MW as compared to PNIPAM arising from the conformation dependence on MW as illustrated in Scheme 3.30

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Scheme 3. Schematic illustration of helicity increasing with MW for PEGylated poly-L-glutamate (reproduced from Ref.30, with permission from Springer)

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Besides the OEG side chain length and conformation of polypeptide, the structure of amino acids had significant influences on the solution properties of PEGylated polypeptides. As illustrated in Figure 1(e), we prepared mono-, di, and tri-ethylene glycol functionalized poly-L-aspartate (poly-L-EGzAsp), whose side chain had one less methylene group than counterpart of poly-L-EGzGlu. The poly-L-EG1Asp was insoluble in water as it formed β-sheet conformation. However, both poly-L-EG2Asp138 and poly-L-EG3Asp106 were readily soluble in water without showing thermo-responsive properties in water. CD and FTIR characterizations revealed that both poly-L-EG2Asp and poly-L-EG3Asp mainly formed random coil in water. As we discussed previously, the intermolecular hydrogen bonding between amide bonds and water will overwhelm the intramolecular hydrogen bonding for α-helical conformation. As a result, the PEGlyated poly-L-aspartate did not show any thermo-responsive properties in water.

In addition to Route I shown in Scheme 1, post-modification of preformed functional polypeptides was also applied to make thermo-responsive polypeptides.

Tang and Zhang reported a general strategy to make functionalized poly-L-glutamates with halide and azide groups subjected to conjugation.48, 49 Chen and coworkers prepared thermo-responsive polypeptides via ROP of γ-propargyl-L-glutamate NCA and subsequent click reaction between the pendant alkyne groups and 1-(2-methoxyethoxy)-2-azidoethane (MEO2-N3) or 1-(2-(2-methoxyethoxy)ethoxy)-2-azidoethane (MEO3-N3).50 The corresponding structures of reported polypeptides are given in Figure 4(a). These thermo-responsive polypeptides with α-helical conformations only showed relatively sharp thermal phase transitions at higher concentration (≥10 g/L). The CP in water could be tuned by the DP, the number of EG repeats, the concentration of the polypeptide and salt concentration from 22 to 74°C.

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Figure 4. Chemical structures of thermo-responsive polypeptides prepared by post-modification.50, 51, 53

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Later on, the same group prepared thermo-responsive POEGMA functionalized poly-L-glutamate via a combination of ROP and ATRP [Fig. 4(b)].51, 52 More recently, the Hammond group reported the preparation of dual pH and thermo-responsive poly-L-glutamate derivatives via ROP and click chemistry between poly(γ-propargyl L-glutamate) and azide functionalized short OEG and diisopropylamine [Fig. 4(c)].53

Besides the above discussed chemistry, amidation of available polymer to form thermo-responsive poly(amino acid)s was also reported in literature. For example, Kobayashi and coworkers54 prepared a biodegradable thermo-responsive poly(N-hydroxyalkyl-α/β-asparagine) from a reaction of poly(succinimide) with a mixture of 5-aminopentanol and 6-aminohexanol. They found that the random copolymers exhibited a CP ranging from 23 to 44 °C depending on the copolymer compositions. The same group also found that poly(N-hydroxylalkyl-γ-glutamine) modified from poly(γ-glutamic acid) had a CP between 21 and 50 °C depending on the functionalities.55 Later, Ohya et al. demonstrated that poly(glycolic acid-N-isopropylasparagine) displayed thermo-responsive property with CP 29 °C.56 Meanwhile, the thermo-responsive poly(amino acid)s were prepared via post-modification of available precursors, and the poor control over functionalities and architectures limited their further applications. Moreover, the obtained materials did not have ordered secondary structures.

REDOX-RESPONSIVE POLYPEPTIDES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

For redox responsive properties, the thiol and thiol ether groups can be oxidized to disulfide bond and sulfone groups, respectively. Using such transformation, redox-stimuli responsive polypeptide materials can be constructed.

Most recently, the Deming group reported the preparation of redox responsive poly(L-glycosylated-cysteine)s via direct NCA ROP.31 The amino acid monomers were prepared by coupling of alkene-functionalized D-galactose or D-glucose to L-cysteine using thiol-ene “click” chemistry, followed by their conversion to the glyco-C NCAs. They realized the controlled ROP of these gylco-C NCAs using transition metal initiator system. The obtained poly(L-glycosylated-cysteine)s adopted stable α-helical conformation in aqueous solution. Furthermore, they demonstrated that the thio-ether bonds in side chains can be selectively oxidized into sulfone groups. Interestingly, the structure transformation induced conformation change from α-helix to random coil [Fig. 5(b)]. In contrast, poly(L-glycosylated-homocysteine)s containing one more carbon in the side chain than poly(L-glycosylated-cysteine)s, kept α-helical conformation after oxidation [Fig. 5(d)].31

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Figure 5. Structral changes before and after the oxidation and corresponding Circular dichroism spectra (reproduced from Ref.31 with permission from American Chemical Society).

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Meanwhile, the oxidation of thiol-ether bond to sulfone group is irreversible. In contrast, the disulfide bond can realize reversible redox transition under appropriate conditions. Also, the disulfide bonds can be selectively cleaved by glutathione, which has large concentration differences in different tissues, so they have been designed as redox-responsive linkages to make a target delivery system. As illustrated in Figure 6, Zhang and coworkers reported such a novel system. They prepared redox responsive micelles loaded with Doxorubicin (DOX) using block copolypeptide containing cysteine segments. These micelles were then crosslinked via selective oxidation to form disulfide bonds.57 The DOX loaded crosslinked micelles can be easily disrupted with the presence of glutathione to accelerate the drug release in vitro. Another is the nanogel crosslinked by disulfide bonds of cysteine segment in the random copolypeptides.58 The nanogel is then loaded with DOX, and the drug release rate was accelerated in the presence of glutathione monoester in vivo.

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Figure 6. Schematic illustration of forming shell crosslinked micelles and intracellular drug release (reproduced from Ref.57, with permission from Royal Society of Chemistry).

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PHOTO-REPONSIVE POLYPEPTIDES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

Light as stimulus has advantages of precise remote control in both time and position, so photo-responsive polymers have been extensively explored in bio- and nano-technology. Preparations of photo-responsive polypeptide materials were still rare. Only recently, the Mezzenga group prepared photo-responsive copolypeptides.59 They used post-modification of PEG-b-poly-L-glutamic acid block copolymer using spiropyran, which can undergo a reversible spiropyran-to-merocyanine light-induced isomerization. As illustrated in Figure 7, they demonstrated a new pathway to make light-responsive systems, which are capable to realize a reversible aggregation-dissolution assembling process in water solutions under light stimulus. Because the stimulus used here is a noninvasive highly penetrating UV source, these photo-responsive biodegradable polypeptides might be promising as viable model systems to study photo-modulated drug release system.59 Most recently, Liu and Dong60 reported the synthesis of a novel photoresponsive block copolymer poly(S-(o-nitrobenzyl)-L-cysteine)-b-PEO from a L-cysteine NCAs. In this system, the nitrobenzyl group can be cleaved from poly(S-(o-nitrobenzyl)-L-cysteine) under irradiation of UV light at 365 nm to obtain thiol group (Fig. 8).

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Figure 7. (Top) Photo-induced structure transformation of photo-responsive copolymer. (Bottom) Schematic illustration of photo-responsive micellization/dissolution process for the copolymer (reproduced from Ref.59, with permission from American Chemical Society).

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Figure 8. Photo induced structure change for the copolymer PEG-b-poly(S-(o-nitrobenzyl)-L-cysteine).60

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BIOMOLECULE RESPONSIVE POLYPEPTIDES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

Biomolecules such as sugars, enzymes can serve as precise recognition sites to construct biomolecule-responsive materials. For example, tetrameric lectin is a well-known activator of cellular signaling, which can interact with cell surface glycoproteins. It has four sugar binding sites, which can specifically bind with mannose and glucose.61, 62 In particular, concanavalin A (Con A) can specifically interact with glucose and mananose. In contrast, Ricinus communis agglutinin (RCA) has strong binding affinity with terminal galactoses.63

Recently, great progress has been made with synthetic glycolpolypeptides, which might mimic glycosylated peptides and proteins in nature. The Deming group firstly synthesized well-defined glycopolypeptides through direct ROP of glycolated amino acids based on lysine64 and cysteine.31 The polar glycosides afford glycopolypeptides nonionic, pH- and buffer-tolerant water solubility. The Gupta group prepared the water soluble lysine-based O-glycopolypeptides via ROP of NCAs.65 They investigated the selective binding of the poly(α-manno-O-lys) with the lectin ConA using precipitation, hemagglutination assays, and isothermal titration calorimetry (ITC).66 To investigate the secondary structure effects on the binding affinity, they also prepared racemic D,L-glycopolypeptides, and found that there is no significant difference in binding affinity between helical L-glycopolypeptide and rac-glycopolypeptide with random coil conformation. The ITC analysis also showed that the binding process is enthalpy driven for both α-helical and random coil structures. Conversely, Krannig and Schlaad prepared statistical copolypeptides containing L-glutamate and glucosylated S-glycopolypeptides.33 The glucocopolypeptides adopted a random coil conformation at physiological pH, and were proven to selectively bind to Con A in turbidity assays. The binding rate is correlated with glucose and mannose epitope densities per polypeptide chain, but not affected by the local epitope density.33

Recently, Heise and coworkers67 have prepared amphiphilic block copolypeptide poly(γ-benzyl-L-glutamate)-b-poly(galactosylated propargyl glycine) via ROP of NCAs and followed by click chemistry. The galactose units on the surfaces of these self-assemblies were proven to display selectively binding ability to RCA.

OTHER POLYPEPTIDES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

It was well known that poly-L-lysine and poly-L-glutamic acid can undergo pH-induced conformation changes between random coil and α-helix. However, they both adopt random coil conformation at physiological pH because of intramolecular electrostatic repulsion of side chain. Recently, Cheng and coworkers made significant progress to make soluble ionic polypeptide, which showed ultrastable helical stability in water.68, 69 To avoid the intramolecular repulsion interaction of side chains from end charged groups, they designed ionic polyglutamate with elongated side chains. The elongated side chains afford ionic polypeptide both good water solubility and helical stability.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

In this article, we summarized the recent progresses in the design, synthesis, structure and property relationship, and potential applications of thermal-responsive, redox-responsive, photo-responsive, and biomolecule-responsive polypeptides materials. They can be easily prepared via two strategies, that is, direct ROP of functional NCA monomers and post-modification of preformed functional polypeptides. More importantly, their physical properties can be tuned by temperature, oxidizing and reducing agent, light and presence of biomolecules. Compared to conventional stimuli-responsive polymers, the properties of polypeptide not only depended on chemical structure of subunits but also replied on the secondary structures. Variation of environmental conditions can cause rearrangement or disruption of ordered chain conformations, which can induce property changes of materials. Considering good biocompatibility and biodegradability of polypeptide materials, these recently developed novel stimuli-responsive polypeptide materials emerge as promising candidates for biomedical applications with respect to construction of smart delivery system or injectable hydrogels.

REFERENCES AND NOTES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information

Biographical Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information
Thumbnail image of

Shusheng Zhang was from Cangzhou, Hebei province, China. He received his B. S. in polymer materials and engineering from Sun Yat-sen University in 2009. Then, he became a Ph.D. candidate under supervision of Prof. Zhibo Li at the Institute of Chemistry, Chinese Academy of Sciences. His current research interests focus on the synthesis of thermo-responsive polypeptide materials and their biomedical applications.

Biographical Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYNTHETIC STRATEGY
  5. THERMO-RESPONSIVE POLYPEPTIDES
  6. REDOX-RESPONSIVE POLYPEPTIDES
  7. PHOTO-REPONSIVE POLYPEPTIDES
  8. BIOMOLECULE RESPONSIVE POLYPEPTIDES
  9. OTHER POLYPEPTIDES
  10. CONCLUSIONS
  11. Acknowledgements
  12. REFERENCES AND NOTES
  13. Biographical Information
  14. Biographical Information
Thumbnail image of

Zhibo Li was born in Hunan Province, China in 1974. He obtained his B.S. (1998) and Master (2001) degree from University of Science and Technology of China. Then in 2001, he went to the Chemistry Department of University of Minnesota, where he completed his Ph.D. under supervision of Prof. Tim Lodge and Prof. Marc Hillmyer. After that, he joined the group of Prof. Tim Deming in University of California, Los Angeles in 2006 and worked two years as postdoctoral fellow. In later 2008, he became a faculty in the Laboratory of Polymer Physics and Chemistry in Institute of Chemistry, Chinese Academy of Sciences (ICCAS). His current research interests include design, synthesis, and applications of synthetic polypeptide materials.