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however, NCA polymerization neither affords perfectly monodisperse materials nor enables precise control of the composition and a-amino acid sequence. This is, of course, in great contrast with natural proteins, and automatically limits the utility of this approach for the generation of biologically-inspired or biomimetic architectures. Nevertheless, because of its simplicity, NCA polymerization has been widely used for preparation of a range of polypeptide homopolymers, random copolymers, (hybrid) block copolymers, and graft copolymers [9, 10].

Very recently, amphiphilic poly(butadiene)-b-poly(L-glutamic acid) copolymers have been reported which were obtained by ring-opening polymerization of g-benzyl-L-glutamate N-carboxyanhydride (Bn-Glu NCA) by use of a poly(butadiene) macroinitiator, followed by a hydrogenation step to remove the benzyl ester protective groups (Scheme 6.6.2) [11]. Amphiphilic (ionic) block copolymers have been extensively studied and are well known to form a variety of supramolecular aggregates in dilute aqueous solution [12]. In contrast with most systems studied so far, the block copolymers shown in Scheme 6.6.2 have a hydrophilic block which can adopt a well-defined a-helical secondary structure. By adjusting the pH of the aqueous solution, the secondary structure of poly( L-glutamic acid) can be reversibly changed from a compact a-helix into a disordered coil, and vice versa [13]. Depending on the relative lengths of the blocks, the polymers shown in Scheme 6.6.2 were found to form spherical micelles or vesicular aggregates (Figure 6.6.1) [11]. The structure and size of these supramolecular aggregates was investigated by a combination of light- and neutron scattering experiments and freeze-fracture transmission electron microscopy. Because these micelles and vesicles bear some structural resemblance to compactly folded globular proteins, this work is a good illustration of the power of self-assembly to generate biologically inspired or bio-mimetic supramolecular architectures.

One factor that contributes to the heterogeneous nature of polypeptides produced by NCA polymerization is the multiple reactivity of the monomers [9]. NCA contain four reactive sites; two electrophilic carbonyl carbons and two nucleophilic centers after deprotonation of the a-CH and NH hydrogen atoms. By use of traditional nucleophilic or basic initiators NCA ring-opening polymerization can proceed simultaneously along different competing pathways, which broadens mo-

25 nm

Fig. 6.6.1. Model for the self-assembly of a poly(butadiene)40-b-poly(l-glutamic acid)100 diblock copolymer into vesicular aggregates. (Subscripts indicate the number-average degree of polymerization of the blocks. Adapted from Ref. [11b]).

25 nm

Fig. 6.6.1. Model for the self-assembly of a poly(butadiene)40-b-poly(l-glutamic acid)100 diblock copolymer into vesicular aggregates. (Subscripts indicate the number-average degree of polymerization of the blocks. Adapted from Ref. [11b]).

lecular weight distributions, restricts accurate control of the composition of the peptides, and hampers the formation of well-defined block copolymers. Several years ago, however, it was discovered that transition-metal complexes such as bpyNi(cod) (bpy = 2,2'-bipyridyl, cod = cycloocta-1,5-dienyl) and Co(PMe3)4 can overcome a number of these drawbacks and enable "living" polymerization of NCA with unprecedented control of chain length and narrow polydispersities [14]. This approach has been successfully used to prepare a variety of random and (hybrid) block copolypeptides [15].

Very recently, transition-metal-mediated NCA polymerization has been used to prepare a series of amphiphilic, ionic block copolypeptides [16]. While the total degree of polymerization was kept constant, the chemical composition and block length ratio of the block copolymers differed. The hydrophilic blocks of the copolymers comprised charged poly( L-lysine) or poly( L-glutamic acid) sequences with no regular secondary structure at neutral pH. The hydrophobic, water-insoluble blocks were based on L-leucine or L-valine, which are known to have a high propensity to form rod-like a-helices or crystalline ¿S-strands, respectively. When attempts were made to prepare dilute aqueous solutions of the block copolymers, gelation was observed instead of the formation of vesicles or micelles. The gels were investigated by use of rheology, small-angle neutron scattering (SANS), laserscanning confocal microscopy, and cryogenic transmission electron microscopy [16, 17]. Interestingly, it was found that the gelation behavior of the block copoly-peptides was related to the secondary structure of the hydrophobic block, with a-

Fig. 6.6.2. Hierarchical self-assembly of an ionic poly(l-lysine)160-b-poly(l-leucine)40 block copolymer amphiphile into nanosized membraneous structures visualized by (a) cryogenic transmission electron microscopy and (b) laser-scanning confocal microscopy. (Subscripts indicate the number-average degree of polymerization of the blocks. Adapted from Ref. [16]).

Fig. 6.6.2. Hierarchical self-assembly of an ionic poly(l-lysine)160-b-poly(l-leucine)40 block copolymer amphiphile into nanosized membraneous structures visualized by (a) cryogenic transmission electron microscopy and (b) laser-scanning confocal microscopy. (Subscripts indicate the number-average degree of polymerization of the blocks. Adapted from Ref. [16]).

helical blocks being slightly better than ¿-strands, which were better than random coils. SANS and microscopy experiments indicated that the gels were hierarchically structured and consisted of nanosized membraneous structures that were assembled into a microscale porous structure. This is illustrated in Figure 6.6.2, where cryogenic transmission electron microscopy (Figure 6.6.2a) and laserscanning confocal microscopy images (Figure 6.6.2b) show the nanoscale and microscopic ordering, respectively, in the hydrogels [16]. These systems are another example of the use of NCA chemistry to generate block copolymers that can self-assemble into hierarchically organized structures by exploiting the capacity of peptide sequences both to adopt well-defined secondary structures and to direct the formation of higher-order assemblies.

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