Copolypeptides

The mechanism of the polymerization of NCA with tertiary amine is still controversial. Mori and Iwatsuki claim that the true initiator is the primary amino group formed by hydrolysis of the NCA with contaminated water and that tertiary amine forms a complex with the NCA and accelerates the addition reaction37 . Harwood et al. confirmed the propagating carbamate by NMR in polymerization initiated with a strong base37 . The successive addition of NCA to the polymer end catalyzed with a strong base affords an alternative procedure for the synthesis of block copolypeptides. Block copolypeptides of poly(oxyethylene) were prepared by triethyl amine catalyzed polymerization of NCA in the presence of poly(oxyethylene)bis-eMoroformate38 . 

Recently, synthesis of many compositionally and topologically different block copolypeptides has been reported [119,124]. In most cases, the copolypeptide block is composed of 7-benzyl... 

Breedveld V., Nowak A.P., Sato J., Deming T.J., and Pine D.J. Rheology of block copolypeptide solutions Hydrogels with tunable properties. Macromolecules, 37, 3943, 2004. 

Pochan D.J., Pakstis L., Ozbas B., Nowak A.P., and Deming T.J. SANS and cryo-TEM study of self-assembled diblock copolypeptide hydrogels with rich nano through microscale morphology. Macromolecules, 35, 5358, 2002. 

Deming T.J., Methodologies for preparation of synthetic block copolypeptides Materials with future promise in dmg dehvery, Adv. Drug Deliv. Rev., 54, 1145, 2002. 

The polymerizations initiated by HMDS and N-TMS amines usually complete within 24 h at ambient temperature with quantitative monomer consumption. These polymerizations in general are slower than those mediated by Deming s Ni(0) or Co (0) initiators (about 30-60 min at ambient temperature) [19, 24, 25], but are much faster than those initiated by amines at low temperature or using amine hydrochloride initiators [20]. These HMDS and N-TMS amine-mediated NCA polymerizations can also be applied to the preparation of block copolypeptides of defined sequence and composition [22]. This organosilicon-mediated NCA polymerization, which was also shown by Zhang and coworkers to be useful for controlled polymerization of y-3-chloropropanyl-L-Glu NCA [43], offers an advantage for the preparation of polypeptides with defined C-terminal end-groups. 

For the examination of model protein-protein interactions and the assembly of novel three-dimensional structures, block copolypeptides are required that have... 

Cha JN, Stucky GD, Morse DE, Deming TJ (2000) Biomimetic synthesis of ordered silica structures mediated by block copolypeptides. Nature 403 289-292... 

Deming TJ (1997) Eacile synthesis of block copolypeptides of defined architecture. Nature 390 386-389... 

Hanson JA, Chang CB, Graves SM, Li ZB, Mason TG, Deming TJ (2008) Nanoscale double emulsions stabilized by single-component block copolypeptides. Nature 455 85-U54... 

In 2000, the first example of ELP diblock copolymers for reversible stimulus-responsive self-assembly of nanoparticles was reported and their potential use in controlled delivery and release was suggested [87]. Later, these type of diblock copolypeptides were also covalently crossUnked through disulfide bond formation after self-assembly into micellar nanoparticles. In addition, the encapsulation of l-anilinonaphthalene-8-sulfonic acid, a hydrophobic fluorescent dye that fluoresces in hydrophobic enviromnent, was used to investigate the capacity of the micelle for hydrophobic drugs [88]. Fujita et al. replaced the hydrophilic ELP block by a polyaspartic acid chain (D ). They created a set of block copolymers with varying... 

ELP-based triblock copolypeptides have also been used to produce stimulus-responsive micelles, and Chaikof and coworkers envisioned the possible application of these micelles as controlled drug delivery vehicles. These amphiphilic triblock copolymers were constructed from two identical hydrophobic ELP endblocks and a hydrophilic ELP midblock. Below the transition temperature, loose and monodispersed micelles were formed that reversibly contracted upon heating, leading to more compact micelles with a reduced size [90]. 

Fig. 1 Vesicle construct formed from poly(L-lysine)-i)-poly(L-leucme) polypeptides where the poly(L-leucine) block corresponds to the a-helical hydrophobic segments and the poly (L-lysine) block corresponds to the random coil hydrophilic segments. Note that this is one specific example and not all vesicle constructs have a-helical and random coil blocks. Moreover, the amphiphilic copolymer can be comprised of either a pure block copolypeptide or a macromolecule consisting of a polypeptide and another type of polymer. Adapted from [20] with permission. Copyright 2010 American Chemical Society...

The most general and frequently used method to synthesize long chains of block copolypeptides for vesicle assembly is successive ring opening polymerizations of a-amino acid-Ai-carboxyanhydride (NCA) monomers [18, 20, 21, 39-51]. NCA monomers are readily prepared from commercially available amino acids, most commonly through direct phosgenation [52]. 

Holowka EP, Sun VZ, Kamei DT, Deming TJ (2007) Polyarginine segments in block copolypeptides drive both vesicular assembly and intracellular delivery. Nat Mater 6 52... 

Such hydrogels have been suggested to be suitable for biotechnological applications (DNA delivery vehicles, cell encapsulation) [28]. Recently, amphiphilic dibock copolypeptide hydrogels of KigoL2o were used in an in vivo study where the hydrogels were injected into the mouse forebrain. Evaluation of samples displayed substantial tissue integration with little or no detectable toxicity in the central nervous system [148]. 

Nowak AP, Breedveld V, Pakstis L et al (2002) Rapidly recovering hydrogel scaffolds from self-assembling diblock copolypeptide amphiphiles. Nature 417 424-428... 

Yang CY, Song BB, Ao Y et al (2009) Biocompatibility of amphiphilic diblock copolypeptide hydrogels in the central nervous system. Biomaterials 30 2881-2898... 

Kim W, Thevenot J, Ibarboure E et al (2010) 5elf-assembly of thermally responsive amphiphilic diblock copolypeptides into spherical micellar nanoparticles. Angew Chem Int Ed 49 4257 260... 

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