Hybrid block copolymers polymerization

In the past two years, a number of new approaches have been reported for obtaining controlled NCA polymerizations. These approaches share a common theme in that they are all improvements on the use of classical primary amine polymerization initiators. This approach is attractive since primary amines are readily available and since the initiator does not need to be removed from the reaction after polymerization. In fact, if the polymerization proceeds without any chain breaking reactions, the amine initiator becomes the C-terminal polypeptide end-group. In this manner, there is potential to form chain-end-functionahzed polypeptides or even hybrid block copolymers if the amine is a macroinitiator. The challenge in this approach is to overcome the numerous side-reactions of these systems without the luxury of a large number of experimental parameters to adjust. 

Despite the drawbacks of this method, it has been used to prepare a tremendous number of polypeptide hybrid block copolymers (Table 1), and when carefully executed provides reasonably well-defined samples. Synthetic polymer domains have been prepared by addition polymerization of conventional vinyl monomers, such as styrene and butadiene, as well as by ringopening polymerization in the cases of ethylene oxide and e-caprolactone. The generality of this approach allows NCA polymerization off of virtually any primary amine functionality, which was exploited in the preparation of star block copolymers by polymerization of sarcosine NCA from an amine-terminated trimethyleneimine dendritic core [37]. In most examples, the polypeptide domain was based on derivatives of either lysine or glutamate, since these form a-helical polypeptides with good solubility characteristics. These residues are also desirable since, when deprotected, they give polypep-... 

A few other methods have been used to prepare polypeptide hybrid copolymers. Inoue polymerized Bn-Glu NCA off of amine-functionalized styrene derivatives, and then copolymerized these end-functionalized polypeptides with either styrene or methyl methacrylate using free radical initiators to yield hybrid comb architecture copolymers [38]. Although unreacted polypeptide was identified and removed by fractionation, copolymers were obtained with polypeptide content that increased with feed ratio. There was no mention if the polypeptide interfered with the radical chemistry. In similar work, Imanishi and coworkers converted the amine-ends of polypeptides to haloacetyl groups that were used to initiate the free radical polymerization of either styrene or methylmethacrylate to yield hybrid block copolymers [39]. Studies using CPC showed that the crude product contained mixtures of copolymers and homopolymers, and so removal of the homopolymers by extraction was necessary. 

Although quite complex hybrid block copolymer architectures can now be synthesized, obtaining these materials in a state of high purity typically requires additional measures. As discussed above, many of the hybrid copolymers contain homopolymer impurities, which must be removed by selective solvent extractions or fractional precipitation when possible. Since conventional NCA polymerizations also usually give polypeptide segments with large chain length distributions, these samples are ideally also fractionated... 

The synthesis of polypeptide hybrid block copolymers is an area that has been under study for three decades. Initially, this field suffered from limitations in the synthesis of the polypeptide components that required excessive sample purification and fractionation to obtain well-defined copolymers. In recent years, vast improvements in NCA polymerizations now allow the synthesis of hybrid block copolymers of controlled dimensions (molecular weight, sequence, composition, and molecular weight distribution). Such well-defined materials will greatly assist in the identification of new self-assembled structures possible using ordered polypeptide segments, as well as yield new materials with a wide range of tunable properties. 

In this review, recent advances in our research on polymeric micelles based on PEG-peptide hybrid block copolymers for drug and gene delivery are... 

Hybrid Block Copolymers Incorporating Oligosasaccharides and D Synthetic Blocks Grown by Controlled Radical Polymerization... 

The polymerization for polyaddition of a monomer that possesses an additional functionality allows the production of dual-function particles. The acyl chloride of the azo-initiator 4,4 -azo-4-cyanopentanoic add was reacted with 2,4-diethyl-l,5-pentanediol to yield a diol-functionahzed monomer, in addition to the azo-bond functional groups [118]. The functionahzed diol was first polymerized in a polyaddition reaction with a diisocyanate subsequently, it was possible to cleave the azo-bonds and to polymerize styrene in the nanodroplets. Such an approach combines free-radical polymerization and polyaddition, to produce hybrid block-copolymer particles. 

The transition from hybrid block copolymers with a homopeptide block toward those with sequence-defined peptide segments enriches the self-assembly behavior strongly. Ayers et smdied water-soluble block copolymers composed of a PEO block and a peptide block with comb architecture, which was obtained by the controlled polymerization of oligopeptide... 

Becker ML, Liu J, Wooley KL (2003) Peptide-polymer bioconjugates hybrid block copolymers generated via living radical polymerizations from resin-supported peptides. Chem Commun 180-181... 

The most likely pathways of NCA polymerization are the so-called amine and the activated monomeP (AM) mechanisms. The amine mechanism is a nucleophilic ring-opening chain growth process where the polymer could grow linearly with monomer conversion if side reactions were absent (eqn [2]). On the other hand, the AM mechanism is initiated by deprotonation of an NCA, which then becomes the nucleophile that initiates chain growth (eqn [3]). It is important to note that a polymerization can switch back and forth between the amine and AM mechanisms many times a propagation step for one mechanism is a side reaction for the other, and vice versa. It is because of these side reactions that block copolypeptides and hybrid block copolymers prepared from NCAs using amine initiators have structures different than predicted by monomer feed compositions and most likely have considerable homopolymer contamination. These side reactions also prevent control of chain-end functionality desirable for many applications. 

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