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Bioinspired Triblock Copolymers Prepared by Atom Transfer Radical Copolymerization Jan C. M. van Hest*, Lee Ayres, Henri Spijker, Matthijn Vos, and Joost Opsteen Department of Organic Chemistry, Nijmegen University, Toernooiveld 1, 6525 E D Nijmegen, The Netherlands *Corresponding author: email:
[email protected] Well-defined block copolymers, comprising bio-related monomers could be conveniently synthesized via Atom Transfer Radical Polymerization. Elastin side chain triblock copolymers were prepared by macroinitiation from a bifunctional polyethylene glycol initiator. The obtained oligopeptide architecture exhibited similar thermoresponsive behavior as its main chain polymer analog. A T R P was performed on methacrylate functionalized nucleobases using an initiator equipped with a primary amine moiety. The resulting nucleobase polymers were successfully coupled to telechelic isocyanate-functional polymethylacrylate, resulting in triblock copolymers that could be interesting building blocks for supramolecular polymers.
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© 2 0 0 3 American Chemical Society
In Advances in Controlled/Living Radical Polymerization; Matyjaszewski, K.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
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Introduction The development of methodologies that allow control over radical polymerization processes has greatly increased the possibilities of design and synthesis of polymer architectures (/). The tolerance of these controlled radical polymerizations toward many functional moieties has furthermore expanded the scope of monomer units that can be incorporated. Especially for the development of bio-related polymers this has been a major improvement, since monomers based on natural compounds are highly functional and therefore normally hard to polymerize via other controlled polymerization techniques (2). The construction of well-defined, bio-related polymers is of great interest for biomedicalAppl.ications,where it is envisaged that these structures can function for example as drug delivery carriers or as scaffolds for tissue engineering. Atom Transfer Radical Polymerization (ATRP) has recently been Appl.ied to construct polymers containing saccharide (3,4,5) and nucleobase moieties (6,7,8), and also polymers with activated ester units have been prepared that could be post modified with oligopeptide fragments (9). Polymer chemists have however only begun to explore ATRP for the preparation of bio-related polymers, and many opportunities are therefore still ahead to create new, highly functional polymers. It is our aim to construct well-defined polymer architectures that are (partly) based on bio-inspired building blocks. In this chapter we describe our research activities for the preparation of two types of triblock copolymers. The first part deals with the construction of elastin side-chain block copolymers. In the second part we describe a modular approach for constructing nucleobasecontaining triblock copolymers.
Elastin side chain polymers Elastin is one of the most important classes of naturally occurring structural proteins (10-14). It is commonly found in ligaments, arteries, skin, and lung tissue of mammals where it functions as an elastomeric material (15, 16). There are many different types of elastin, but tropoelastin (the precursor protein of mammalian elastin) is one of the most studied. It was found to have V P G V G (V = valine, Ρ = proline and G = glycine) as its most prominent amino acid repeat (17). The aggregation, conformational and mechanical properties of both chemically synthesized (13,18,19) and recombinantly prepared poly(VPGVG) (20-22) have been extensively investigated. It was discovered that poly(VPGVG) is soluble in water at room temperature but as the temperature is increased the solubility of this polypeptide is decreased. This remarkable lower critical solution temperature (LCST) behavior, which is completely reversible, is a result of a conformational change in elastin from random coil to β-spiral, which is caused by hydrophobic dehydration of the valine side chains (23).
In Advances in Controlled/Living Radical Polymerization; Matyjaszewski, K.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
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396 Optimization of these hydrophobic interactions occurs when three of these long chain β spirals twist together into a larger aggregate. This L C S T behavior makes elastin like peptides, or ELP's, of interest for a wide range ofAppl.ications,for example as thermally responsive hydrogels with an inverse temperature transition (27). It has also been shown that these peptide sequences are biologically compatible (24, 25), opening up the possibility of medicalAppl.icationsfor ELP's (26, 27). Until now all of the investigations that have been carried out have focused on linear polyVPGVG. However, it has been shown that this inverse temperature transition not only occurs in poly(VPGVG)„ (where η > 10) but even in a single repeating unit of V P G V G (28). This has inspired us to investigate the possibility of synthesizing polymers with similar L C S T behavior by introducing single repeats of V P G V G into the side chain. Connecting side chain elastin oligomers to the ends of a polymer chain could result in a versatile approach to producing thermally responsive triblock copolymers. Although oligopeptide based monomers have been polymerized using a wide range of techniques (2, 29) to the best of our knowledge, however, there has been no example in which ATRP is used.
Results and Discussion The preparation of V P G V G monomers was performed via solid phase peptide synthesis methods (figure 1). After constructing the pentapeptide via Fmoc chemistry, the Fmoc group of the last valine residue was removed and the free amine was allowed to react with an excess of a 2-(methacryloyloxy)ethyl isocyanate (30). This resulted in complete conversion to a methacrylate functional peptide. Because the high molecular weight (583 g/mol) of the oligopeptide did not allow a high concentration of polymerizable groups, a methacrylate moiety was preferred because of its high reactivity under A T R P conditions. Two initiators were Appl.ied for the polymerization of the oligopeptide monomer: the standard initiator ethyl-a-bromo-isobutyrate (EBIB) and a bifunctional polyethylene glycol (PEG) initiator (di-a,
