Synthesis and characterization of bio-hybrids with complex architectures

Over the last past decades, progress in the synthesis towards peptide containing rod-coil block copolymers, has lead towards new areas of potential applications in the field of drug delivery. These so called biohybrids or chimeras were, up to now, always obtained in a multi-step approach including one or more modifications of a reactive end-group. Mostly, people used ionic or controlled radical polymerization techniques to obtain well defined vinyl-polymers. The obtained polymers were then converted onto a potential initiator for polymerization of the peptide block. Several different approaches were performed to have control over the polymerization of peptide part. However, for the most of these techniques, sophisticated equipment was required or there was made use of transition metal catalyzed reactions. The avoidance of any metal catalyst would be a clear advantage for the use of these materials in medical applications. In this PhD research, the goal was to synthesize different biohybrids via a combination of controlled polymerization techniques. These polymerization techniques are ring opening polymerization (ROP) of N-carboxy-anhydride (NCA) to obtain the peptide part. The vinyl part should be obtained by controlled radical polymerization, like nitroxide mediated radical polymerization (NMRP) or atom transfer radical polymerization (ATRP). The key in our approach is the use of a double headed or bifunctional initiator. This double headed or bifunctional initiator is capable to initiate the ROP of NCA on one side. On the other side it will allow us to perform a controlled radical polymerization technique. Macroinitiation of the ring opening polymerization of NCA will be circumvented by this approach. The full potential of this approach will be tested by the synthesis of different polymeric architectures like rod-coil block copolymers, graft copolymers and also peptide based core/ shell nanoparticles. In chapter one, an overview is given over all possible polymerization techniques used for ROP of NCA. Also a short review is incorporated about the controlled living radical polymerization techniques and finally all approaches towards block copolymers are reviewed. In Chapter two, the polymerization of a rod-coil block copolymer is described by making use of a double headed initiator. This initiator combines a bipyNi(COD) initiator developed by Deming et al. for ROP of NCA on one side, together with ATRP or NMRP. The use of ATRP is attractive since this technique is able to polymerize a range of different monomers, this in opposite to NMRP which is only tolerant to styrene- and acrylic monomers. The combination of the bipyNi(COD) system combined with ATRP of methylmethacrylate lead toward well defined P(BGL-b-MMA) rod-coil block copolymers with polydispersity of 1.2. NMRP was also combined with bipyNi(COD), but this did not lead to conclusive results. The successful synthesis of a rod-coil block copolymer by metal free polymerization of NCA in combination with nitroxide mediated radical polymerization is described in chapter 3. This was achieved with a bifunctional initiator containing an amine moiety for initiation of NCA ring opening polymerization and a nitroxide moiety for controlled radical polymerization of olefins. Block copolymers were obtained in two consecutive polymerization steps and in a one-pot approach. In both approaches, first the NCA polymerization was performed at 0°C, followed by polymerization of styrene. To get a better insight in the macroinitiation of the polymerization of styrene, a study of the kinetics is performed. Via this approach a well-defined rod-coil block copolymer was obtained with a polydispersity index around 1.1. In chapter 4, this research was expanded. Since the obtained block copolymers still contains the nitroxide moiety for NMRP, a cross-linking reactions of the rod-coil block copolymers with divinylbenzene were performed. First the kinetics was monitored to get a better insight in the cross-linking reaction. This knowledge was transferred to macroinitiation of divinylbenzene with P(BLG-b-S) in a schematic way. This cross linking is performed up to different cross-link densities and in this way it was possible to obtain peptide core/ shell nanoparticles with good control over size of the core, the length of the arms and the amount of arms per star. The NCA polymerization performed at 0°C has some other advantages which are explored in chapter 5. While in previous chapters, a macroinitiator approach was performed, in this chapter, a macromonomer approach is performed. The low reaction temperature for NCA polymerization allowed us to synthesize a vinyl bond containing macromonomer in one step. First the synthesis of a styrene monomer containing an amine moiety was performed. This amine moiety was used as an initiator for the ring opening polymerization of NCA. The obtained macromonomer was used in nitroxide mediated radical polymerization. The synthesis of graft copolymers is described, whereby the ratio acromonomer to styrene was varied. Also an attempt was made to form peptide core shell nanoparticles comparable with the structures from chapter 4. The main advantage of this approach is the avoidance of the tedious synthesis of a bifunctional initiator and even the possibility to use a commercial available NMRP initiator. In this chapter some preliminary results are shown which shows the potential of this macromonomer approach, however, much more effort should be spend to achieve the full power of this technique