## 2 Synthetic Approaches for Peptide-Synthetic Polymer Hybrids
### Liquid-Phase Peptide Synthesis. Preparation of Peptide-Synthetic Polymer Hybrids in Liquid-Phase
The \"_grafing from_\" approach can also be exploited in order to obtain ABC triblock copolymers as [PERSON] _et al._ have recently documented [30]. In this work, PEG-peptide hybrid drug carriers, specifically poly(ethylene glycol)-_b_-poly(L-cysteine)-_b_-poly(L-phenylalanine) (PEG-PCys-PPhe) triblock copolymers, were prepared via the ring-opening polymerization of amino acid N-carboxyanhydrides. The copolymers were able to self-assemble to form core-shell-corona micelles in aqueous solutions. The shell of these micelles had the ability to self-cross-link by the oxidation of thiol groups in the PCys segments. The _in vitro_ drug release was also studied, which demonstrated that the cross-linked shell could be helpful to reduce the drug loss in the extracellular environment. The \"_grafing from_\" is one of the most employed routes to the synthesis of linear peptide-polymer hybrids. Moreover nowadays this frequently pathway is being exploited by combining it with new controlled, \"_living_\" radical polymerization techniques, which are expanding the scope of these \"_grafing_\" methodologies [10]. Techniques such as atom transfer radical polymerization (ATRP) [31], reversible addition-fragmentation chain transfer (RAFT) polymerization [32, 33], and nitroxide mediated polymerization (NMP) [34], allow for the synthesis of low-dispersity polymers. The combination of controlled radical polymerization and \(N\)-carboxyanhydride (NCA) ring-opening polymerization enables the generation of well-defined block copolymers. A clear example is the synthesis of amphiphilic hybrid block copolymers based on block or random \(\gamma\)-benzyl-L-glutamate/L-alanine peptide sequences and polystyrene or poly(\(n\)-butyl acrylate) as synthetic segments [35]. A bifunctional initiator was employed so as to conduct NMP and NCA ROP polymerizations. This strategy led to block copolymers with low molar mass dispersities (\(\approx\)1.1) and moderate molecular weights (7500-25,200 g/mol). It was also shown that the elastase-induced degradation was related to the composition of the hydrophilic peptide block (_i.e._, the higher the L-alanine content the faster degradation of the micelle) and the composition of the hydrophobic non-degradable block. This strategy was also employed to prepare cross-linked star polymers based on amphiphilic diblock copolymers of poly(\(\gamma\)-benzyl-L-glutamate-_b_-styrene) (PBLG-_b_-PS) [36]. Firstly, a PBLG macroinitiator was synthesized by means of NCA polymerization with nitroxide terminal-groups. In a second step, styrene was polymerized by NMP resulting in block copolymers. The cross-linking of the terminal groups of the block copolymer chains was conducted in a last step by using divinylbenzene (DVB) as cross-linker. Using this strategy, high molecular weights (_i.e._, \(M_{\mathrm{n}}\) ranged from 47,000 to 548,000 g/mol) and relatively narrow dispersities (1.3-1.9) were attained. After cleavage of the PBLG chains, pH responsive particles with a poly(L-glutamic acid) shell and polystyrene core were obtained (Scheme VI). **Scheme VI. ** Depiction of pH responsive peptide-based core-shell nanoparticles assuming a helix-coil transition induced by a pH change [36]. Solid-Phase Peptide Synthesis. Preparation of Peptide-Synthetic Polymer Hybrids in Liquid- or Solid-Phase  
Solid phase peptide synthesis (SPPS) is nowadays a routine technique that allows access to peptides containing up to 50 amino acid residues with perfect control over the chain length and monomer sequence [37; 38; 39]. This is a special feature in comparison to NCAs polymerization because the latter remains limited to the preparation of homopolyeptides thus lacking the ability to play with biomolecular sequence. SPPS allows versatile modifications of the peptides, ranging from single position mutants, where one amino acid is substituted, to the synthesis of pseudo-peptides comprising of non-peptide backbones. In the early of 1980s, a simple method of using SPPS to access peptide-polymer block copolymers was developed.