## 2 Synthetic Approaches for Peptide-Synthetic Polymer Hybrids
### Liquid-Phase Peptide Synthesis. Preparation of Peptide-Synthetic Polymer Hybrids in Liquid-Phase
Interestingly, the synthesis of poly(L-lactide) macroinitiators was performed using novel metal complexes of Li, Na or K, which led to controlled polymerizations and products with narrow molar-mass dispersity indices. The \"_grafting to_\" methodology results also efficient towards the synthesis of hybrid amphiphilic block copolymers. For example, [PERSON] _et al._[26] have recently documented a system based on poly(\(N\)-vinylpyrrolidone) (PVP) as a hydrophilic component and poly(\(\gamma\)-benzyl-L-glutamate) (PBLG) as a hydrophobic peptide, which led to a pH-sensitive bioconjugate. A modular approach was used for the synthesis of these conjugates. Optimized procedures were developed to obtain \(\omega\)-aldehyde end-functional PVP and to synthesize cysteine end-functional PBLG. The latter makes use of a modified deprotection step for the thiol-protecting acetamidomethyl group. Finally, the conjugates were obtained by means of a thiazolidine linkage between both parts. The self-assembly behavior and pH dependence of the PVP-PBLG bioconjugate was demonstrated and opened the potential applications of the system as a smart drug delivery vehicle. Generally the accessible synthetic approaches can be combined so as to obtain more complex block copolymers constituted by different peptide or synthetic polymer segments in the same structure. Recently, amphiphilic triblock copolymers based on poly(L-lactic acid)-_block_-poly(L-lysine)-_block_-poly(ethylene glycol) (PLA-_b_-PLL-_b_-MPEG) were synthesized in three steps. Firstly, the diblock copolymer PLA-_b_-PZLL was synthesized by ROP of Lys(Z)-NCA using \(\alpha\)-amino-functionalized PLA (PLA-NH\({}_{2}\)) as macroinitiator. The triblock copolymer was synthesized by amidation of PLA-_b_-PZLL using MPEG-COOH and then by removing the side chain protected groups with HBr. The obtained copolymers were able to form spherical polymeric micelles in water exhibiting a low cytotoxicity [27]. Another recent study combined the \"_graffing to_\" and the \"_graffing from_\" approaches in order to obtain dendron-like triblock copolymers (Scheme V) [28]. Concretely; an azide-terminated polycaprolactone was obtained and used to couple; by click chemistry; an alkyne-terminated poly(amidoamide) (PAMAM) dendron (Dm) containing from 1 to 8 primary amine groups. Subsequently; by means of NCA polymerization; poly(\(\gamma\)-benzyl-L-glutamate) (PBLG) chains were grown. Molecular weights of the final structures ranged between 7800 and 45,700 g/mol as estimated by NMR analyses. **Scheme V.** Synthesis of PBLG-Dm-PCL-Dm-PBLG triblock copolymers by combining ROP and click chemistry based on [28]. Reagents and conditions: i) Sn(Oct)\({}_{2}\), 115 \({}^{\circ}\)C; ii) TsCl, 24 h, r.t., NaN\({}_{3}\), 24 h, r.t.; iii) [2]/[Dm]/[CuBr]/[PMDETA] = 2.4/0.4/0.4, 24 h, 35 \({}^{\circ}\)C; iv) 24 h, r.t. The crystallinity of the central PCL segment within these copolymers was increasingly suppressed by the flanking of PBLG chains, whereas the PBLG segments gradually changed from a \(\beta\)-sheet to \(\alpha\)-helix conformation on increasing the degree of polymerization of PBLG wedges. In addition, these triblock copolymers formed thermoreversible organogels in toluene with critical gelation concentrations controlled by the dendritic topology of the PBLG wedges. Easier synthetic methodologies can also be used to obtain stimuli-responsive peptide-based triblock copolymers. Recently, ABA triblock copolymers were obtained by employing diamine-functionalizedpolyppropylene oxides (average degree of polymerization of 33 or 68) as macroinitiators to polymerize Z-lysine NCA. In this way, triblock copolymers with a degree of polymerization of the polylysine segments ranging from 27 to 46 were obtained and used to study the micelle-to-vesicle or micelle-to-disk transitions as function of pH. The unique responsive behavior of such system could be exploited in areas such as drug delivery, whereby a delivered drug could be spontaneously released upon pH-driven morphology transitions [29].