## 2 Synthetic Approaches for Peptide-Synthetic Polymer Hybrids
### Liquid-Phase Peptide Synthesis. Preparation of Peptide-Synthetic Polymer Hybrids in Liquid-Phase
The peptide linkage between the polymer blocks could be cut by a metalloprotease (collagenase), leading to \"shedding\" of the corona of the micelles. This technology offers new possibilities for enzyme-triggered drug delivery. Other related works, in terms of the selected synthetic methodology, were conducted by [PERSON] _et al._[48, 49]. Oligopeptide initiators were designed and used to polymerize \(\varepsilon\)-caprolactone or methyl methacrylate by means of ring-opening polymerization or ATRP, respectively. The obtained hybrid polymers presented narrow molar mass dispersities (ranging from 1.20 to 1.50 in the case of PMMA blocks and from 1.3 to 2.2 for PCL blocks) and relatively high molecular weights, especially those containing PMMA blocks. Both block copolymer structures self-assembled into micelles depending on the solvent. These micelles could undergo a secondary aggregation as function of time resulting in micro or nanospheres. The obtained hybrid spheres are interesting due to their potential to be used as micro- or nanocarriers for drug delivery. Finally, another common synthetic strategy, in which SPPS is also employed, is based on the conjugation of a designed peptide to the synthetic polymer chain by means of bioorthogonal coupling reactions such as, amide formation, thioether formation, Pd\({}^{\circ}\)-catalyzed coupling reactions, Staudinger ligation, cycloaddition reactions (Diels-Alder, 1,3-dipolar cycloaddition), reductive alkylation or amination, oxime and hydrazone formation, thiol addition reactions, or oxidative coupling [7, 50]. Looking to the wide variety of coupling reactions it is obvious that they provide ample opportunities for the synthesis of complex peptide-synthetic polymer conjugates without the need for possible complex protective group strategies. For example, a well-defined protected glycopolymer (_i.e._, poly(2-(2,3,4,6-tetra-O-acetyl-\(\beta\)-D-glucosyloxy)ethyl methacrylate) (PAcGlcEMA)) was recently synthesized by RAFT polymerization. In the presence of ethanolamine and 2,2'-dithiodipyridine, PAcGlcEMA-PDS with a terminal thiol-reactive pyridyldisulfide (PDS) group was generated by one-pot approach. After deprotection of PAcGlcEMA, a tripeptide reduced glutathione (GSH) was conjugated to PGlcEMA-PDS by a thiol-disulfide exchange reaction under mild conditions. The specific recognition with protein Concanavalin A and its antioxidant activity justify that the proposed peptide-glycopolymer bioconjugate has a great interest for biomedical applications such as biodetection, biomimetics and targeted antioxidant delivery [51]. Related to the amide bond formation an original work appeared in which this coupling reaction was used to obtain complex polymer architectures (_i.e._, star polymer). Concretely, a thermo-sensitive elastin-like oligopeptide was successfully assembled onto a poly(amidoamine) dendrimer surface [52]. The obtained hybrid peptide/dendrimer was found to exhibit low critical superior temperature (LCST) behavior at physiological temperature range under neutral pH variation. This dual-responsive character can play an important role in biological applications based on the ability to storage and render a controlled-release of small molecules as a response to specific environmental conditions. A related work, focused on the use of a elastin-like peptide to obtain hybrid brush copolymers was the one proposed by [PERSON] _et al._[53]. In this study, poly(pentafluorophenyl methacrylate), obtained by ATRP, was first modified with allylamine to give polymers with pendant alkene groups. Subsequently, the modified polymer was conjugated with a thiol-terminated elastin-derived peptide sequence by means of a thiol-ene addition (Scheme VIII). The achieved grafting density was about 50%. The use of this tandem postpolymerization modification can present the opportunity to synthesize complex copolymers as smart/responsive materials, peptidic drug carriers, or as precursors for nanocarriers.