## 2 Synthetic Approaches for Peptide-Synthetic Polymer Hybrids
### Liquid-Phase Peptide Synthesis. Preparation of Peptide-Synthetic Polymer Hybrids in Liquid-Phase
Secondly, the grafting of PA-PEG chains onto chitosan (7500 g/mol) was performed using EDC/NHS as catalysts in the coupling reaction. A grafting ratio of nearly 50% was achieved and the copolymer became sensitive to pH and temperature through conformational changes of their constitutive chitosan, polyalanine and PEG blocks. Parallel to efforts to research into polymer brushes, multiarm star polymers are one of the most investigated topologies due to the possibility to possess a great number of peptides per molecule by using hyperbranched polymers or dendrimers as macroinitiators. The \"_grafting from_\" is normally the most common synthetic methodology employed to obtain this architecture. For example, well-defined star polypeptides were successfully synthesized by initiation of \(\gamma\)-benzyl-L-glutamate \(N\)-carboxyanhydride from polypropylene imine (PPI) dendrimers. The dendrimer generation and the dendrimer to NCA ratio were systematically varied to afford a range of star shaped architectures with a maximum of 8 to 64 poly(\(\gamma\)-benzyl-L-glutamate) (PBLG) arms. High molecular weights up to 500,000 g/mol were obtained, which could not otherwise be achieved from the analogous linear polypeptides in the absence of the dendrimer core. The resulting hybrid materials were employed as a drug delivery system (DDS) providing highly specific temporal and spatial controlled release [21]. A related work consisted in the synthesis of amphiphilic multiarm star polymers based on a polyethylene imine (PEI) as a core molecule and polyphenylalanine (PPhe) arms of different degree of polymerization (_i.e._, 40-120), which were obtained by means of the corresponding NCA polymerization. The multiarm stars were subsequently used as gene carriers on studying the transfection efficiency with different cell lines [22]. Despite of the expanding research on complex polymer architectures, the synthetic strategies on linear hybrid copolymers are being day by day updated so as to get smart structures based on different synthetic blocks with a different role inside the macromolecule. [PERSON] _et al._[23], have recently designed different photoresponsive poly(\(S\)-(\(o\)-nitrobenzyl)-L-cysteine)-\(b\)-poly(ethylene glycol) block copolymers taking advantage of photocleavable behavior of \(o\)-nitrobenzyl groups by means of UV irradiation (Scheme IV). The obtained block copolymers showed self-assembling into spherical nanoparticles in aqueous solution and had a photoresponsive self-assembling behavior together with a size reduction of nanoparticles after irradiation. Anticancer drugs (e.g., doxorubicin) could be loaded in the polymer matrix and released in a controlled manner by changing the light irradiation time. Thus, the proposed strategy appears suitable for nanomedicine applications such as anticancer therapy. **Scheme IV. ** Syntheses of photoresponsive NCA monomer derived from cysteine (**a**), the related block copolymer based on poly(ethylene glycol) (**b**) and characteristic photolecavage reaction (**c**). Another recent study involved the synthesis of an amphiphilic poly(ethylene glycol)-_block_-poly (\(\gamma\)-cholesterol-L-glutamate) diblock copolymer by means of the \"_grafting from_\" approach. Specifically, an amino-terminated poly(ethylene glycol) (\(M_{\mathrm{n}}\) 2200 g/mol) was used as macroinitiator for the ROP polymerization of \(\gamma\)-cholesterol-L-glutamate-\(N\)-carboxyanhydride. In this way, a well-defined structure with a molecular weight of 8600 g/mol and a narrow molar-mass dispersity (\(\approx\)1.1) was obtained. The copolymer was used to prepare nanoparticles with low cellular toxicity and potential applicability as a drug delivery system (DDS) [24]. A related work, based on the same synthetic methodology, was carried out to get biodegradable poly(L-lactide)-_block_-(\(N_{\mathrm{i}}\)-carbobenzyloxy-L-lysine) copolymers [25].