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Atom transfer radical polymerization (ATRP) has been successfully employed to obtain a new derivative of hyaluronic acid (HA) able to change its solubility as a function of external pH and then to be potentially useful for intestinal release of bioactive molecules, included enzymes and proteins.In particular, a macroinitiator has been prepared by linking 2-bromo-2-methypropionic acid (BMP) to the amino groups of ethylenediamino derivative of tetrabutyl ammonium salt of HA (HA-TBA-EDA). This macroinititor, named HA-TBA-EDA-BMP has been used for the ATRP of sodium methacrylate (MANa) using a complex of Cu(I) and 2,2 ′ -bipyridyl (Byp) as a catalyst.The resulting copolymer, named HA-EDA-BMP-MANa, has been characterized by 1 H NMR and size exclusion chromatography (SEC) analyses. A turbidimetric analysis has showed its pH sensitive behavior, being insoluble in simulated gastric fluid but soluble when pH increases more than 2.5. To confirm the ability of HA-EDA-BMP-MANa in protecting peptides or proteins from denaturation in acidic medium, ␣-chymotrypsin has been chosen as a model of protein molecule and its activity has been evaluated after entrapment into HA-EDA-BMP-MANa chains and treatment under simulated gastric conditions. Finally, cell compatibility has been evaluated by performing a MTS assay on murine dermal fibroblasts cultured with HA-EDA-BMP-MANa solutions.

A simple and efficient method for the synthesis of polyaspartamide-based brush copolymers using Atom Transfer Radical Polymerization (ATRP) is here presented. The syntheses were performed by using two subsequent steps. In the first step the macroinitiator was obtained by the conjugation of a proper number of 2-bromoisobutyryl bromide (BIB) residues to the R,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) side chains, obtaining the PHEA-BIB copolymer. PHEA-BIB copolymer was used as "multi-functional macroinitiator" for the polymerization via ATRP of hydrophilic methacrylic monomers, such as methacrylic acid (MA), obtaining PHEA-IB-poly(MA) copolymer, sodium methacrylate (MANa + ), obtaining PHEA-IB-poly(MANa + ) copolymer, or hydrophobic monomer such as butyl methacrylate (BMA), obtaining PHEA-IB-poly(BMA) copolymer. BMA was also homopolymerized subsequently MANa + polymerization, extending the poly(MANa + ) chains by poly(BMA) chains arising PHEA-IB-poly(MANa + )-block-poly(BMA) copolymer. Different solvent and temperature conditions were used in order to obtain the best ATRP conditions for each monomer in term of high polymerization efficiency in PHEA side chain. All the synthesized PHEA-based brush copolymers were widely characterized and copolymer self-assembling properties in aqueous media were evaluated by turbidimetry measurements, light scattering and SEM analyses. PHEA-IB-poly(MANa + ) resulted able to form spherical microparticles at pH 2, with a diameter from 1 -5 µm. PHEA-IB-poly(MANa + )-block-poly(BMA) copolymer formed particles at elliptic shape and an internal hollow architecture with an outer diameter of 1-4 µm. Finally, PHEA-IB-poly(BMA) copolymer resulted able to produce microfibers in aqueous medium, with an homogeneous tube shape and a thickness ranging from 3 to 5 µm.