Green strategies applied to the synthesis of polymer particles for protein delivery

With the recent progresses in biotechnology that enable the production of various peptides and proteins, there is a growing interest for their use as therapeutic agents. Indeed, since the introduction of the first recombinant therapeutic protein, human insulin, 30 years ago, the interest for pharmaceutical proteins have increased remarkably for various therapeutic purposes. Nevertheless, several challenges still remain such as the preservation of the quite fragile complex protein structure of these proteins to warrant their therapeutic activity after storage and administration into the body. Protecting them against chemical/enzymatic degradation from the environment is a prerequisite to efficiency. To reach this goal and prolong/trigger the release of therapeutic proteins in the body, different carriers were developed and investigated. Among them, polymer nanogels and microcpasules appear as quite promising systems. The thesis focuses on the preparation of novel carriers for protein delivery while using “green” strategies. More precisely, protein carriers are produced by two approaches. The first one investigates the preparation of hydrophilic nanogels by free radical dispersion polymerization of hydroxyethyl methacrylate (HEMA) in supercritical carbon dioxide. The development of dedicated stabilizers efficient in this green medium is thus first considered particularly focussing on the study of the influence of the stabilizer architecture. Then, the optimized candidate is used for the size- controlled nanogels preparation. A strategy allowing the removal of the hydrophobic component of the stabilizer is then investigated based on the synthesis of a photocleavable copolymer. The performances of these as-obtained novel nanogels to load and release proteins is then investigated. In a second approach, the synthesis of protein-loaded microcapsules offering a tunable permeability in response to the external glucose concentration is investigated. For that purpose, the layer-by-layer assembly of dedicated copolymer polyelectrolytes including glucose-sensitive diol/boronic acid bonds was performed on the surface of protein-loaded calcium carbonate particles. After dissolution of the calcium salt, microcapsules able to tune the release of the encapsulated protein in response to glucose concentration are obtained.