Design of poly(HEMA) particles in supercritical carbon dioxide for protein delivery

Since many decades, polymers proved to be excellent candidates for the development of drug carriers in the pharmaceutical field. Indeed, the range of biocompatible polymers available on the market place allows to prospect new developments of drug carriers for active principle. A vast majority of the polymer nanocarriers have been designed and developed for the controlled and targeted release of hydrophobic drugs. Indeed, the development of delivery systems allowing (i) the solubilization of poorly soluble drugs, (ii) their transport and (iii) selective release to a specific site is a major challenge in the pharmaceutical field. Therefore, several types of nanosized vehicles have been developed, typically nanoparticles, dendrimers, or self-assembling systems such as liposomes or polymer micelles. However, there are still some challenges to design appropriate carriers for the delivery of therapeutic proteins or peptides. Although the history of the protein/peptide-based drugs dates back to insulin production, they have taken great attention since the last decades due to their possible broad range of therapeutic applications. They might offer more specific and safer therapies in comparison to small molecules drugs. Nonetheless, their encapsulation remains challenging specially to preserve their specific structure and activity in the formulations. For this purpose, hydrogel particles (nano-/microgels) have emerged as promising polymer carriers for such proteins. This work focuses on the synthesis of nano-/microgels encapsulating therapeutic proteins and peptides in supercritical carbon dioxide which confers environmentally benign features to the synthesis method. More precisely, hydrogel particles were obtained by free-radical dispersion polymerization of 2-hydroxyethyl methacrylate (HEMA) in supercritical carbon dioxide in presence of a crosslinker and a suitable stabilizer. Typically, the stabilizer, a block copolymer presenting a CO2-philic and a hydrophilic block, have been especially designed to present a photocleavable bond at the junction of the two blocks with the purpose to remove the fluorinated block after particles synthesis and as a consequence allows the poly(HEMA) particles to swell in water. The optimization of the dispersion polymerization conditions led to well-defined cross-linked particles. The process was robust enough to incorporate a drug or a peptide to encapsulate in one-pot synthesis into the particle network. In a subsequent step such drug loaded particles were dispersed successfully in aqueous media and shown sustained release of their content. This was demonstrated notably for the release of a bactericidal peptide.