Development of 2-oxazoline-based hydrogels and porous polyester microparticles in scCO2

Thesis submitted to Faculdade de Ciências e Tecnologia from Universidade Nova de Lisboa in partial fulfillment of the requirements for the obtention of the degree of Master of Science in Biotechnology

The emergent demand in medicine and in the biomedical field for polymers that can deliver otherwise insoluble or unstable therapeutic compounds, to reduce the amount of those compounds and to localize the delivery of potent compounds has driven research and pharmaceutical industry to invent new molecules and new synthetic approaches to produce these kinds of “smart” polymers.!! Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. Thus, in this work two different types of polymeric matrices for the controlled release of bioactive molecules were developed: a) oxazoline-based hydrogel polymers with biological responsiveness built in and b) glycerol dimethacrylate mesoporous microparticles for inhalation into the lungs. For the development of oxazoline-based hydrogels, several methods were tested to achieve the end-capping of living poly(2-ethyl-2-oxazoline) P(EtOx) with a methacrylate unit and it was found that the end-capping with triethylammonium methacrylate was the most suitable methodology for this propose. The obtained macromonomer, P(EtOxMA),was subsequently copolymerized with different percentages (25 and 80%) of glycidyl methacrylate (GMA). The copolymers were characterized by FTIR, 1H NMR and gel permeation chromatography (GPC). The low critical solution temperature (LCST) behavior of aqueous polymer solutions was investigated by turbidity measurements revealing cloud points that can be tuned from 80 to 55.7 °C by increasing the GMA content. Glycerol dimethacrylate (GDMA) mesoporous microbeads were synthesized by a single-stage free radical polymerization. The effect of added stabilizers (Krytox and Fluorolink C) was investigated. The synthesized polymers were characterized by FTIR,solid state CP-MAS 13C NMR, Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Differential Scanning Calorimetry (DSC) and mercury porosimetry. Surface area was also analyzed by the Brunauer-Emmett-Teller (BET)theory. Small mass density particles (0.19-0.37 g cm-3) with controlled size (1 to 3 μm) and homogeneous morphology were obtained by the addition of stabilizers to the polymerization media. The production of the described materials was performed using the green supercritical carbon dioxide technology, leading to well defined polymers providing a sustainable alternative to organic solvents used in conventional synthesis.