Design, Synthesis, and Biological Evaluation of a Modular Polymer-based Platform for Antimicrobial Photodynamic Therapy

The emergence of antibiotic-resistant bacteria, particularly in respiratory infections, presents an urgent need for alternative therapeutic approaches. This thesis describes the development of polymer-based antimicrobial photodynamic therapy systems designed specifically for treating Pseudomonas aeruginosa respiratory infections. Two complementary synthetic strategies were employed to create functional polymeric materials incorporating photosensitizers and other active ingredients (biofilm-disrupting agents). The first approach involved post-polymerization modification of active ester polymers, enabling controlled incorporation of both ruthenium complexes and phenalenone derivatives as photosensitizers. The second strategy utilized direct free radical polymerization of photosensitizer-containing monomers alongside functional comonomers. Both approaches successfully yielded water-soluble polymers intended for nebulization-based delivery. Compared to free photosensitizers, these polymer-based systems offer advantages including enhanced local drug concentration through multivalent presentation and improved solubility, addressing key limitations of conventional photosensitizers. Comprehensive biological evaluation highlighted various properties of the polymers designed with identification of structure-activity relationships. Some of these materials can effectively inactivate and/or eliminate both planktonic bacteria and biofilms upon visible light illumination, with activity maintained in physiologically relevant conditions. Notably, certain polymers also showed enhanced efficacy in high-salt environments representative for respiratory infections such as cystic fibrosis. The materials exhibited excellent biocompatibility with human bronchial epithelial cells and maintained their structural integrity and antimicrobial activity through nebulization, supporting their potential for therapeutic applications. This work establishes a promising platform for treating respiratory infections through controlled, light-activated antimicrobial activity, offering advantages over conventional antibiotic treatments while maintaining compatibility with clinical delivery methods.