POLY(GLYCEROL SEBACATE) COPOLYMERS FOR DRUG DELIVERY

Poly(glycerol sebacate) (PGS) is a biocompatible elastomer having high biomedical interest; however, its application in advanced drug delivery systems has been historically limited due to its inherent hydrophobicity and the resulting difficulties in the preparation of aqueous formulations. This thesis addressed this challenge by developing a versatile and scalable nanotechnological PGS platform based on a careful macromolecular design. To overcome processability limitations a novel copolymer, poly(glycerol sebacate-co-oleic acid) (PGSO), was synthesized: the use of oleic acid as a monofunctional chain terminator allowed for the modulation of the polymer architecture, limiting uncontrolled crosslinking and enhancing the material's processability. This specific structural modification enabled the production of stable, high-concentration (10% w/w) aqueous dispersions via an inherently scalable and entirely solvent-free phase inversion technique. Process optimization highlighted the key role of triethanolamine (TEAOH), successfully employed not only as a salifying and stabilizing agent due to its steric hindrance, but also for its known function as a transdermal permeation enhancer. The true potential of the system was investigated by addressing the encapsulation of curcumin, a molecule known for severe formulation criticalities related to low water solubility and a strong tendency towards crystalline self-aggregation. As classical physical approaches proved ineffective, this obstacle was overcome through a chemical compatibilization strategy. The PGSO matrix was combined with a custom-engineered active agent by synthesizing a novel Curcumin-Zinc-Oleate complex. Solid-state investigations (XRPD, FT-IR) alongside NMR spectroscopy confirmed the successful complexation which, by masking the groups responsible for hydrogen bonding, inhibited the drug's recrystallization. Concurrently, the lipophilic nature of the oleate ligand increased the thermodynamic affinity with the polymer core. This integrated approach ensured the formation of stable, homogeneously loaded and dimensionally controlled nanoparticles (~150 nm). The formulation versatility of the platform was confirmed by its ability to encapsulate other lipophilic active ingredients, such as piroxicam and cinnamic acid. To complete the work, preliminary in vitro biocompatibility evaluations confirmed the absence of cytotoxicity for the empty nanocarrier and the preservation of the antiproliferative activity of the encapsulated complex. Furthermore, exploratory studies on the reactivity of the PGSO double bonds via photo-initiated thiol-ene chemistry provided encouraging indications regarding the feasibility of using this dispersion to develop in situ photo-crosslinkable biomaterials. In conclusion, this thesis provides a robust methodological toolkit for the application of PGS. The results confirm how the synergy between controlled polymer synthesis, solvent-free formulation processes, and chemical engineering of the therapeutic payload represents a highly effective pathway for the development of targeted and industrially transferable nanocarriers.