In situ forming hydrogels for local and controlled delivery of polymeric nanoparticles and therapeutics

Abstract

The research presented in this thesis discusses advancements in pharmaceutical technology, specifically drug delivery systems (DDSs), which aim to enhance the effectiveness of therapeutic products. These DDSs encompass a range of systems, from macro to nanoscale, and have shown promising results in (pre)clinical applications. Synthetic polymeric delivery systems within the field of DDSs are particularly interesting due to their chemical tunability and the ability to introduce different functionalities. This thesis explores the design and development of multiple DDSs for local and controlled release of therapeutics. Various polymers have been synthesized using polymerization techniques such as free radical polymerization (FRP), reversible addition-fragmentation chain-transfer polymerization (RAFT), and atom transfer radical polymerization (ATRP) to prepare nanoparticles and hydrogels. The manuscript delves into the use of nanoparticles for nucleic acid delivery and polymeric micelles as platforms for loading and administering hydrophobic drugs. It also highlights the use of hydrogels as hydrated polymeric networks that can slow down the degradation pathways of biotherapeutics and act as releasing depots for pharmaceuticals. The hydrogels presented are explored as standalone systems and as components of dual delivery formulations, enabling the encapsulation and subsequent release of embedded nanoparticles. In detail, this thesis focuses on the application of these DDSs in the delivery of antimicrobial peptides, the prevention and treatment of orthopedic biofilm-associated infections, stabilization of antimicrobial peptides, and the delivery of nucleic acids to tumor tissues and for heart regeneration. In each case, the design, synthesis, and performance of the DDSs are discussed, highlighting their potential therapeutic efficacy. The thesis concludes by emphasizing the applicability of nanoparticles and hydrogels for the delivery of therapeutic peptides, nucleic acids, and small hydrophobic molecules.