Design of exeriment-based optimization of nebulized pulmonary PBAE-siRNA delivery systems

Kromer, Adrian (2025): Design of exeriment-based optimization of nebulized pulmonary PBAE-siRNA delivery systems. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

The aim of this work was the development of a PBAE polymer-based siRNA therapy delivery system for pulmonary application using DoE as streamlining tool. To achieve this, siRNA was encapsulated into polyplexes through electrostatic interaction with PBAE polymers which were then nebulized to achieve deep lung deposition. For this cause, in a first step the polymer synthesis was optimized and characterized to gain control and understanding of the process. Here, DoE was applied to reduce the number of experiments and resources spent to control the synthesis. Utilizing the controlled synthesis, numerous polymers were prepared and tested regarding their stability, toxicity and efficiency in vitro and in vivo. Here, core principles governing the nanoparticles performance were identified and optimized. To achieve the goal of pulmonary application, different nanoparticles were tested for nebulization-based delivery. Therefore, nanoparticle stability in regards of physicochemical characteristics and efficacy after VMN based nebulization was investigated. Nanoparticles encapsulating therapeutic siRNA were able to mitigate disease relevant gene expression after nebulization and application onto diseased ex vivo human tissue. Finally, the manufacturing process of the nanoparticles was optimized applying DoE on a microfluidic setup. Large scale production of clinically relevant batch size was tested and evaluated.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 23. September 2025
• 1. Bericht­erstatter:in: Merkel, Olivia