Ackerley, Samuel Frederic; (2024) Systematically Probing Nanoparticle Synthesis and Design for Encapsulation of Therapeutics and Imaging Agents. Doctoral thesis (Ph.D), UCL (University College London).

Text Samuel Ackerley Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 September 2025. Download (56MB)

Abstract

Delivering hydrophobic drugs is challenging due to poor water solubility, which impedes their dissolution. Encapsulation in polymers, particularly FDA-approved poly(lactic-co-glycolic acid) (PLGA), improves solubility and provides good biocompatibility and non-toxic degradation products. Traditionally, PLGA particles are produced by batch synthesis, which presents reproducibility and scalability challenges. Recently, continuous flow chemistry, which allows for the constant input and output of reagents and products, has emerged as a promising alternative in the pharmaceutical industry, offering greater control over nanoparticle properties and straight-forward scalability. This work explores the numerous factors associated with the nanoprecipitation reaction of PLGA nanoparticles via novel use of a flow chemistry device, the fReactor. Exploration of factors allowed identification of important parameters, which facilitate system optimisation. In this way, we have achieved bio-relevant size ranges and improved particle homogeneity. Design of experiments (DoE) is a powerful approach for conducting experiments, leveraging statistical models to enable elucidation of complex relationships between various factors and responses. Building on the insights gained from our initial PLGA flow work, we investigated the impact of drug concentration, PLGA concentration, stir rate, and surfactant use on nanoparticle synthesis, revealing significant effects on particle size and drug loading. Additionally, we explored the synthesis of mesoporous silica nanoparticles (MSNs) with theranostic capabilities, incorporating a model drug, ibuprofen, and a paramagnetic chelate for enhancing magnetic resonance imaging (MRI) scans. These MSNs, with controllable pore and particle sizes capable of high drug loadings up to 65%, demonstrated the potential for real-time drug release monitoring through MRI, offering an interesting application of this imaging technique. In summary, this thesis presents optimised methods for synthesising drug-encapsulated PLGA nanoparticles via flow chemistry, surpassing traditional batch methods. Furthermore, we highlight the effectiveness of DoE in understanding synthesis parameters and introduce innovative theranostic MSNs for drug delivery and MRI-based tracking.

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