Thesis

Formulation and manufacture of lipid nanoparticles using the micropore AXF crossflow systems

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Awarding institution
  • University of Strathclyde
Date of award
  • 2025
Thesis identifier
  • T17208
Person Identifier (Local)
  • 202369669
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Since its discovery in 1961, the therapeutic utilisation of messenger RNA (mRNA) to combat viral infection and genetic predispositions became a strong focal point for the field of molecular biology. Unlike DNA, mRNA’s transient single strand structure alleviated concerns associated with long-circulation times and consequential offtarget toxicity whilst simultaneously harbouring a reduced risk of genetic recombination. Although promising, challenges facing effective mRNA delivery to the cell cytosol hindered its therapeutic potential. Both exogenous mRNA’s intrinsic immunostimulatory activity and susceptibility to host endonucleases inhibited mRNA’s translational activity and potency. The result led to the exploration of two avenues to mitigate these pitfalls: nucleoside modification of mRNA to protect against innate immune clearance mechanisms and optimisation of lipid nanoparticles (LNPs) to enable successful delivery and uptake to the cell cytosol. Expedited by the SARSCoV2 response, both played critical roles in the rapid development and success of Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax response. Despite the success of this LNP- based vaccine roll out, bottlenecks in the manufacture of LNPs highlighted the necessity for a scale-independent, uniform design, capable of formulating LNPs at benchtop to manufacturing throughputs. As such, varying microfluidic-based synthesis methods are being explored, one of which is the AXF crossflow technology developed by Micropore Technologies. This project aims to develop a thorough understanding of the effect of the process parameters and fluid mixing dynamics within the range of Micropore’s crossflow devices to support the fast and easy scale-up of LNP production processes and to enable local vaccine manufacture within developing countries. This will be achieved by evaluating the impact of operating speed, lipid concentration, choice of ionizable lipid on LNP critical quality attributes (CQAs) using Micropore AXF-Mini crossflow device. Succeeding this, LNP efficacy in vitro and methods scaling to an in vivo dosage concentration will be evaluated.
Advisor / supervisor
  • Perrie, Yvonne
Resource Type
DOI
Date Created
  • 2024

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