Therapeutic design for nasal powder delivery

Student thesis: Doctoral Thesis


Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The response to the pandemic saw widespread diagnostic testing, and the development of vaccines at speed, with global distribution ahead of emergency regulatory approval. Antibody conjugation with nanoparticles (NPs) through Staphylococcus Protein A (SpA) can be used a platform for the development of new diagnostics, and Molecular Dynamics (MD) simulations were used to investigate SpA for its potential as an antibody conjugation agent with model NPs. The simulations showed the model negatively charged silica surface produced favourable SpA adsorption, that facilitated the binding of antibodies at the Fc region to functionalise the system. The SpA was blocked on both sides when it bound to the model gold surface, and the SpA receptor binding domain (RBD) is blocked on the model positive silica surface. Overall, these results indicate SpA is a promising agent to guide the development of a new diagnostic for COVID-19. The initial aim was to develop a novel diagnostic for COVID-19. However, after the withdrawal of my original industrial partner, and the project workplan change with my new industrial partner, it was decided to pursue the development of a dry powder intranasal (IN) vaccine. Therefore, the aim of this thesis is to design a dry-powder IN vaccine for COVID-19, by studying the SARS-CoV-2 RBD interactions with model NPs. The SARS-CoV-2 RBD and SARS-CoV-2 RBD with histidine tag (His-Tag) were studied by MD simulations with model silica NPs (SiNPs) and model carboxyl terminated SiNPs (COOH SiNPs). The MD simulations indicate SARS-CoV-2 RBD binds preferentially on the model SiNPs and SARS-CoV-2 RBD with His-Tag binds preferentially to the model COOH SiNPs. These model systems were used to guide the experimental production of a dry-powder IN vaccine for COVID-19. The simulations guided the laboratory work, where a spray-dryer was used along with other characterisation equipment for the production, and analysis of a dry powder IN vaccine formulation for COVID-19. Alpha lactose monohydrate spheres, used as the excipient in the dry-powder IN vaccine formulation, were successfully spray-dried to the required size. Despite the overall unsuccessful attempt at IN vaccine production for COVID 19, this project has opened up many possibilities for the future, as the MD simulations showed the NPs are suitable for a vaccine formulation, and the experimental component of this project also contributed to the development of an IN vaccine.
Date of Award11 Jun 2024
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorPaul Mulheran (Supervisor) & Valerie Ferro (Supervisor)

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