Brain, Danielle 
ORCID: 0000-0002-1671-8477
(2023)
Investigating the impact of, novel, therapeutic delivery systems on immunological responses - determination of short, and long-term, exposure effects.
PhD thesis, University of Liverpool.
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Abstract
Long-acting therapeutics are being explored for their use in improving adherence to medication and enhancing overall treatment outcomes. Due to increased residence time at the site of administration e.g., subcutaneous, long-acting formulations may affect the responses of local immune cells, due to modifications in the long-acting formulations to improve administration and allow the drugs to be released over specific time periods. Therefore, adaptation of current safety assessments must be considered, to safely translate these formulations into clinical studies. Long-acting formulations of the Nucleotide Reverse Transcriptase Inhibitors (NRTIs): FTC, 3TC and TAF were developed for subcutaneous administration for the treatment of HIV, hereafter termed Polymer of Prodrug (POP) formulations. This thesis starts to explore the immunocompatibility of these POP formulations and their interactions with cells and components of the immune system. Complement analysis showed concentration dependent activation from the linear poly(FTC) formulation. Impact of repeated exposure of the NRTI drugs FTC, 3TC and the POP formulation linear poly(FTC) to cell lines was explored, responses were cell line and drug specific, the linear poly(FTC) formulation was only tested in the MUTZ-3 cell line and led to particularly interesting significant changes in marker expression. In vivo analysis of three FTC containing POP polymers were assessed for cytokine perturbations alongside the pharmacokinetic analysis, no significant perturbations were seen across the board for any of the three implants tested. Early analysis of TAF carbamate pro drugs was carried out to determine whether they could alter cell health and cytotoxicity, no significant perturbations were seen, suggesting that POP implants made from these prodrugs may be safe. The model systems used and developed in this thesis will help to characterise and assess the immunocompatibility of long-acting formulations in the future, particularly those administered subcutaneously.
| Item Type: | Thesis (PhD) |
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| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 10 Aug 2023 15:47 |
| Last Modified: | 10 Aug 2023 15:48 |
| DOI: | 10.17638/03171196 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3171196 |
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