Optimisation of microparticle formulations for IL-4 delivery for macrophage modulation in spinal cord injury

Stening, Jasmine Z. (2020) Optimisation of microparticle formulations for IL-4 delivery for macrophage modulation in spinal cord injury. PhD thesis, University of Nottingham.

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Spinal cord injury currently lacks treatment capable of restoring limb function and sensation. Current strategies, using pharmaceuticals and physiotherapy, focus on alleviating the high inflammatory environment triggered as a result of injury. These often result in adverse side effects and no rehabilitation. The discovery of macrophage phenotypes and their roles in inflammation within spinal cord injury has provided a new target for treatment development. Understanding macrophage behaviour and the roles of their sub-phenotypes has suggested a method for controlling inflammation by modulation towards a pro-immunoregulatory subgroup using cytokine interleukin 4 (IL-4). The hypothesis was that sustained delivery of IL-4 could modulate macrophage phenotype and provide resolution in the context of inflammation in spinal cord injury.

The use of microparticles is widely reported as a drug delivery method for controlled and sustained release in pharmaceutical strategies. The ability to tailor the release of proteins from microparticles by changing their composition ensures a specific release pattern can be obtained for specific applications. Poly(lactic-co-glycolic acid) and various release modifiers such as polaxamers F127 or P188 and triblock co-polymer were used to tailor microparticle release in this project.

IL-4 was encapsulated following the tailoring of microparticle release using a model protein. These particles were used to treat two cell macrophage models, THP-1 cells and immortalised bone marrow derived macrophage cells. The effects of exogenous IL-4 delivery and microparticle IL-4 delivery on macrophage modulation were compared, the aim being to modulate towards a pro-immunoregulatory subgroup.

The use of different microparticle formulations to obtain a database of release profiles was explored in this work, in order to obtain controlled and sustained protein release. From the microparticle formulations tested, 20 % w/v total polymer 40 % w/w TB4 85:15 PLGA was chosen as the optimal formulation to result in sustained delivery of a model protein, and this was replicated using IL-4. Difficulties in characterising a dynamic macrophage population in vitro are also highlighted in this work. The exogenous modulation of macrophage cells to specific subgroups was examined and compared with the results of microparticle induced modulation. The main findings were that the treatment of macrophage cell models with IL-4-containing microparticles resulted in a reduction of proinflammatory cell markers in a similar manner to the treatment with exogenous IL-4. These results also demonstrated the release of active IL-4 from polymeric microparticles. It is hoped that this approach will lead to a therapy targeting the inflammatory environment in spinal cord and in doing so aid repair and regeneration.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: White, Lisa J
Rose, Felicity RAJ
Keywords: Inflammation, Macrophages, Spinal cord injury, Microparticles, Drug delivery systems.
Subjects: R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 60758
Depositing User: Stening, Jasmine
Date Deposited: 31 Jan 2023 08:32
Last Modified: 31 Jan 2023 08:33
URI: https://eprints.nottingham.ac.uk/id/eprint/60758

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