Onyekuru, Lesley Chinazo; (2020) Electrohydrodynamic atomisation to fabricate model biotherapeutic particulates. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Biologically-based medicines such as vaccines and therapeutic proteins are routinely used in the clinic. While recombinant technologies are firmly entrenched and biotherapeutics will continue to be developed, maximising clinical efficacy requires optimal pharmacokinetics and duration of action. Treatment failures have also been known to occur due to poor adherence, compliance and access to healthcare. Generally, it is advantageous to have sustained protein delivery systems to reduce dosing frequency, to have fewer side effects, and to increase patient compliance. Controlled release protein-loaded particles or depots are options for less frequent dose administration. Similarly, with vaccines, there is often a need to administer boosting dose, so long acting or pulsatile vaccine formulations could provide clinical benefit. This thesis focuses on using electrohydrodynamic processes to fabricate polymeric fibres and particles that could form the basis for controlled release of biotherapeutics. Chapters 1 and 2 describe the relevant background and the materials and methods that were used. Chapter 3 reports the processes essential for the fabrication of alkaline phosphatase (ALP) encapsulated by polyethylene oxide (PEO) fibres and particles, to help understand the effect of electrohydrodynamic atomisation (EHD) processing techniques on the enzyme activity. There was evidence of change to the activity of the enzyme, which can be minimised by reduction of voltage used in processes. Chapter 4 describes the production of albumin-loaded from electrosprayed PLGA and Eudragit particles. Biphasic release systems could be generated by either mixing the two particle sets, or by forming core-shell structures. Albumin was used as a model antigen. Physicochemical and in vitro cytokine secretion assays were conducted to correlate particle properties with processing parameters. It was possible to vary the albumin release profiles and the poly(lactic-co-glycolic acid) (PLGA) particles significantly increase the production of tumour necrosis factor (TNF- α) but no other cytokines from macrophage-like cells. Chapter 5 describes optimisation of the processing parameters that affect particle shape and examines the effect of PLGA particle morphology on macrophage-like cells. Rod-like particles had more of an immunostimulatory effect than spherical particles and might hence be better suited to delivery of vaccines. In conclusion, materials fabricated using EHD can be tailored to achieve desired structures, shapes and release profiles.

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