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Swainson, Sadie M E (2020) Development of a Size Targeted Formulation to Treat Pulmonary Arterial Hypertension. PhD thesis, University of Nottingham.

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Abstract

The aim of this thesis is to develop a novel formulation for the treatment of Pulmonary Arterial Hypertension (PAH). PAH is a rare but serious disease which is invariably fatal without treatment. Vascular remodelling and an increase in vascular resistance lead to increased pulmonary arterial pressure and right ventricular overload, which ultimately result in right-sided heart failure and death. While treatments are available for PAH, they suffer from a lack of proven effect on mortality, serious administration problems and systemic side effects which can have a significant effect on patients’ quality of life.

This project follows the development of a new approach to tackling the problems with current PAH treatments. A novel nanoparticle aggregate formulation has been produced using the biodegradable and biocompatible polymer, poly(glycerol adipate). This formulation is intended to use particle size to become mechanically trapped in the lung vasculature following intravenous administration, allowing the prostacyclin to be released in situ with the hope that this will improve drug efficacy and decrease the occurrence of side effects, thereby improving the quality of life and life expectancy of patients with PAH.

A range of modifications of PGA were produced for use in this project. These included novel polymer-drug conjugates such as PGA-Iloprost and PGA- Ambrisentan. A range of techniques have been used to characterise the enzymatic degradation of PGA and provide an indication of the way the polymer will behave and release drug payloads in vivo. The results of these degradation studies confirm PGA is deserving of the labels biodegradable and biocompatible.

The influence of a variety of factors on the particle size of both microparticle and nanoparticle aggregate formulations has been studied. In contrast to much of the literature, processing parameters were found to have no effect on particle size, which was instead dependent on the modifications to the polymer backbone and the way in which the polymer chains interacted.

Finally, the cytotoxicity of PGA has been assessed, with the polymer having no effect on the metabolic activity of BAE-1 bovine aortic endothelial cells. PGA- Iloprost nanoparticles were found to elevate the levels of cyclic adenosine monophosphate in human pulmonary arterial smooth muscle cells isolated from a patient with PAH, indicating pharmacological efficacy.

Overall, the results presented in this thesis suggest that size-targeted lung delivery of a prostacyclin is a viable approach to treating PAH which warrants further investigation.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Garnett, Martin Bosquillon, Cynthia Clapp, Lucie McAllister, Mark Ager, Barry
Keywords:	polymer modification, enzymatic degradation, size-targeting, polymers, pulmonary arterial hypertension, PAH, nanomedicine
Subjects:	Q Science > QP Physiology > QP501 Animal biochemistry R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	59517
Depositing User:	Swainson, Sadie
Date Deposited:	05 Oct 2023 12:31
Last Modified:	05 Oct 2023 12:37
URI:	https://eprints.nottingham.ac.uk/id/eprint/59517

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