Development of adenoviral and miRNA eluting stents

Stepto, Hannah (2015) Development of adenoviral and miRNA eluting stents. PhD thesis, University of Glasgow.

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Abstract

Cardiovascular disease (CVD) is the most common cause of death worldwide, accounting for 31% of the annual deaths per year. The term cardiovascular disease refers to many different disorders of the heart and blood vessels, the most prolific of which is coronary heart disease (CHD). The root cause of CHD is atherosclerosis, which is the build-up of plaque in the intima of the arteries, restricting the blood supply which reaches the heart. If left untreated, the plaques lining the vessel can rupture and cause thrombosis and myocardial infarction (MI). Taking into account an individual’s risk-benefit ratio, a suitable treatment is considered with the aim to prevent MI from occurring. The two main revascularisation strategies are coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI), the latter being the most frequently used; within the UK 80% of revascularisation is performed by PCI. A PCI procedure is non-invasive and involves the deployment of an intravascular stent into the diseased vessel, which acts as a permanent scaffold that mechanically re-widens the vessel. However, despite the prolific use of intravascular stents within the clinic, there are significant problems associated with this revascularisation technique, such as in-stent restenosis (ISR) and late stent thrombosis (LST). ISR is the re-narrowing of arteries after stent deployment, characterised by a neointima growth within the lumen of the vessel. ISR is a significant clinical problem, because it can lead to repeat revascularisation procedures and often patients present frequently with unstable symptoms, fulfilling the criteria for an MI diagnosis. ISR occurs as a complex wound healing response caused by the stent deployment. Denudation and tearing of the endothelium and the mechanical stress endured by the vascular smooth muscle cells (VSMC) is a stimulus for hyperplasia. VSMC de-differentiate from the contractile to synthetic states and proliferate and migrate into the lumen of the vessel, secreting ECM which forms the bulk of the neointima. The neointima growth will continue to form until the endothelium has re-established itself. As a treatment to prevent ISR, drug-eluting stents (DES) were introduced which were coated with anti-proliferative drugs, to prevent ISR from occurring. DES proved to be very successful at preventing ISR; however elevated rates of LST were associated with these stents. This elevated event rate for DES by LST is thought to be caused as a result of delayed re-endothelialisation and by inflammatory reactions to the polymer used in the coating of DES. The aim of this study was consequently to investigate methods for delivery and coating of novel therapeutics, adenoviruses and miRNA onto stent surfaces. This would allow investigation into the prevention of ISR using these therapeutics, taking advantage of the localised stent setting. It was hoped that local delivery would provide significant advantages over systemic delivery by decreasing the dosage required, avoiding systemic side-effects and increasing delivery to the targeted area, thereby enhancing the therapeutic effect. For the development of coating methods for adenovirus eluting stents, the majority of the work conducted was done using Ad5 as a model virus vector. Three different methods were investigated and evaluated in vitro; deposition onto polyelectrolyte multilayer (PEM) surfaces, by direct conjugation with a modified poly(lactic acid) (PLA) surface through covalent bond formation and collagen gel entrapment. The development of coating methods for miRNA eluting stents focussed initially on collagen gel entrapment; however it was discovered that direct application onto a PLA surface provided a system whereby excellent delivery of the miRNA could be achieved. This methodology was extensively investigated and evaluated in vitro from stent material surfaces, and in vivo in both the porcine and murine stenting models. The results presented here have extended current methodology for both miRNA and adenovirus eluting stents. To the best of our knowledge, this is the first time that miRNA eluting stents have been used in these animal models and therefore contributes significantly to the field of miRNA-based therapeutics.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Funder's Name: UNSPECIFIED
Supervisor's Name: Baker, Prof. Andrew and Cronin, Prof. Lee and Oldroyd, Prof. Keith
Date of Award: 2015
Depositing User: Miss Hannah Stepto
Unique ID: glathesis:2015-7175
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 06 Apr 2016 08:54
Last Modified: 26 Apr 2016 07:51
URI: http://theses.gla.ac.uk/id/eprint/7175

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