Restoration of blood vessel function, using nanotechnology

Astley, Cai (2020) Restoration of blood vessel function, using nanotechnology. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Nanoparticles are emerging drug delivery platforms for improved stability and bioavailability of drugs and vasoprotective nutraceutical compounds, such as resveratrol (RV) for the treatment of cardiovascular disease (CVD). Hypertension is a significant contributor to CVD, and while its pathophysiology is unclear, oxidative stress is thought to be a key contributor. It is evident that there is a growing need for treatment strategies to prevent future cardiovascular events. This project aimed to develop a potential therapeutic tool for the treatment of CVDs associated with oxidative stress. Nanoparticles (inorganic and organic) were synthesised and characterised using a range of chemianalytical techniques and their potential for the delivery of nutraceutical compounds assessed. The effects of the drug-loaded nanoparticles were assessed using human coronary artery endothelial cells (HCAECs) in vitro and using a developed model of acute hypertension in isolated coronary and cerebral vessels to replicate an oxidative environment. Silica nanoparticles (SiNPs) functionalised with cerium oxide (CeO2) reduced SiNP surface reactivity and demonstrated antioxidant capacity, improving biocompatibility in vitro. Uptake of novel RV-loaded NLCs (RV-NLCs) by HCAECs maintained their viability and reduced both mitochondrial and cytosolic superoxide levels; vessel incubation in RV-NLCs restored the magnitude of dilation via NO following acute pressure elevation, mediated via AMPK in the coronary artery. In contrast, organic nanoparticles (RV-NLCs and TMSliposomes) were incapable of restoring elevated pressure induced attenuated dilation in cerebral arteries, suggesting alternate mechanisms of impairment. Findings from the present study support the use of nanoparticles for the treatment of CVD, whereby they offer improved biocompatibility, potency and sustained drug release into the vasculature; whilst also highlighting the tissue-specific variability in treatment responses, hence a need for in-depth, comparative studies in the development of novel clinical solutions.