A shear-stress responsive nano-container to target critically constricted arteries

Atherosclerosis and associated cardiovascular diseases are the world's biggest cause of mortality. During the acute case of heart attack, vasodilators are administered to open up the constricted artery and allow blood perfusion to the surrounding tissue. However, there are currently no treatments on the market that allow such drugs to be delivered locally to the site of a critically constricted artery. Such a targeted delivery method could significantly improve patient prognosis. The presented thesis is an account of the development of a shear-stress responsive nano-container that could fill this gap in the medic's toolbox, using the physical trigger of increased endogenous shear-stresses in critically constricted human coronary arteries. In Chapter 2.1, an imaging protocol is presented that sequentially uses laboratory micro computed tomography (µCT), absorption- and phase-contrast synchrotron radiation-based µCT (SRµCT) to gather information on morphology and tissue composition of calcified and subsequently decalcified coronary arteries. This paves the way for micrometre-resolution data on the morphology and tissue distribution of a variety of typical critically constricted vessels. For flow experiments using shear-stress responsive nano-containers, an vitro model of the human circulatory system in the healthy and diseased state is developed using plastic model arteries connected to a heart pump designed for use in heart bypass surgery. The micrometer resolution, three dimensional data from human coronary arteries gathered in Chapter 2.1 are invaluable for validating the morphology of these specifically designed plastic models of healthy and critically constricted arteries. Chapter 2.2 quantitatively compares the morphology of the plastic model arteries with a critically constricted human coronary artery and a murine model. Using the validated in vitro model and liposomes formulated from the artificial phospholipid Pad-PCPad, Chapter 2.3 presents the first proof-of-principle that mechano-sensitive nano-containers could be used in targeted drug delivery. Lumen meshes extracted from the µCT datasets are required for computer simulations to truly understand the localised shear-stresses at play in atherosclerotic vessels. Further experiments to construct a micrometre-resolution shear-stress profile of a typical critically constricted vessel will allow predefined, physiologically relevant 'breakpoint' shear-stresses to be determined, above which, the nano-containers should become unstable and release their contents. Such optimised nano-container formulations could have far reaching implications for the treatment of cardiovascular diseases and beyond.