This thesis focuses on using liposomes in two different treatment strategies; vaccination (or immunotherapy) and delivery of a small molecule, and in two different disease models; cancer and... Show moreThis thesis focuses on using liposomes in two different treatment strategies; vaccination (or immunotherapy) and delivery of a small molecule, and in two different disease models; cancer and atherosclerosis. For each of these treatment strategies, the liposomal formulation was tailored to obtain the desired therapeutic effect. Chapter 2 reviews some of the most important physicochemical properties (size, shape, and rigidity) that determine the immunological effects of liposomes and other nanoparticles. In chapter 3 we present a detailed study on the effect of the rigidity of anionic liposomes, as measured by atomic force microscopy, on antigen-specific regulatory T-cell (Treg) responses. In chapter 4, we show that our optimized anionic liposomes can induce potent antigen-specific Treg responses, and can be used to delay atherosclerosis progression in a mouse model. Chapter 5 also focuses on liposomal treatment of atherosclerosis, but here targeted liposomes were prepared to successfully deliver a small molecule to foam cells in atherosclerotic plaques. In Chapter 6, we used cationic liposomes in combination with an adjuvant for cancer immunotherapy in mice. Finally, we summarize the overall findings in chapter 7 and discuss perspectives of using liposomes for vaccination and targeted drug delivery. Show less
Microneedle-based transcutaneous immunisation is an appealing alternative to the classical manner of injecting vaccines by intramuscular or subcutaneous route. Importantly, as a consequence of the... Show moreMicroneedle-based transcutaneous immunisation is an appealing alternative to the classical manner of injecting vaccines by intramuscular or subcutaneous route. Importantly, as a consequence of the fact that the skin is in direct contact with the environment and should protect the body against pathogens, it contains more antigen presenting cells, such as dendritic cells than the muscles or subcutaneous tissue and thereby offers the possibility to induce a more effective immune response. The combination of microneedles and adjuvanted subunit vaccines may offer effective vaccination whereas ensuring patient safety and vaccine application in a painless manner. The principal aim of this thesis was to design subunit vaccine formulations that can be combined with microneedles for transcutaneous immunisation. The approaches described in this thesis have generated new insights into the main requirements for transcutaneous immunisation. Microneedles definitively have the potential to be an excellent utensil for the delivery of vaccines into the skin. However, the skin is a very elastic organ and the actual conduits formed by microneedle pre-treatment will be considerably smaller than the diameter of the microneedles. Therefore, a small antigen-adjuvant entity is the preferred formulation, as it will be transported efficiently through the microneedle conduits while it retains the co-delivery of antigen and adjuvant. Show less
Atherosclerosis, the predominantly underlying pathology of cardiovascular events, is the consequence of lipid deposition in the arterial wall, mostly as consequence of high levels of serum... Show moreAtherosclerosis, the predominantly underlying pathology of cardiovascular events, is the consequence of lipid deposition in the arterial wall, mostly as consequence of high levels of serum cholesterol. Treatment of atherosclerosis is mainly focused at the reduction of cholesterol levels by lipid lowering medication, such as statins. Despite the use of statins and prophylactic treatments, such as a reduction in blood pressure and a reduction in risk factors to prevent atherosclerosis, cardiovascular disease is still the major cause of death in the Western world.1-3 As the struggle against atherosclerosis continues and its prevalence is increasing in the world, it is pivotal to find new targets for implementing new strategies against atherosclerosis. Inflammation is considered to be a major component in the process of atherosclerosis and is involved in initiation, progression and destabilization of the atherosclerotic lesion. Although the beneficial effects of statins on atherosclerosis may partly be ascribed to their anti-inflammatory properties, relatively little is known about the exact mechanism and contribution of different inflammatory cells and products in atherosclerosis. The aim of this thesis was to further elucidate the contribution of various components of the inflammatory response in atherosclerosis and thereby finding new intervention points to reduce the incidence and the consequences of atherosclerosis. Show less
