Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations. CVD is primarily caused by atherosclerosis, a systemic disease characterized by lipid deposition in the subendothelial space with a concomitant, low-grade inflammatory reaction. Nowadays, most therapeutic interventions aimed at lowering CVD have thus far focused on modulating lipid levels, either lowering LDLc or increasing HDLc levels. Yet, since the introduction of statins 20 years ago, there have been few breakthroughs in the treatment of this disease. In fact, the recent failure of a potent HDL-increasing drug, i.e. torcetrapib, has emphasized the need to also consider non-lipid modulating targets.~A promising strategy to reduce CVD is to directly target inflammation at the level of the vessel wall. A potential drawback of anti-inflammatory strategies pertains to the thin line between inhibiting 'inappropriate' inflammation versus inducing immuno-suppression. One of the strategies to limit systemic immunosuppression is to strive for local delivery and prolonged efficacy and low systemic burden of the drug by encapsulating the compound in liposomes.~Liposome-encapsulated drugs efficiently target lesions and accumulate at a much higher extent at desired areas of interest. This approach is currently used for the clinical treatment of different types of cancer(liposomal doxorubicin) and fungal infections (liposomal amphotericine-B). Liposomes for other applications (rheumatoid arthritis, cystic fibrosis, multiple sclerosis and atherosclerosis) are being pre-clinically developed or investigated in clinical trials.~Recent pre-clinical studies in animal models corroborate that liposomal glucocorticoids effectively attenuate atherosclerotic plaque inflammation and exhibit improved pharmacokinetics and biodistribution. Also, local delivery through localization of liposomes at inflammatory sites and in local macrophages was demonstrated in animal models.~In humans, the potential of PEG-liposomes to target inflammatory sites has been showed by imaging of radioactive liposomes. However, the concept of local delivery and (prolonged) efficacy of liposomal corticosteroids at the inflammatory sites, such as atherosclerosis, and at local macrophages remains to be determined in humans.~Thus, local delivery and prolonged efficacy can be very important tools to overcome the potential drawback anti-inflammatory drugs; namely an inappropriate immune suppression. To proof this concept, the investigators need to evaluate the local delivery and efficacy at the site of inflammation (atherosclerosis) of intravenously administered liposomal glucocorticoids (Nanocort) compared to free glucocorticoids (Prednison). Only by comparing these two drugs, the investigators can prove the potential benefits of nanomedicine as a vehicle for local drug delivery. This can have major implications in future drug strategies for cardiovascular disease.~In the present project, the investigators therefore aim to evaluate the delivery and superior efficacy of Nanocort above Prednison or placebo in patients with peripheral artery disease due to atherosclerosis. Because these patients will undergo an endarteriectomy the investigators will be able to collect atherosclerotic material after drug administration and thus evaluate the local delivery and compare the effects of Nanocort to Prednison or Placebo.
A promising strategy to reduce CVD is to directly target inflammation at the level of the vessel wall. A potential drawback of anti-inflammatory strategies pertains to the thin line between inhibiting 'inappropriate' inflammation versus inducing immuno-suppression. One of the strategies to limit systemic immunosuppression is to strive for local delivery and prolonged efficacy and low systemic burden of the drug by encapsulating the compound in liposomes.~Liposome-encapsulated drugs efficiently target lesions and accumulate at a much higher extent at desired areas of interest. Thus, local delivery and prolonged efficacy can be very important tools to overcome the potential drawback anti-inflammatory drugs; namely an inappropriate immune suppression. In the present project, the investigators therefore aim to evaluate the delivery and superior efficacy of Nanocort above Prednison or placebo in patients with peripheral artery disease due to atherosclerosis. Because these patients will undergo an endarteriectomy the investigators will be able to collect atherosclerotic material after drug administration and thus evaluate the local delivery and compare the effects of Nanocort to Prednison or Placebo.