Microbubbles (MB) are routinely used as contrast agents for ultrasound (US) imaging. We describe different types of targeted and drug-loaded poly(n-butyl cyanoacrylate) (PBCA) MB, and demonstrate their suitability for multiple biomedical applications, including molecular US imaging and US-mediated drug delivery. Molecular imaging of angiogenic tumor blood vessels and inflamed atherosclerotic endothelium is performed by modifying the surface of PBCA MB with peptides and antibodies recognizing E-selectin and VCAM-1. Stable and inertial cavitation of PBCA MB enables sonoporation and permeabilization of blood vessels in tumors and in the brain, which can be employed for direct and indirect drug delivery. Direct drug delivery is based on USinduced release of (model) drug molecules from the MB shell. Indirect drug delivery refers to USand MB-mediated enhancement of extravasation and penetration of co-administered drugs and drug delivery systems. These findings are in line with recently reported pioneering proof-ofprinciple studies showing the usefulness of (phospholipid) MB for molecular US imaging and sonoporation-enhanced drug delivery in patients. They aim to exemplify the potential and the broad applicability of combining MB with US to improve disease diagnosis and therapy.
C hemokines, acting through various mechanisms including the recruitment of immune cells and smooth muscle progenitor cells (SPCs) to the vessel wall, 1,2 are crucial for vascular remodeling and atherosclerosis. In addition, chemokines are critical for monocyte and neutrophil homeostasis. Hyperlipidemia-induced monocytosis results from the combined action of various chemokine receptors, such as CCR2, which are expressed by immune cells (including monocytes), and facilitates atherosclerosis.3-5 By contrast, the CXCL12 receptor, CXCR4, protects against atherosclerosis by controlling the mobilization of neutrophils, 6 whereas the mobilization and recruitment of SPCs by CXCL12 during vascular repair aggravates neointima formation, which indicates a contextspecific role for this chemokine-receptor axis in arterial remodeling.7,8 Accordingly, increased levels of CXCL12 and SPCs are observed in patients with severe cardiac allograft vasculopathy.9 Systemic treatment with CXCL12 induces the release of SPCs, which accumulate in atherosclerotic lesions and thus lead to plaque stabilization. 10 Whereas most of the effects of CXCL12 are linked to its interaction with CXCR4, the function of the alternative CXCL12 receptor, CXCR7, in atherogenesis and vascular remodeling is unclear. Clinical Perspective on p 1253Background-The aim of this study was to determine the role of the chemokine receptor CXCR7 in atherosclerosis and vascular remodeling. CXCR7 is the alternative receptor of CXCL12, which regulates stem cell-mediated vascular repair and limits atherosclerosis via its receptor, CXCR4. Methods and Results-Wire-induced injury of the carotid artery was performed in mice with a ubiquitous, conditional deletion of CXCR7 and in mice treated with the synthetic CXCR7 ligand CCX771. The effect of CCX771 treatment on atherosclerosis was studied in apolipoprotein E-deficient (Apoe) mice fed a high-fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe −/− mice by fast protein liquid chromatography. Uptake of DiI-labeled very low-density lipoprotein to adipose tissue was determined by 2-photon microscopy. We show that genetic deficiency of Cxcr7 increased neointima formation and lesional macrophage accumulation in hyperlipidemic mice after vascular injury. This was related to increased serum cholesterol levels and subsequent hyperlipidemia-induced monocytosis. Conversely, administration of the CXCR7 ligand CCX771 to Apoe −/− mice inhibited lesion formation and ameliorated hyperlipidemia after vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating very lowdensity lipoprotein levels but not low-density lipoprotein or high-density lipoprotein levels and increased uptake of very low-density lipoprotein into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced expression of Angptl4 in adipose tissue. Conclusions-CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected choleste...
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