The efficient delivery of nanomaterials to specific targets for in vivo biomedical imaging is hindered by rapid sequestration by the reticuloendothelial system (RES) and consequent short circulation times. To overcome these two problems, we have prepared a new stealth PEG polymer conjugate containing a terminal 1,1-bisphosphonate (BP) group for strong and stable binding to the surface of ultrasmall-superparamagnetic oxide nanomaterials (USPIOs). This polymer, PEG(5)-BP, can be used to exchange the hydrophobic surfactants commonly used in the synthesis of USPIOs very efficiently and at room temperature using a simple method in 1 h. The resulting nanoparticles, PEG(5)-BP-USPIOs are stable in water or saline for at least 7 months and display a near-zero ζ-potential at neutral pH. The longitudinal (r1) and transverse (r2) relaxivities were measured at a clinically relevant magnetic field (3 T), revealing a high r1 of 9.5 mM–1 s–1 and low r2/r1 ratio of 2.97, making these USPIOs attractive as T1-weighted MRI contrast agents at high magnetic fields. The strong T1-effect was demonstrated in vivo, revealing that PEG(5)-BP-USPIOs remain in the bloodstream and enhance its signal 6-fold, allowing the visualization of blood vessels and vascular organs with high spatial definition. Furthermore, the optimal relaxivity properties allow us to inject a dose 4 times lower than with other USPIOs. PEG(5)-BP-USPIOs can also be labeled using a radiolabeled-BP for visualization with single photon emission computed tomography (SPECT), and thus affording dual-modality contrast. The SPECT studies confirmed low RES uptake and long blood circulation times (t1/2 = 2.97 h). These results demonstrate the potential of PEG(5)-BP-USPIOs for the development of targeted multimodal imaging agents for molecular imaging.

Background-Endothelial dysfunction promotes atherosclerosis and precedes acute cardiovascular events. We investigated whether in vivo magnetic resonance imaging with the use of an albumin-binding contrast agent, gadofosveset, could detect endothelial damage associated with atherosclerosis in apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice. Furthermore, we tested whether magnetic resonance imaging could noninvasively assess endothelial function by measuring the endothelial-dependent vasodilation in response to acetylcholine. Methods and Results-ApoEϪ/Ϫ mice were imaged at 4, 8, and 12 weeks after commencement of a high-fat diet. Statin-treated ApoE Ϫ/Ϫ mice were scanned after 12 weeks of a high-fat diet. Wild-type mice were imaged before and 48 hours after injection of Russell's viper venom, an endothelial toxin. Delayed enhancement magnetic resonance imaging and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R 1 ) with progression of atherosclerosis in ApoE (R 1 ϭ3.0Ϯ0.65) mice showed less enhancement. Uptake of gadofosveset correlated with Evans blue staining, morphological changes of endothelial cells, and widening of the cell-cell junctions, suggesting that uptake occurs in regions of increased vascular permeability. Endothelial-dependent vasomotor responses showed vasoconstriction of the arteries of the ApoE Ϫ/Ϫ (Ϫ22.22Ϯ7.95%) and Russell's viper venom-injected (Ϫ10.37Ϯ17.60%) mice compared with wild-type mice (32.45Ϯ12.35%). Statin treatment improved endothelium morphology and function (Ϫ8.12Ϯ8.22%). Conclusions-We demonstrate the noninvasive assessment of endothelial permeability and function with the use of an albumin-binding magnetic resonance contrast agent. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim to restore the endothelium. (Circulation. 2012;126:707-719.)Key Words: atherosclerosis Ⅲ endothelial dysfunction Ⅲ gadofosveset Ⅲ magnetic resonance imaging Ⅲ permeability A therosclerosis is a chronic disease of the vessels and a major cause of death in Western societies. Dysfunction of the vascular endothelium triggers leukocyte transmigration, platelet activation, smooth muscle cell proliferation, and vasoconstriction, which collectively promote the development of atherosclerosis. 1 Additionally, damaged endothelium can precipitate the complications of atherosclerosis through vasospasm and thrombosis, causing life-threatening cardiovascular events. Clinical Perspective on p 719Transport across the normal endothelium occurs between endothelial cells (ECs) (intercellular pathway) and/or through the ECs (transcytosis). Intercellular junctions with a diameter of Ϸ2 nm allow transport of small water-soluble molecules up to that diameter, 2 whereas breaks in the tight junctions with a diameter of Ϸ20 nm 3,4 accommodate the influx of albumin (diameter of Ϸ6 nm) and Evans blue dye (EBD). At the molecular level, oxidized low-density lipoprotein (1) decreases...