Individually Stabilized, Superparamagnetic Nanoparticles with Controlled Shell and Size Leading to Exceptional Stealth Properties and High Relaxivities

Superparamagnetic iron oxide nanoparticles (SPION) have received immense interest for biomedical applications, with the first clinical application as negative contrast agent in magnetic resonance imaging (MRI). However, the first generation MRI contrast agents with dextran-enwrapped, polydisperse iron oxide nanoparticle clusters are limited to imaging of the liver and spleen; this is related to their poor colloidal stability in biological media and inability to evade clearance by the reticulo­endothelial system. We investigate the qualitatively different performance of a new generation of individually PEG-grafted core–shell SPION in terms of relaxivity and cell uptake and compare them to benchmark iron oxide contrast agents. These PEG-grafted SPION uniquely enable relaxivity measurements in aqueous suspension without aggregation even at 9.4 T magnetic fields due to their extraordinary colloidal stability. This allows for determination of the size-dependent scaling of relaxivity, which is shown to follow a <i>d</i>² dependence for identical core–shell structures. The here introduced core–shell SPION with ∼15 nm core diameter yield a higher <i>R</i>₂ relaxivity than previous clinically used contrast agents as well as previous generations of individually stabilized SPION. The colloidal stability extends to control over evasion of macrophage clearance and stimulated uptake by SPION functionalized with protein ligands, which is a key requirement for targeted MRI

Overlapping and Distinct Features of Cardiac Pathology in Inherited Human and Murine Ether Lipid Deficiency

Inherited deficiency in ether lipids, a subgroup of glycerophospholipids with unique biochemical and biophysical properties, evokes severe symptoms in humans resulting in a multi-organ syndrome. Mouse models with defects in ether lipid biosynthesis have widely been used to understand the pathophysiology of human disease and to study the roles of ether lipids in various cell types and tissues. However, little is known about the function of these lipids in cardiac tissue. Previous studies included case reports of cardiac defects in ether-lipid-deficient patients, but a systematic analysis of the impact of ether lipid deficiency on the mammalian heart is still missing. Here, we utilize a mouse model of complete ether lipid deficiency (Gnpat KO) to accomplish this task. Similar to a subgroup of human patients with rhizomelic chondrodysplasia punctata (RCDP), a fraction of Gnpat KO fetuses present with defects in ventricular septation, presumably evoked by a developmental delay. We did not detect any signs of cardiomyopathy but identified increased left ventricular end-systolic and end-diastolic pressure in middle-aged ether-lipid-deficient mice. By comprehensive electrocardiographic characterization, we consistently found reduced ventricular conduction velocity, as indicated by a prolonged QRS complex, as well as increased QRS and QT dispersion in the Gnpat KO group. Furthermore, a shift of the Wenckebach point to longer cycle lengths indicated depressed atrioventricular nodal function. To complement our findings in mice, we analyzed medical records and performed electrocardiography in ether-lipid-deficient human patients, which, in contrast to the murine phenotype, indicated a trend towards shortened QT intervals. Taken together, our findings demonstrate that the cardiac phenotype upon ether lipid deficiency is highly heterogeneous, and although the manifestations in the mouse model only partially match the abnormalities in human patients, the results add to our understanding of the physiological role of ether lipids and emphasize their importance for proper cardiac development and function

MP [¹¹C]Acetate PET-MRI performed in a 68-year-old patient with an elevated prostate-specific antigen (PSA) level (5.3ng/ml) at the time of imaging.

<p>(a) Axial 3-mm thick T2-w image (TR/TE/TI 4000/101/230ms) of the middle third of the prostate. The observers described a focal hypointense lesion in the left peripheral zone (T2w-positive). (b) On the ADC map, the lesion presents as a focal area with low signal intensity, with corresponding high signal intensity on b800s/mm2 images (DWI-positive). (c-d) ¹H-MRSI shows an elevated choline/citrate ratio in the suspicious region (¹H-MRSI-positive). (e-f) The DCE-MRI shows a focal contrast enhancement for the suspicious area (e –T1w image 80s post contrast, f—K^trans map overlaid on T2w image) (DCE-positive). (g) [¹¹C]Acetate PET-MRI shows a focal tracer hotspot in this area with a maximal SUV 6.5 (PET-positive). Multiparametric [¹¹C]Acetate PET-MRI was rated true-positive in this patient. (h) Histopathological work-up after RPE confirmed a high-grade PCa Gleason 9 (5+4) tumor.</p

Histopathological characteristics of the dominant intraprostatic lesion and maximum standard uptake values from [¹¹C]Acetate.

<p>Histopathological characteristics of the dominant intraprostatic lesion and maximum standard uptake values from [¹¹C]Acetate.</p

ROC curves for all lesions of the prostate independent of the Gleason score depict the diagnostic accuracy of all investigated MP reading approaches.

<p>ROC curves for all lesions of the prostate independent of the Gleason score depict the diagnostic accuracy of all investigated MP reading approaches.</p

Multiparametric [¹¹C]Acetate positron emission tomography-magnetic resonance imaging in the assessment and staging of prostate cancer

<div><p>Background</p><p>The aim of this study was to evaluate whether MP [¹¹C]Acetate PET-MRI enables an accurate differentiation of benign and malignant prostate tumors as well as local and distant staging.</p><p>Materials and methods</p><p>Fifty-six consecutive patients fulfilling the following criteria were included in this IRB-approved prospective study: elevated PSA levels or suspicious findings at digital rectal examination or TRUS; and histopathological verification. All patients underwent MP [¹¹C]Acetate PET-MRI of the prostate performed on separate scanners with PET/CT using [¹¹C]Acetate and 3T MP MR imaging. Appropriate statistical tests were used to determine diagnostic accuracy, local and distant staging.</p><p>Results</p><p>MP imaging with two MRI parameters (T2w and DWI) achieved the highest sensitivity, specificity, and diagnostic accuracy of 95%, 68.8%, and 88%, with an AUC of 0.82 for primary PCa detection. Neither assessments with a single parameter (AUC, 0.54–0.79), nor different combinations with up to five parameters (AUC, 0.67–0.79) achieved equally good results. MP [¹¹C]Acetate PET-MRI improved local staging with a sensitivity, specificity, and diagnostic accuracy of 100%, 96%, and 97% compared to MRI alone with 72.2%, 100%, and 95.5%. MP [¹¹C]Acetate PET-MRI correctly detected osseous and liver metastases in five patients.</p><p>Conclusions</p><p>MP [¹¹C]Acetate PET-MRI merges morphologic with functional information, and allows insights into tumor biology. MP [¹¹C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) yields the highest diagnostic accuracy. The addition of more parameters does not improve diagnostic accuracy of primary PCa detection. MP [¹¹C]Acetate PET-MRI facilitates improved local and distant staging, providing “one-stop” staging in patients with primary PCa, and therefore has the potential to improve therapy.</p><p>Patient summary</p><p>In this report we investigated MP [¹¹C]Acetate PET-MRI for detection, local and distant staging of prostate cancer. We demonstrate that MP [¹¹C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) achieves the best diagnostic accuracy for primary prostate cancer detection and that MP [¹¹C]Acetate PET-MRI enables an improved local and distant staging.</p></div