Matthias Taupitz

Phase I Clinical Evaluation of Citrate-coated Monocrystalline Very Small Superparamagnetic Iron Oxide Particles as a New Contrast Medium for Magnetic Resonance Imaging

Rationale and Objectives:To evaluate the safety and pharmacokinetics of a newly developed MR contrast medium consisting of very small superparamagnetic iron oxide particles (VSOP) coated with citrate (VSOP-C184) in a clinical phase I trial. Methods:A total of 18 healthy subjects received either VSOP-C184 (core diameter: 4 nm; total diameter: 7 ± 0.15 nm; relaxivities in water at 0.47 T (T1) 18.7 and (T2) 30 L/(mmol*seconds)) at doses of 0.015, 0.045, or 0.075 mmol Fe/kg (n = 5 per dose) or placebo (n = 1 per dose) as intravenous injections. Physical status and vital parameters were recorded, blood samples were collected for clinical chemistry and relaxometry (0.94 T), and urinalyses were performed before and for up to 2 weeks after administration. Results:No serious adverse events occurred. The most pronounced adverse events occurred in 2 subjects of the highest dose group 45–50 minutes after injection. These were a drop in blood pressure and a drop in oxygen saturation, which were considered to be possibly drug-related and rapidly resolved without medication. Otherwise, no relevant changes in vital and laboratory parameters were observed. The parameters of iron metabolism exhibited short-term, dose-related changes. The injection of VSOP-C184 decreased T1 relaxation time of blood below 100 milliseconds for 18 minutes after a dose of 0.045 μmol Fe/kg and for 60 minutes after 0.075 μmol Fe/kg. Conclusions:The favorable data on the safety, tolerability, and efficacy of VSOP-C184 justify further clinical phase II and III trials as a contrast medium for MRI.

Local staging of rectal cancer: the current role of MRI

With the advent of powerful gradient coil systems and high-resolution surface coils, magnetic resonance imaging (MRI) has recently extended its role in the staging of rectal cancer. MRI is superior to endorectal ultrasound, the most widely used staging modality in patients with rectal tumors, in that it visualizes not only the intestinal wall but also the surrounding pelvic anatomy. The crucial advantage of MRI is not that it enables exact T-staging but precise evaluation of the topographic relationship of a tumor to the mesorectal fascia. This fascia is the most important anatomic landmark for the feasibility of total mesorectal excision, which has evolved into the standard operative procedure for the resection of cancer located in the middle or lower third of the rectum. MRI is currently the only imaging modality that is highly accurate in predicting whether or not it is likely that a tumor-free margin can be achieved and thus provides important information for planning of an effective therapeutic strategy, especially in patients with advanced rectal cancer.

Monomer-coated very small superparamagnetic iron oxide particles as contrast medium for magnetic resonance imaging: preclinical in vivo characterization.

Wagner S, Schnorr J, Pilgrimm H, et al. Monomer-coated very small superparamagnetic iron oxide particles as contrast medium for magnetic resonance imaging: preclinical in vivo characterization. Invest Radiol 2002;37:167–177. rationale and objectives. Preclinical in-vivo characterization of a newly developed MR contrast medium consisting of very small superparamagnetic iron oxide particles (VSOP) coated with citrate (VSOP-C184). methods. VSOP-C184 (core diameter: 4 nm; total diameter: 8.6 nm; relaxivities in water at 0.94 T (T1) 20.1 and (T2) 37.1 l/[mmol*sec]) was investigated to determine its pharmacokinetics, efficacy, acute single dose toxicity, repeated dose toxicity, and genotoxicity. results. The plasma elimination half-life at 0.045 mmol Fe/kg was 21.3 ± 5.5 minutes in rats and 36.1 ± 4.2 minutes in pigs, resulting in a T1-relaxation time of plasma of < 100 milliseconds for 30 minutes in pigs. The particles are mainly cleared via the phagocytosing system of the liver. MR angiography at a dose of 0.045 mmol Fe/kg shows an excellent depiction of the thoracic and abdominal vasculature in rats and of the coronary arteries in pigs. The LD50 in mice is > 17.9 mmol Fe/kg. A good tolerance and safety profile was found. conclusions. The experiments indicate, that VSOP-C184 may be a well tolerated and safe contrast medium for MR imaging that can be effectively used for MR angiography including visualization of the coronary arteries.

Differentiation of hepatic hemangiomas from metastases by dynamic contrast-enhanced MR imaging

Twenty-nine patients with hepatic hemangiomas (n = 14) and hepatic metastases (n = 15) underwent magnetic resonance (MR) imaging prior to and after an intravenous bolus injection of Gd-diethylenetriamine pentaacetic acid (0.2 mmol/kg). Before contrast application, a T2-weighted spin echo sequence (SE 1,600/105) and a T1-weighted gradient echo sequence (GE 315/14/90 degrees pulse angle) were performed. Beginning with injection of the contrast agent, a dynamic study was conducted for 10 min using a moderately T1-weighted gradient echo sequence (GE 40/14/40 degrees) with an acquisition time of 10.2 s per image. Delayed (11 min) and late (60 min) postcontrast images were obtained using a T1-weighted sequence (GE 315/14/90 degrees). In the dynamic study (0-10 min) the hemangiomas were characterized by peripheral contrast enhancement and a subsequent hyperintense fill-in. The metastases showed very mixed patterns of enhancement after contrast administration, and their signal intensity remained low compared with that of the hepatic tissue. In the delayed postcontrast examination (11 min) the hemangiomas had a very high and homogeneous signal intensity and the metastases were characterized by an inhomogeneous, hypointense to isointense signal. The contrast between tumor and liver [signal-difference-to-noise ratio (SD/N)] was higher for all hemangiomas than it was for the metastases. In the T2-weighted precontrast examination, on the other hand, five hemangiomas and seven metastases showed an overlap in the SD/N. The late postcontrast images (60 min) did not yield any further diagnostic information. We conclude that the combination of a dynamic MR study with delayed postcontrast T1-weighted imaging is a useful method of diagnosing hepatic hemangiomas.

Evaluation of normal prostate tissue, chronic prostatitis, and prostate cancer by quantitative perfusion analysis using a dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence.

Objective:To quantify independent pharmacokinetic parameters for differentiation of prostate pathology. Material and Methods:Twenty-seven patients with biopsy-proven prostate cancer (PSA: 1.4–16.1 ng/mL) underwent magnetic resonance imaging with a new dynamic contrast-enhanced, inversion-prepared dual-contrast gradient echo sequence (T1/T2*-weighted, 1.65 seconds temporal resolution) using a combined endorectal/body phased-array coil at 1.5 Tesla. Perfusion, blood volume, mean transit time, delay, and dispersion were calculated using a sequential 3-compartment model. Twenty-three patients underwent prostatectomy. For histologic correlation a pathologist mapped areas of normal prostate tissue, chronic prostatitis, and prostate cancer (total of 63 areas) on histologic sections corresponding to the magnetic resonance imaging planes. Results:Compared with normal prostate tissue, low-grade cancer (Gleason score ≤6) only showed higher perfusion (1.01 mL/cm3/min vs. 0.26 mL/cm3/min, P = 0.050), whereas high-grade cancer showed higher perfusion (1.21 mL/cm3/min vs. 0.26 mL/cm3/min, P ≤ 0.001), higher blood volume (1.44% vs. 0.95%, P = 0.005), shorter mean transit time (3.55 seconds vs. 4.40 seconds, P = 0.019), shorter delay (10.15 seconds vs. 13.36 seconds, P = 0.015), and smaller dispersion (8.56 seconds vs. 12.11 seconds, P = 0.020). High-grade cancer showed higher perfusion than chronic prostatitis (1.21 mL/cm3/min vs. 0.90 mL/cm3/min, P = 0.041). Chronic prostatitis showed higher perfusion (0.90 mL/cm3/min vs. 0.26 mL/cm3/min, P = 0.006), higher blood volume (1.53% vs. 0.95%, P = 0.046), shorter delay (11.42 seconds vs. 13.36 seconds, P = 0.015), and smaller dispersion (10.49 seconds vs. 12.11 seconds, P = 0.020) than normal prostate tissue. There were no statistically significant differences between low-grade and high-grade cancer or between low-grade cancer and chronic prostatitis. Conclusion:The pharmacokinetic parameters investigated, especially perfusion, allow statistically significant in situ differentiation of normal prostate tissue from cancer and chronic prostatitis and of high-grade cancer from chronic prostatitis.

First-pass whole-body magnetic resonance angiography (MRA) using the blood-pool contrast medium gadofosveset trisodium : Comparison to gadopentetate dimeglumine

Objectives:To evaluate gadofosveset trisodium for first-pass magnetic resonance angiography (MRA) in the setting of whole-body MRA (WB-MRA). Materials and Methods:Forty patients were examined using either 10 mL gadofosveset trisodium (n = 20) or 30 mL gadopentetate dimeglumine (n = 20), followed by arterial-phase imaging of 4 consecutive anatomic regions. Signal intensity was measured in 2 vessels per region. Relative contrast values (RC) were calculated. Arterial contrast, venous overlay, and image quality were rated by 2 radiologists. The Mann–Whitney U test was used to test for significance. Results:Compared with gadopentetate dimeglumine, gadofosveset trisodium enhanced imaging revealed higher RC values in 2 vessel regions, with the differences being significant in 3 of 4 vessel segments. Gadofosveset trisodium revealed lower RC values in 2 regions with significant differences in 2 segments. Qualitative evaluation revealed higher ratings for gadofosveset trisodium regarding all 3 criteria with significant differences in 2 regions. Conclusions:Gadofosveset trisodium serves well for first-pass imaging in WB-MRA.

Assessment of vascular remodeling under antiangiogenic therapy using DCE-MRI and vessel size imaging†

To assess vascular remodeling in tumors during two different antiangiogenic therapies with dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and vessel size imaging and to evaluate the vessel size index (VSI) as a novel biomarker of therapy response.

Gadolinium-enhanced MR angiography of the breast: Is breast cancer associated with ipsilateral higher vascularity?

Abstract The aim of this study was to assess a possible association between breast malignancy and ipsilateral higher vascularity on gadolinium-enhanced MR angiography. One hundred six patients were examined by dynamic gadolinium-enhanced 3D MR imaging. Magnetic resonance angiographic views were generated by image subtraction and maximum intensity projection. The study included 85 patients with unilateral malignant breast neoplasms and 21 with unilateral benign lesions. Three blinded readers independently reviewed the MR angiograms after masking the lesions and the corresponding contralateral sites. The readers were asked to determine whether vascularity was higher on the right side, higher on the left side, or equal on both sides. The results were analyzed by the Kappa statistic and Pearsons chi-square test. The blood vessels of the breasts were clearly seen in all cases. There was good agreement among the observers (kappa > 0.54 ) in assessing vascularity on both sides. Breasts harboring malignant neoplasms were found to have a higher vascularity than the contralateral breasts (p < 0.005). This sign of malignancy had a sensitivity of 76.5 %, a specificity of 57 %, and an accuracy of 72.6 %. Blood vessels of the breast can be depicted by MR angiography. Unilateral malignant neoplasms are associated with a higher ipsilateral vascularity. In conjunction with other indications of malignancy on gadolinium-enhanced MR images, a higher ipsilateral vascularity may serve as an additional sign of malignancy.

Highly monodisperse water-dispersable iron oxide nanoparticles for biomedical applications

We demonstrate a unique approach for preparing high quality iron oxide (Fe3O4) nanoparticles functionalized by newly developed multifunctional dendron ligands for biomedical applications. These particles are suitable for magnetic resonance imaging (MRI), highly stable in aqueous solutions as well as physiological media and not cytotoxic. In particular, oleic acid capped Fe3O4 particles (d = 12 ± 0.8 nm) were modified in a ligand exchange process by investigating several dendron ligands of variable size and an adjustable number of polar end groups. The dendron based ligands lead only to a slight increase in hydrodynamic diameter of the nanoparticles after the ligand exchange process (∼6 nm). They also allow an adjustment of the particle polarity as well as a gradually variable surface functionalization. Light scattering, transmission electron microscopy, and visible spectroscopy studies show consistently that the dendron-capped iron oxide nanoparticles exhibit excellent stability in various physiological media as well as aqueous solutions in a broad pH range. It is also demonstrated by magnetic resonance studies that the magnetic relaxivity is almost not affected by the ligand exchange. Therefore, such small particles might be of specific interest for cardiovascular MRI and MRI of extravascular targets. In addition, the present approach opens new possibilities for the specific linking of biomolecules to the particle surface, which can be beneficial for various biological sensing and therapeutic applications. The cytotoxicity of the Fe3O4 nanoparticles was evaluated using the WST-8 assay. In the examined concentration range up to 100 μg Fe/mL no significant decrease in cell viability was detected.

Protease-Specific Nanosensors for Magnetic Resonance Imaging

Imaging of enzyme activity is a central goal of molecular imaging. With the introduction of fluorescent smart probes, optical imaging has become the modality of choice for experimental in vivo detection of enzyme activity. Here, we present a novel high-relaxivity nanosensor that is suitable for in vivo imaging of protease activity by magnetic resonance imaging. Upon specific protease cleavage, the nanoparticles rapidly switch from a stable low-relaxivity stealth state to become adhesive, aggregating high-relaxivity particles. To demonstrate the principle, we chose a cleavage motif of matrix metalloproteinase 9 (MMP-9), an enzyme important in inflammation, atherosclerosis, tumor progression, and many other diseases with alterations of the extracellular matrix. On the basis of clinically tested very small iron oxide particles (VSOP), the MMP-9-activatable protease-specific iron oxide particles (PSOP) have a hydrodynamic diameter of only 25 nm. PSOP are rapidly activated, resulting in aggregation and increased T2*-relaxivity.