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Published online before print March 14, 2002, 10.1148/radiol.2232010241
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(Radiology 2002;223:432-438.)
© RSNA, 2002

Experimental Studies

Contrast-enhanced Blood-Pool MR Angiography with Optimized Iron Oxides: Effect of Size and Dose on Vascular Contrast Enhancement in Rabbits1

Thomas Allkemper, MD, Christoph Bremer, MD, Lars Matuszewski, MD, Wolfgang Ebert, PhD and Peter Reimer, MD

1 From the Department of Clinical Radiology, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48129 Münster, Germany (T.A., C.B., L.M., P.R.); and Schering AG, Berlin, Germany (W.E.). Received January 8, 2001; revision requested February 14; revision received August 20; accepted October 1. Address correspondence to T.A.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To investigate intravascular enhancement of bolus-injectable small and ultrasmall superparamagnetic iron oxides (USPIOs) of different particle sizes and relaxivities for first-pass and blood-pool magnetic resonance (MR) angiography.

MATERIALS AND METHODS: Iron oxides with different particle sizes (hydrodynamic diameters, 21, 33, 46, and 65 nm) were bolus injected intravenously at three doses (10, 20, and 40 µmol per kilogram body weight). An extracellular contrast agent (gadopentetate dimeglumine) served as a control. MR angiography was performed multiple times after intravenous injection (5–120 minutes and 24 hours later). Signal enhancement was calculated from signal intensity measurements in the abdominal aorta and renal and iliac arteries.

RESULTS: Highest enhancement was seen during the first pass with all contrast agents. USPIO enhancement in the abdominal aorta increased significantly with decreasing particle size (65 nm vs 33 nm, 65 nm vs 21 nm; P < .01).

CONCLUSION: The smallest iron oxide provided signal enhancement comparable with that of gadopentetate dimeglumine at 40 µmol iron per kilogram for first-pass investigations, with prolonged signal enhancement up to 25 minutes, allowing multiple measurements after injection of a single bolus.

© RSNA, 2002

Index terms: Contrast media, comparative studies • Contrast media, experimental studies • Gadolinium • Magnetic resonance (MR), contrast media • Magnetic resonance (MR), vascular studies, 94.12942, 94.12943, 94.12949


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Breath-hold high-spatial-resolution three-dimensional gradient-echo sequences combined with intravenous injection of gadolinium chelates for magnetic resonance (MR) angiography have been established in clinical practice (1,2).

Injected gadolinium chelates reduce the T1 relaxation time of blood during the first pass and enhance intravascular signal intensity (SI) on T1-weighted images. To obtain high intravascular signal, low-molecular-weight contrast media are typically injected at rates of 2–5 mL/sec (eg, 0.1–0.2 mmol per kilogram body weight gadopentetate dimeglumine) for first-pass MR angiography. These low-molecular gadolinium chelates show rapid extravasation into the interstitium and are rapidly excreted by the kidneys (t1/2 {approx} 1.5 hours) (1–4).

The time window for data acquisition is therefore mainly limited to the first pass. Several contrast media offering a blood-pool effect and allowing acquisition of high–spatial-resolution data sets of multiple vascular regions during the steady state are currently being investigated. Various designs of blood-pool agents have been investigated that use gadolinium temporarily bound to plasma proteins, large gadolinium-bearing molecules with no or little renal extravasation, or ultrasmall superparamagnetic iron oxides (USPIOs) with long circulation times (5–11).

The potential of superparamagnetic iron oxides for contrast material–enhanced blood-pool MR angiography has been described by Frank et al (12). The uptake rate of iron oxide into the reticuloendothelial system is inversely related to its particle size. Thus, decreasing particle size results in prolonged intravascular retention (5–11).

The purpose of our study was to investigate the intravascular enhancement of four bolus-injectable USPIOs (SH U 555 A and USPIOs L, M, and S) of different particle sizes and relaxivities for first-pass and blood-pool MR angiography up to 24 hours after injection.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Animals
The study was approved by our institution’s animal care committee. Experiments were carried out in 52 female New Zealand White rabbits weighing approximately 3–4 kg, which were anesthetized with intramuscular injection of 50.0 mg/kg ketamine hydrochloride (Sanofi-CHEVA, Düsseldorf, Germany) and 2.5 mg/kg xylazine hydrochloride (Medistar, Holzwickede, Germany). A 24-gauge intravenous access catheter was placed into an ear vein for contrast media injections.

Contrast Media
SH U 555 A (Resovist; Schering, Berlin, Germany) consists of superparamagnetic iron oxide particles coated with carboxydextran, with a relaxivity r1 of approximately 25 s-1mM-1 and a relaxivity r2 of approximately 164 s-1mM-1 at 0.47 T, 37°C in water. The size of the iron oxide core is 3–5 nm, as measured with electron microscopy. Photon-correlation spectroscopy enabled documentation of a mean hydrodynamic diameter of approximately 65 nm (13,14). Three "Resovist-type" bolus-injectable carboxydextran superparamagnetic iron oxides (USPIOs L, M, and S [Schering]) with mean hydrodynamic diameters of 46, 33, and 21 nm, respectively, were prepared by using a fractionation procedure from the original formulation of SH U 555 A (15). Relaxation times T1 and T2 of SH U 555 A and the three carboxydextran USPIOs were measured at 37°C in water (0.47 T [minispec pc20; Bruker, Karlsruhe, Germany]). Relaxivity values (r1, r2) were calculated from relaxation rates R1 (= 1/T1) and R2 (= 1/T2) at different concentrations by using linear regression (Table 1).


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  		TABLE 1. Physical Properties of Iron Oxide Particles used for Contrast-enhanced MR Angiography

 
Each of these four iron oxide agents was bolus injected intravenously at doses of 10, 20, and 40 µmol of iron per kilogram. Four rabbits were studied for each dose and particle size (48 rabbits total). MR angiography was started immediately after bolus injection of contrast media, followed by a 3.0-mL saline flush injected in 2 seconds.

Furthermore, 0.2 mmol/kg gadopentetate dimeglumine (Magnevist; Schering) served as a control in four animals (52 animals total). MR angiography was performed before and immediately after intravenous injection. Measurements were repeated 5, 10, 15, 25, 40, 50, 60, and 120 minutes after, as well as 24 hours after contrast medium application.

MR Imaging
All animals underwent MR imaging (Magnetom Vision; Siemens, Erlangen, Germany) at 1.5 T with a body phased-array coil. Images of the major abdominal vessels were obtained with a coronally oriented three-dimensional fast low-angle shot (FLASH) MR angiographic sequence (repetition time msec/echo time msec, 5.8/1.8; matrix, 192 x 512 pixels; section thickness, 2.0 mm). A slab of 60.0 mm with 30 sections was acquired in 35 seconds. Imaging parameters and radiofrequency transmit and receive attenuations were set for precontrast images and kept constant for postcontrast images to allow precise quantitative analysis of SI changes.

Image Analysis
For quantitative image analysis, SI was measured with region of interest placement within the abdominal aorta, iliac arteries, and renal arteries by two investigators (C.B., L.M.). Region of interest size was chosen as two thirds the maximum diameter of each structure. Relative signal enhancement was calculated by using SI measurements before (SIpre) and after (SIpost) contrast material application by using the formula: [(SIpost - SIpre)/SIpre] x 100.

Statistical evaluation was performed by using analysis of variance, with Bonferroni correction for multiple comparisons. For each time point, separate statistical analysis was performed by comparing all contrast media given in various doses for each investigated vessel. A P value of .01 or less was considered to indicate a significant difference (21,22). Maximum intensity projection images were calculated from MR angiographic data for illustration of quantitative measurements.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Relaxivity Values
Relaxivity values for SH U 555 A and the three carboxydextran USPIOs showed decreasing r1 and especially r2 values with decreasing particle size, resulting in a lower r2/r1 ratio (Table 1).

Image Analysis
Relative signal enhancement was highest during the first pass for all contrast agents and for all doses in the abdominal aorta, renal arteries, and iliac arteries (Table 2, Fig 1). Increasing doses resulted in increasing enhancement values during the first pass and blood-pool phase for all contrast agents. During the first pass, peak enhancement increased significantly for all doses, with decreasing particle size in all investigated vessel segments (65 vs 21 nm, P < .01), except for the iliac arteries at a dose of 10 µmol of iron per kilogram (65 vs 21 nm, P > .05).


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  		TABLE 2. Relative Enhancement for Different Particle Sizes of 65-21 nm at Highest Dose of 40 µmol Fe/kg Compared with Gadopentetate Dimeglumine

 


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  		Figure 1a. Graphs show relative enhancement for particle sizes of 65-21 nm at different doses, as compared with that of gadopentetate dimeglumine (abdominal aorta). Enhancement during the first pass and blood-pool phase increased at increasing doses for all contrast agents. Peak enhancement during the first pass increased significantly with decreasing particle size. (a-d) Diamond = USPIO 40 µmol, square = USPIO 20 µmol, circle = USPIO 10 µmol, triangle = gadopentetate dimeglumine. (e) Graph shows relative enhancement for different particle sizes at a fixed dose of 40 µmol of iron per kilogram. The smallest particle sizes of 21 and 33 nm at the highest dose of 40 µmol iron per kilogram provided the strongest signal enhancement. BW = body weight, dashed line = USPIO 65 nm, circle = USPIO 46 nm, square = USPIO 33 nm, diamond = USPIO 21 nm, triangle = gadopentetate dimeglumine.

 


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  		Figure 1b. Graphs show relative enhancement for particle sizes of 65-21 nm at different doses, as compared with that of gadopentetate dimeglumine (abdominal aorta). Enhancement during the first pass and blood-pool phase increased at increasing doses for all contrast agents. Peak enhancement during the first pass increased significantly with decreasing particle size. (a-d) Diamond = USPIO 40 µmol, square = USPIO 20 µmol, circle = USPIO 10 µmol, triangle = gadopentetate dimeglumine. (e) Graph shows relative enhancement for different particle sizes at a fixed dose of 40 µmol of iron per kilogram. The smallest particle sizes of 21 and 33 nm at the highest dose of 40 µmol iron per kilogram provided the strongest signal enhancement. BW = body weight, dashed line = USPIO 65 nm, circle = USPIO 46 nm, square = USPIO 33 nm, diamond = USPIO 21 nm, triangle = gadopentetate dimeglumine.

 


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  		Figure 1c. Graphs show relative enhancement for particle sizes of 65-21 nm at different doses, as compared with that of gadopentetate dimeglumine (abdominal aorta). Enhancement during the first pass and blood-pool phase increased at increasing doses for all contrast agents. Peak enhancement during the first pass increased significantly with decreasing particle size. (a-d) Diamond = USPIO 40 µmol, square = USPIO 20 µmol, circle = USPIO 10 µmol, triangle = gadopentetate dimeglumine. (e) Graph shows relative enhancement for different particle sizes at a fixed dose of 40 µmol of iron per kilogram. The smallest particle sizes of 21 and 33 nm at the highest dose of 40 µmol iron per kilogram provided the strongest signal enhancement. BW = body weight, dashed line = USPIO 65 nm, circle = USPIO 46 nm, square = USPIO 33 nm, diamond = USPIO 21 nm, triangle = gadopentetate dimeglumine.

 


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  		Figure 1d. Graphs show relative enhancement for particle sizes of 65-21 nm at different doses, as compared with that of gadopentetate dimeglumine (abdominal aorta). Enhancement during the first pass and blood-pool phase increased at increasing doses for all contrast agents. Peak enhancement during the first pass increased significantly with decreasing particle size. (a-d) Diamond = USPIO 40 µmol, square = USPIO 20 µmol, circle = USPIO 10 µmol, triangle = gadopentetate dimeglumine. (e) Graph shows relative enhancement for different particle sizes at a fixed dose of 40 µmol of iron per kilogram. The smallest particle sizes of 21 and 33 nm at the highest dose of 40 µmol iron per kilogram provided the strongest signal enhancement. BW = body weight, dashed line = USPIO 65 nm, circle = USPIO 46 nm, square = USPIO 33 nm, diamond = USPIO 21 nm, triangle = gadopentetate dimeglumine.

 


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  		Figure 1e. Graphs show relative enhancement for particle sizes of 65-21 nm at different doses, as compared with that of gadopentetate dimeglumine (abdominal aorta). Enhancement during the first pass and blood-pool phase increased at increasing doses for all contrast agents. Peak enhancement during the first pass increased significantly with decreasing particle size. (a-d) Diamond = USPIO 40 µmol, square = USPIO 20 µmol, circle = USPIO 10 µmol, triangle = gadopentetate dimeglumine. (e) Graph shows relative enhancement for different particle sizes at a fixed dose of 40 µmol of iron per kilogram. The smallest particle sizes of 21 and 33 nm at the highest dose of 40 µmol iron per kilogram provided the strongest signal enhancement. BW = body weight, dashed line = USPIO 65 nm, circle = USPIO 46 nm, square = USPIO 33 nm, diamond = USPIO 21 nm, triangle = gadopentetate dimeglumine.

 
Peak enhancement of contiguous particle sizes during the first pass differed significantly for only 33, 46, and 65 nm at a dose of 40 µmol of iron per kilogram in the abdominal aorta (33 vs 46 nm, P < .01; 46 vs 65 nm; P < .01) and at a dose of 20 µmol of iron per kilogram in the renal and iliac arteries (33 vs 46 nm, P < .01; 46 vs 65 nm; P < .01), respectively. Peak enhancement values of 21 and 33 nm during the first pass differed significantly in only the renal arteries at a dose of 20 µmol of iron per kilogram (21 vs 33 nm, P < .01). The highest dose (40 µmol of iron per kilogram) of the smallest investigated particle size (21 nm) showed the strongest signal enhancement during the first pass, which did not differ significantly from that obtained with a double dose of gadopentetate dimeglumine during the first pass (P > .01). Statistical significance was tested as described in Materials and Methods.

During the blood-pool phase, relative intravascular signal enhancement in the abdominal aorta at doses of 20 and 40 µmol of iron per kilogram was significantly (P < .01) higher for the two smaller preparations (21 and 33 nm, respectively), as compared with the two larger preparations (46 and 65 nm, respectively), resulting in visible enhancement up to 25 minutes after intravenous injection (SI in abdominal aorta [21 nm, first pass], 1,135.0 ± 58.1; SI in abdominal aorta [21 nm, after 25 minutes], 532.9 ± 66.4 [40 µmol of iron per kilogram]) (Table 2). Relative signal enhancement was highest for the highest dose of 40 µmol of iron per kilogram for all preparations and all vessel segments during the first pass and the blood-pool phase (Figs 2, 3).



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  		Figure 2. Iron oxide-enhanced (33-nm mean particle size, 40 µmol of iron per kilogram) three-dimensional FLASH MR angiographic images (5.8/1.8) acquired at given intervals after contrast material application. Maximum intensity projection images show strong initial vessel enhancement. Vessel contrast decreases slowly, and vessels remain visible up to 25 minutes after injection because of prolonged blood half life (eg, in the abdominal aorta [arrowheads]).

 


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  		Figure 3. Iron oxide-enhanced (21-nm mean particle size, 40 µmol of iron per kilogram) three-dimensional FLASH MR angiographic images (5.8/1.8) acquired at given intervals after contrast material application. Maximum intensity projection images show improved vessel contrast, as compared with the mean particle size of 33 nm (eg, in the abdominal aorta [arrowheads]) in Figure 2. Again, smaller vessels like the iliac arteries (arrows) remain visible up to 25 minutes after contrast material application.

 
Intravascular enhancement following intravenous injection of gadopentetate dimeglumine significantly decreased after the first pass (P < .01) (SI of abdominal aorta [gadopentetate dimeglumine, first pass], 1,253.6 ± 86.3; SI of abdominal aorta [gadopentetate dimeglumine, after 25 minutes], 199.3 ± 61.7) (Table 2, Fig 4).



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  		Figure 4. Gadopentetate dimeglumine-enhanced (0.2 mmol/kg) three-dimensional FLASH MR angiographic images (5.8/1.8) acquired at given intervals after contrast material application. Maximum intensity projection images show strong initial vessel enhancement, with rapid loss of vessel contrast (eg, in abdominal aorta [arrowheads]), already visible 5 minutes after contrast material application.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Several concepts for the development of iron oxide-based blood-pool agents for contrast-enhanced MR angiography are currently under investigation in several studies; however, there is still a lack of data regarding optimization of iron oxides in terms of particle size, dose, and relaxivity.

Decreasing particle size of iron oxides results in lower r2/r1 ratios because of a pronounced decrease of T2* effects and a decreased uptake rate of iron oxides into the reticuloendothelial system (5–11). The combination of a prolonged intravascular retention with an improved r2/r1 ratio should result in an optimized iron oxide–based blood-pool contrast medium (23). Therefore, we investigated the influence of particle size, dose, and relaxivity of bolus-injectable iron oxides on intravascular signal enhancement during the first pass and blood-pool phase, as compared with gadolinium-enhanced MR angiography in a rabbit model.

Our results demonstrate that bolus-injectable carboxydextran-USPIO preparations provide an excellent T1 effect during the first pass and provide prolonged signal enhancement over time with decreasing particle sizes and increasing doses. Particle sizes of 21 and 33 nm revealed the strongest initial intravascular enhancement at the highest dose of 40 µmol of iron per kilogram, followed by a slow SI decrease, with significant enhancement persisting up to at least 25 minutes after injection.

Investigators in other studies performed at 0.5 T reported nearly constant signal enhancement levels up to 30 minutes after injection as well but also noted variations in SI, most likely because of susceptibility effects caused by prolonged echo times at 0.5 T (24). However, with use of significantly shorter echo times, these effects were not evident in our image data, despite the higher field strength of 1.5 T. These observations closely correlate with general relaxation theory (25).

Our relaxivity measurements documented a decrease in r1 and r2 with decreasing particle size. The effect is more pronounced in r2 and smaller particle preparations, with mean diameters of 21 and 33 nm, respectively, providing the lowest r2/r1 ratios (Table 1). These results closely correlate with findings of previous studies (16,26) demonstrating relaxivity as a function of iron oxide particle size, depending on iron oxide core size as well as hydrodynamic particle size in solution, which is influenced by the individual coating. Efforts have been undertaken to develop different surface coatings because of their important roles in pharmacokinetics and biodistribution, which are influenced by factors such as surface charge, interaction with blood components (protein absorption), and opsonization (26). By considering these facts, a variety of iron oxide preparations has been investigated regarding their properties as potential blood-pool contrast agents (Table 1) (8,9,12,17,26–38).

AMI-25 and SH U 555 A were initially developed for reticuloendothelial system–specific imaging of the liver and spleen and were also investigated regarding their applicability for contrast-enhanced MR angiography of the portal venous system (13,27,39,40,41–44). Investigators in further investigations (8,9,12,20,26,35,37) demonstrated that preparations with smaller particle sizes, such as MION-37, MION-46, NC100150, or AMI-227, a derivative of AMI-25, provide a significant increase in plasma half life and T1 effect. Among these substances, NC100150 reveals the smallest particle size, with a mean hydrodynamic diameter of 11.9 nm and the lowest r2/r1 ratio of 1.6 (Table 1). This seems to render NC100150 ideal for high-field MR angiography, since r1 decreases with increasing field strength more strongly the higher the value of the r2/r1 ratio. Comparative investigations of NC100150 and MION-46 (36), providing r2/r1 ratios at 20 MHz that are comparable with those of USPIO S and AMI-227, showed 36% greater r1 relaxivity of NC100150 at 50 MHz.

However, another important contribution to clinical applications of iron oxide agents arises from nonuniform spatial distribution in the vascular space, which is the basis for susceptibility effects that are independent of the r2/r1 ratio measured in water. These effects depend on concentration and magnetization of the particles at a given field strength. The high field limit of magnetization, or Msat, is 18% greater for NC100150 at 50 MHz than that for MION-46. In addition, investigators in first-pass myocardial perfusion studies (45) reported that low doses of NC100150 in combination with short echo times are required to minimize T2* effects, which predominately affected intravascular signal at higher doses (3–4 mg of iron per kilogram) and field strength (1.5 T). As mentioned before, none of the iron oxide preparations tested in the current study (SH U 555 A, and USPIOs L, M, and S) showed visible signal distortions at 1.5 T because of susceptibility effects.

SH U 555 A has passed phase 3 clinical trials and has been approved in Europe. It has proven to be a safe and effective contrast agent that can be safely bolus injected into humans with no relevant side effects and thus can be used for first-pass investigations (39–41,46). It can be speculated that USPIOs L, M, and S will exhibit pharmacologic characteristics similar to those of SH U 555 A and therefore will also be bolus injectable for first-pass examinations. Indeed, SH U 555 C (a carboxydextran-USPIO formulation very similar to USPIO S) has recently been bolus injected into healthy volunteers in a phase 1 clinical trial, without relevant side effects (47). However, iron oxide preparations such as AMI-25 and AMI-227 may not be bolus injectable because of cardiovascular side effects and lumbar pain, and MION-37 and MION-46 preparations have been tested in only animal models so far (8,43).

Our study had some limitations. Iron kinetics were not studied because internal physiologic blood iron pools result in a significant background, preventing reliable quantification of iron measurements. Furthermore, the temporal and spatial resolution for acquisition of first-pass images in rabbits is limited by very short circulation times (48).

Additionally, saturation doses for different particle sizes were not investigated, and it remains unclear whether doses higher than 40 µmol of iron per kilogram will further increase initial signal enhancement or deteriorate image quality because of increasing T2* side effects.

Practical application: The bolus injectability of small iron oxides like USPIO S, combined with a strong first-pass effect, provides excellent blood-to-tissue contrast for MR angiography and offers the opportunity to study tissue perfusion. The persistent intravascular enhancement allows acquisition of MR angiographic images under steady-state conditions with high spatial resolution or multistage examinations, such as in the pelvis or lower extremities. This is even more important for coronary and pulmonary MR angiographic studies, in which acquisition times are prolonged when using cardiac or respiratory gating.

Because of these results, clinical phase 1 trials in humans with carboxydextran-USPIOs with a mean particle size of about 20 nm and doses of approximately 40 µmol of iron per kilogram are currently underway, and the first results regarding safety and efficacy in humans are expected in the near future.


   FOOTNOTES
 
Abbreviations: FLASH = fast low-angle shot, SI = signal intensity, USPIO = ultrasmall superparamagnetic iron oxide

Author contributions: Guarantors of integrity of entire study, T.A., C.B., P.R.; study concepts and design, T.A., C.B., P.R.; literature research, T.A., L.M.; experimental studies, W.E., T.A., C.B.; data acquisition, W.E., T.A., C.B.; data analysis/interpretation, W.E., T.A., C.B., L.M.; statistical analysis, L.M.; manuscript preparation and editing, T.A., C.B.; manuscript definition of intellectual content, T.A., C.B., P.R.; manuscript revision/review, C.B., P.R., W.E.; manuscript final version approval, T.A., W.E., P.R.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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