MS-325: albumin-targeted contrast agent for MR angiography.

PURPOSE: To evaluate the protein-binding and signal enhancement characteristics of MS-325, a gadolinium-based magnetic resonance (MR) imaging blood pool agent that binds to albumin, and compare results with those obtained with existing gadolinium- and iron oxide-based agents. MATERIALS AND METHODS: Protein binding in human plasma was measured by means of ultrafiltration. T1 relaxation times (20 MHz) were measured in human plasma or ex vivo samples from rabbits and monkeys injected with 0.1 mmol of MS-325 per kilogram of body weight. Imaging (three-dimensional fast imaging with steady-state precession, or FISP) was performed at 1.0 T in phantoms, which contained varying concentrations of different agents, or rabbits after injection of 0.015-0.100 mmol/kg MS-325. RESULTS: MS-325 is 80%-96% bound in human plasma and exhibits a relaxivity approximately six to 10 times that of gadolinium diethylenetriaminepentaacetic acid (DTPA). Images of phantoms containing MS-325 were significantly brighter than those containing existing gadolinium chelates or iron particles (monocrystalline iron oxide nanoparticle, or MION) at equivalent concentrations. Findings of in vivo studies indicated strong, persistent plasma T1 reduction with MS-325 for 1 hour (T1 of MS-325, 50-100 msec; T1 of Gd-DTPA, 200-400 msec) and strong vascular enhancement on MR images. CONCLUSION: MS-325 is highly protein bound after injection and provides vascular signal enhancement superior to that provided with other agents. As the first gadolinium-based blood pool agent in human trials, MS-325 has the potential to enhance both dynamic and steady-state MR angiograms.

Preclinical evaluation of the pharmacokinetics, biodistribution, and elimination of MS-325, a blood pool agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors evaluate MS-325, a new albumin-targeted magnetic resonance imaging (MRI) contrast agent, for its pharmacokinetics, biodistribution, and elimination characteristics in multiple animal species. METHODS: Studies were performed in rats, rabbits, and nonhuman primates at intravenous doses ranging from 0.025 to 0.20 mmol/kg. Concentrations of MS-325 in blood, urine, feces, and organs were determined using gadolinium-153-labeled MS-325 and gamma counting or by using non-labeled MS-325 and inductively coupled plasma atomic emission spectrometry. RESULTS: In rabbits and nonhuman primates, MS-325 is approximately 85% to 95% bound to serum proteins and, as a result, exhibits low volume of distribution (Vd) values, 0.11 to 0.14 L/kg, and a long elimination half-life (Te1/2), 2 to 3 hours. Some dose-dependence in the parameters is apparent in rabbits. MS-325 is eliminated primarily through the renal system in non-human primates. In contrast, the behavior of MS-325 in rats is different, exhibiting increased biliary excretion, a larger Vd value, and a shorter Te1/2. CONCLUSIONS: The pharmacokinetics and elimination profile of MS-325, including vascular retention and renal excretion, are favorable for use in humans as an intravascular contrast agent for MRI.

Rigorous swim training impairs mitochondrial function in post-ischaemic rat heart.

The effect of rigorous swim training (6 h day-1, 5 days week-1 for an average of 191 h) on mitochondrial respiratory function was investigated in rat heart subjected to in vivo ischaemia reperfusion (I-R). Mitochondria was isolated from the risk region of the left ventricle subjected to 60 min occlusion of the main left coronary artery followed by 30 min reperfusion. Heart weight and heart-to-body weight ratio was increased by 21 and 28% (P < 0.01), respectively, in the trained (T, n = 15) vs. control rats (C, n = 20). I-R per se showed minimal effect on heart mitochondria regardless of training status. In sham, state 4 respiration rate was 26 and 32% (P < 0.05) lower in T vs. C rats, using malate-pyruvate (M-P) and 2-oxoglutarate (OG) as substrates, respectively. Training also reduced state 3 respiration by 28% (M-P) and 50% (OG) (P < 0.01). The respiratory control index (RCI) was unaltered in T with M-P, but decreased with OG (P < 0.01). In vitro exposure to superoxide radicals severely reduced state 4 and 3 respiration and RCI, but T hearts showed greater reductions of state 4 and 3 rates than C. Mitochondria from T hearts also revealed a greater state 4 inhibition by H2O2 and HO. compared with C. A lower glutathione content and a higher gamma-glutamyl transpeptidase activity (P < 0.05) was observed in T vs. C. It is concluded that rigorous swim training impairs heart mitochondrial function, making them more susceptible to in vivo and in vitro oxidative stress, and that this damaging effect may be related to a diminished glutathione reserve.

Ischaemia-reperfusion induced alterations of mitochondrial function in hypertrophied rat heart.

The impact of in vivo ischaemia and ischaemia-reperfusion (I-R) on mitochondrial respiratory function was investigated in hypertrophied (HP) hearts with aortic constriction compared with control hearts using an open-chest rat surgical model. Moreover, mitochondrial susceptibility to superoxide radicals (O2-.) in vitro was examined in HP and control hearts with or without I-R. With the site I substrates pyruvate-malate, mitochondrial state 4 (basal) respiration and the respiratory control index (RCI) were not affected by either ischaemia alone or I-R in both HP and control hearts. State 3 (ADP-stimulated) respiration was increased with I-R in control hearts, but showed a reduction after I-R in the HP hearts. Exposure of mitochondria to O2-. (20 nM hypoxanthine in the presence of 0.13 unit mL-1 xanthine oxidase) significantly increased state 4 respiration, whereas state 3 respiration and RCI were decreased in all treatment groups. I-R hearts in both HP and control showed greater increases in state 4 respiration with O2-. than either sham or ischaemic hearts. HP hearts exhibited a significantly lesser extent of inhibition in state 3 respiration and RCI by O2-. compared with control hearts. These changes in mitochondrial respiratory properties were not observed with the site II substrate succinate. Myocardial reduced vs. oxidized glutathione ratio was significantly decreased after I-R in both control and HP hearts. Malondialdehyde content showed an increase with I-R, but the increase was significant only in control hearts. These data indicate that short-term in vivo I-R does not impair heart mitochondrial respiratory function, but renders the organelles more vulnerable to imposed oxidative stress. Mitochondria from the HP hearts are more resistant to free radical damage under normal and ischaemic conditions; however, this advantage is severely compromised after reperfusion.

Dynamic Gd-DTPA enhanced MRI measurement of tissue cell volume fraction.

A new technique for measuring tissue cellular volume fraction, based on an improved modeling of the dynamic distribution of Gd-DTPA and the effect of proton exchange, is described. This technique uses peak T1 enhancement and blood Gd-DTPA concentration to compute tissue cellular volume fraction. The feasibility of this technique is demonstrated with computer simulations that explore the limits of the simplifying assumptions (small vascular space, slow vascular-extravascular proton exchange), and by direct comparison of MR and radionuclide cell fraction measurements made in muscle, liver, and tumor tissue in a rat model. The computer simulations demonstrate that with slow to intermediate vascular proton exchange and vascular fractions less than 10% the error in our cell fraction measurements typically remains less than 10%. Consistent with this prediction, a direct comparison between MR and radionuclide measurements of cell fraction demonstrates mean percent differences of less than 10%:1.9% in muscle (n = 4); 9% in liver (n = 1) and 9.5% in tumor (n = 4). Similarly, for all rats studied, the MR-measured cell fractions (muscle (0.92 +/- 0.04, n = 20); liver (0.76 +/- 0.11, n = 9); whole tumor (0.69 +/- 0.15, n = 22)) agree with the cell fraction values reported in the literature. In general, the authors' results demonstrate the feasibility of a simple method for measuring tissue cell fraction that is robust across a broad range of vascular volume, flow, and exchange conditions. Consequently, this method may prove to be an important means for evaluating the response of tumors to therapy.