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A novel magnetic resonance imaging (MRI) contrast agent based on gadolinium meso-tetrakis(4-pyridyl)porphyrin [Gd(TPyP)] conjugated with chitosan nanoparticles has been developed. The chitosan nanoparticles were synthesized following an ionic gelation method and the conditions optimized to generate small nanoparticles (CNs) with a narrow size distribution of 35-65 nm. The gadolinium meso-tetrakis(4-pyridyl)porphyrin [Gd(TPyP)] was loaded into chitosan nanoparticles by passive adsorption. The interaction of chitosan with Gd(TPyP) has been examined by UV-visible, Fourier transform infrared spectroscopies (FT-IR) and inductively coupled plasma mass spectrometry (ICP-MS), which indicate the successful association of Gd(TPyP) without any structural distortion throughout the chitosan nanoparticles. The potential of Gd(TPyP)-CNs as MRI contrast agent has been investigated by magnetic resonance imaging (MRI) in-vitro. Relaxivities of Gd(TPyP)-CNs obtained from T1-weighted images, increased with Gd concentration and attained an optimum r1 of 38.35 mM(-1) s(-1), which is 12-fold higher compared to commercial Gd-DOTA (~4 mM(-1) s(-1) at 3T). The combination of such strong MRI contrast with the known properties of porphyrins in photodynamic therapy and biocompatibility of chitosan, presents a new perspective in using these compounds in cancer theranostics., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Rationale and Objectives: To summarize the chemical synthesis, physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P743, a new macromolecular iodinated contrast medium., Methods: The synthesis and molecular modeling of the iodinated macromolecule P743 are described. The pharmacokinetic profile was established in rabbits and rats. Acute toxicity in mice, renal tolerance in normal rabbits, and renal tolerance in uninephrectomized, dehydrated rats undergoing selective intrarenal injection was evaluated. In vitro permeability effects on isolated mastocytes and on the coagulation pathways were carried out. Computed tomography vascular imaging was performed after intravenous injection of P743 (300 mg I/kg) in rabbits and compared with the nonspecific nonionic agent iobitridol., Results: P743 is a monodisperse, macromolecular iodinated contrast medium. In both rabbits and rats, P743 showed a pharmacokinetic profile consistent with that of a rapid-clearance blood-pool agent. Its diffusion through the endothelium was found to be low in vitro, thus confirming early confinement of this macromolecule, unlike nonspecific contrast media. In both species, P743 was excreted by glomerular filtration. Acute toxicity disclosed no mortality at the highest volume that could be injected into mice, leading to a median lethal dose greater than 8.9 g I/kg. Renal tolerance was found to be good in both euvolemic rabbits and uninephrectomized, dehydrated rats. No histamine or leukotriene B4 release was found on RBL-2H3 isolated mastocytes. P743 did not interfere with the coagulation pathways. Imaging experiments confirmed that P743 remains in the vascular compartment for a longer time than does iobitridol, thus allowing vascular enhancement that is twice as high as that of iobitridol in the recirculation phase., Conclusions: The pharmacokinetic and imaging profiles of P743, a new, monodisperse, macromolecular blood-pool iodinated contrast medium, were consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Further experimental imaging studies are required to define the clinical interest in such molecules.

Rationale and Objectives: To evaluate the use of two new blood pool contrast agents (P760, P775) compared with a low-molecular-weight gadolinium chelate in MR angiography., Methods: The r1 efficiency of P760 was evaluated in vitro at 1.5 T; 3D abdominal contrast-enhanced MR angiography with qualitative analysis was compared in four rabbits after injection of incremental doses of P760 and in one rabbit after Gd-DOTA. A dynamic MR study was performed using a 2D T1-weighted turbo-flash MR sequence after injection of P760, P775, and Gd-DOTA. Each compound was tested at equivalent doses in three rabbits to assess r1 efficiency. Quantitative analysis of signal intensity in the aorta, the inferior vena cava, the renal cortex, and the medulla was performed., Results: In vitro, the r1 efficiency of P760 was 23.3 mmol(-1) x L x sec(-1) at 1.5 T. Injection of a dose of P760 10 times less than Gd-DOTA allowed similar vessel visualization. The signal intensity peak and first-pass contrast kinetics in the aorta and the inferior vena cava were similar with the three products. Compared with P760 and Gd-DOTA, P775 allowed a greater renal cortex signal intensity at the first pass and a faster decrease on delayed images., Conclusions: The superior r1 efficiency of P760 and P775 was confirmed in vitro and in vivo at 1.5 T compared with Gd-DOTA, and P775 proved to be a rapid-clearance blood pool agent.

Rationale and Objectives: In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties., Methods: The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging., Results and Conclusion: Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications.

Purpose: To assess the value of P760, a gadolinium chelate with slow interstitial diffusion and high relaxivity, for magnetic resonance (MR) imaging of acute myocardial infarction in pigs., Materials and Methods: First-pass gradient-echo MR imaging and spin-echo MR imaging were performed with P760 and then with gadoterate meglumine in eight pigs with occlusive acute myocardial infarction. P760 signal intensity enhancement and clearance were compared with those of gadoterate meglumine., Results: The first-pass enhancement ratio of P760 in normal myocardium was higher than that in infarcted myocardium (1.37 +/- 0.06 [SEM] vs 1.05 +/- 0.03, P = .03). The myocardial first pass showed a blood pool-like curve for P760. The blood pool enhancement ratio 40 seconds after injection was higher for P760 than for gadoterate meglumine (left ventricular cavity, 1.75 +/- 0.06 vs 1.45 +/- 0.06, P = .009). Spin-echo MR imaging showed improved contrast between normal and infarcted myocardium after P760 administration: The ratio before contrast material administration was 0.21 +/- 0.03, that at 15 minutes was 0.48 +/- 0.05 (P = .002), and that at 25 minutes was 0.47 +/- 0.07 (P = .003)., Conclusion: P760 is an MR imaging contrast agent characterized by low diffusion, a blood pool effect soon after low-dose administration, and fast elimination. This agent is useful for improved myocardial perfusion MR imaging of acute myocardial infarction.

The authors suggest that ultra-small paramagnetic iron oxide (USPIO) particles used as blood pool contrast agents may increase the sensitivity of midfield MRI (i.e., less than 1.5 Tesla) to physiological variations in cerebral blood volume. This hypothesis was tested on a rabbit model of apnea which increases pCO2 and cerebral blood volume. Using Sinerern as the USPIO at a blood concentration of 60 mumol Iron/kg body weight, an 8% T2*-weighted signal decrease could be observed at 1.0 T with 25-33% increase in pCO2. Comparatively, in the absence of USPIO, T2*-weighted signal dropped only 4% during apnea and after mild hyperoxygenation beforehand, due to increased deoxyhemoglobin content. These preliminary data suggest that USPIOs could play an important role in functional MRI at midfield strength, by sensitizing the signal to cerebral blood volume changes.

Rationale and Objectives: The authors evaluate the efficiency of various doses of a paramagnetic macromolecular contrast agent, a gadolinium (Gd)-DTPA-dextran conjugate, as a blood-pool contrast media, in a transverse three-dimensional time-of-flight (TOF) magnetic resonance (MR) angiography sequence of the abdominal aorta in rabbits., Methods: Imaging experiments were performed on a 1.5-T magnet, using a transverse three-dimensional TOF tilted optimized nonsaturating excitation (TONE) sequence. The macromolecular contrast media used was a carboxymethyl-dextran-Gd-DTPA (CMD-Gd-DTPA). Different concentrations of CMD-Gd-DTPA (0.005, 0.01, 0.03, 0.05 mmol Gd/kg) were evaluated. A comparative study using Gd-DOTA (0.01 and 0.1 mmol/kg) was performed. A visual analysis based on the gain in the visualized length of small arteries (renal arteries), and a quantitative analysis based on the percent contrast enhancement of the aorta plotted against distance in the slab from the top edge of the acquisition volume were obtained., Results: A signal-to-noise ratio enhancement of the distal part of the aorta and an improvement in the visualized length of the renal arteries were noted for concentrations of CMD-Gd-DTPA ranging form 0.01 to 0.05 mmol Gd/kg. Venous enhancement was noted for concentrations greater than 0.01 mmol Gd/kg when using CMD-Gd-DTPA or Gd-DOTA., Conclusion: Carboxymethyl-dextran-Gd-DTPA reduced, in part, the saturation effect in a three-dimensional transverse TOF TONE MR angiography in rabbits. To prevent venous enhancement, observed with the higher concentrations used in this study, a decrease in the polydispersity of the polymer should be a goal in the future. Rapid extravasation of the low-molecular weight fraction of the polymer could explain the venous enhancement.

Contrast agents may be categorised as non-specific or specific agents. Non-specific agents are freely diffusible in the extracellular and extravascular compartment with the exception of the brain where only blood brain barrier lesions enables the contrast agent to pass. In the specific agent group, a new class of products has been developed, that of blood pool contrast agent, which are distributed in the total intravascular volume and are slowly cleared from the blood. Crossing the healthy capillary wall is limited and depends both on the pathological state of the endothelial permeability tissue of the organ under interest and on the characteristics of the contrast agent (size, charge, molecular shape...). The diagnostic efficacy in perfusion imaging including cerebral perfusion is modulated by the pharmacokinetic profile of the blood pool contrast agent. One way to improve the vascular residence time, consists in binding a vector such as synthetic polymer or a biological macromolecule and a lanthanide like Gd3+, Mn2+, Dy3+ or metal ions. A second way is the synthesis of ultrasmall iron oxide nanoparticles which could escape rapid recognition by the monocyte macrophage phagocytic system mainly of liver and spleen. Because of their cristalline structure and the large number of non-paired spins, five electrons for the iron metal, the nanoparticles behave as magnetic domain when an external field is applied. They consequently have a high dipolar magnetic moment, and can produce a T2 effect in vivo, resulting in a drop in the magnetic resonance signal. Possible interests and developments toward perfusion imaging are demonstrated in experimental models studies.

Purpose: A new nonionic low-osmolality contrast medium, iobitridol (Xenetix 350) was compared with iohexol (Omnipaque) after i.v. injection in anesthetized rabbits to assess efficacy in CT examinations and biodistribution., Material and Methods: The densities in test tubes and the pharmacogenetics and biodistribution of iobitridol 350 and iohexol were compared in rabbits. CT of the brain, liver, the abdominal aorta and the kidneys was performed before and after injection of the contrast media., Results: In aqueous medium, iobitridol absorbed roentgen rays in a manner exactly identical to that of iohexol. Within 15 min following injection of iohexol and iobitridol at a dose of 300 mg I/kg, both contrast agents resulted in aortic enhancement which decreased with time. An increased attenuation of the liver also occurred, decreasing with time. There was no significant enhancement in the brain but enhancement was found in the renal pelvocalyceal cavities 10 min postinjection. No significant difference was found between the 2 contrast agents under the study conditions., Conclusion: As could be expected from its behavior as a tracer of extracellular fluid, iobitridol resulted in significant changes in the signal, corresponding to its vascular, hepatic and renal pharmacokinetics in rabbits.

Enhanced-MR imaging in combination with ultrasmall superparamagnetic iron oxide (USPIO) was used in the glycerol-induced model of acute renal failure (ARF) in the rabbit to detect renal perfusion abnormalities. A control group (n = 5) and an ARF group (n = 5) were studied after intramuscular injection of glycerol (10 ml/kg) with T2-weighted spin-echo sequence at 1.5 T and a 27 mumol/kg IV dose of iron. The signal intensity (SI) was quantified in the cortex, the outer medulla (OM), and the inner medulla (IM). In control rabbits, the maximum SI decrease after USPIO injection was in the OM (76% +/- 3.6), as this is the region of maximal vascular density, then in the IM (73.4% +/- 2.9). In the glycerol group, SI loss in the OM (61% +/- 12.6) and the IM (45.2% +/- 16.24) was significant less than in the control group (p < .05). Pathology results showed fibrinous thrombus in the efferent arterioles and congestive aspect of the vasa recta in the medulla. We argue that a reduced medullary concentration of USPIO in the renal failure group is indicative of medullary hypoperfusion.

Magnetic resonance imaging (MRI) has been used to characterize tissues in morphological studies. Here, 23Na NMR imaging was used to study the distribution in muscle of brine (5 M NaCl), injected before onset of rigor mortis. First, the distribution of brine was monitored in excised muscle from rabbits for 6 hr following arterial brine injection. Immediately after injection, distribution was clearly heterogeneous. After 6 hr, a steady state was achieved but the observed brine distribution was not fully homogeneous. Second, the same was done for ham processed in various ways (tumbling, cooking). Tumbling increased the homogeneity of distribution in our experimental conditions but only cooking afforded full homogenization of brine in ham. Concentrations of NMR-visible sodium in the muscles were appreciably lower than the expected values calculated from the volume of injected brine. The invisible sodium presumably has T2 values which are too short compared with the echo time in our conventional spectrometer.