Herve Tournier

Gadolinium-Containing Mixed Micelle Formulations: A New Class of Blood Pool MRI/MRA Contrast Agents

Because cardiovascular diseases have been the leading cause of death in the United States and Europe since 1900, it is evident that there is a medical need for noninvasive diagnostic procedures for the detection and assessment of coronary artery disease. In the future, magnetic resonance coronary angiography could be an alternative procedure to the largely used but invasive x-ray coronary angiography. In today’s health care environment, an alternative procedure offering the same information at a substantially lower degree of invasiveness and at a fraction of the cost would probably be capable of overcoming even strong resistance to change. A major problem is related to spatial resolution; to improve it, the use of an efficient contrast agent is necessary. Several products have been proposed and studied as blood pool contrast agents for magnetic resonance angiography (MRA), in particular gadolinium chelates bound to albumin (1), polylysine, dextran or carboxydextran (2), and dendrimers (3). Other approaches investigated included magnetites (4–6) and albumin-binding agents (7). The use of liposomes as MR contrast agents has also been evaluated and described by various authors in recent years (8). Contrast agents entrapped within the internal aqueous space of liposomes (9), as well as liposomes incorporating lipophilic contrast agents in the lipid bilayer (10,11), have been prepared and tested. When chelates such as gadopentetate dimeglumine (Gd-DTPA), gadobenate dimeglumine (Gd-BOPTA), and gadoteridol (GdHP-DO3A) are entrapped within the internal aqueous space of lipid vesicles, the main target is the liver (Kupffer cells), and clearance of gadolinium is slow (12). While investigating blood vessels and the possibility of using these liposomes for MRA application, it was observed that their enhancement capacity is limited because the relaxivity of liposomes entrapping gadolinium chelates is about two to five times lower than that of the free gadolinium chelate in solution. It was also observed that the relaxivity depends on the size of the liposomes, with smaller vesicles showing higher relaxivity than larger ones. We are proposing a new approach based on mixed micelle formulations. Physically stable mixed micelle formulations can be obtained by mixing a lipophilic gadolinium chelate, a phospholipid (or phospholipids), and a surfactant. In this way, the relative concentration of gadolinium can be strongly increased compared to liposomes because the physical stability of the mixed micelles is easily achieved with relatively low amounts of lipids and surfactants. It is a large advantage compared to liposomes, for which the relative weight ratio of the lipophilic gadolinium chelate to the other lipids forming the liposome membrane has to be low (10%–20%) to obtain physically stable vesicles. Moreover, with mixed micelles, all gadolinium ions are exposed to the outside and can interact directly with water molecules.

Detection of experimental hepatic tumors using long circulating superparamagnetic particles.

Sayegh Y, Pochon S, Vallée J-P, et al. Detection of experimental hepatic tumors using long circulating superparamagnetic particles. Invest Radiol 2001;36:15–21. RATIONALE AND OBJECTIVES.To evaluate the potential of an iron oxide-based MR contrast agent for the detection and delineation of experimental liver tumors during the early vascular phase of the compound. METHODS.Superparamagnetic blood pool agent (SBPA) was administered intravenously to rabbits bearing VX2 tumors. Images were acquired before the injection, immediately after, and 1 or 3 weeks later. The variations of signal intensity were measured in the tumors and in several tissues for various T1-weighted spin-echo, T2-weighted fast spin-echo, and T2-weighted gradient-recalled-echo sequences. RESULTS.Fourteen and 12 of the 16 tumors were detected immediately after SBPA injection using, respectively, the T2-weighted fast spin-echo and T2-weighted gradient-recalled-echo sequences. A significant decrease in signal intensity was observed in well-perfused organs, and blood signal was abolished even at the lowest injected dose and using a T1-weighted sequence. In the late phase, the loss in signal intensity of the liver was even more pronounced. CONCLUSION.The dominant T2 effect of SBPA induces an increase in the tumor-to-liver and tumor-to-blood contrast during the vascular phase, improving the detection of the tumors and allowing the distinction between small lesions and vessels through plane. This effect on the liver signal persists for several days because of the incorporation of SBPA in the reticuloendothelial system.