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

Abstract

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.