13-04 Targeted and Organ-Specific Contrast Agents
One of the ultimate goals of contrast agent research in MR imaging is the development of compounds that actively identify specific tissues or pathologies. In order to target organs and to obtain higher disease specificity, iron oxides and liposomes have attracted particular interest. To optimize such agents, one has to evaluate at least three parameters:
Improvement of tolerance – although tolerance of existing com-
pounds is already very good; this includes chemical and biological
inertness, as well as complete elimination from the body;
Improvement of the enhancing effect; high and ultrahigh fields
require a different contrast agent than low and medium/high fields;
Selective distribution in the body to reach high local concen-
trations (organ or pathology specific tracers).
Iron oxides. Iron-oxide particles are incorporated into cells of the reticulo-endothelial system (RES) through phagocytosis. This opens a selective access route to liver, spleen, lymph nodes, and bone marrow. These particles can also be applied for receptor and antibody imaging, as well as perfusion imaging of the heart and the brain.
These agents can either be positive (T1) or negative (T2/T2*) enhancers, depending on particle size (Table 13-04), composition and concentration, saturation magnetization of the material, as well as equipment hardware and pulse sequences used. Their biodistribution is determined by size, shape, charge, hydrophilicity, chemical composition, and surface coating (cf. negative contrast agents | susceptibility effects) [review article: ⇒ Corot, ⇒ Laurent 2008].
Classes of superparamagnetic nanoparticles depending on their particle size.
The majority of compounds are polydisperse (more than one size population of iron oxide crystals) and polycrystalline (particle aggregates). Actively targeted iron oxides [⇒ Chertok 2008] preferably contain smaller superparamagnetic labels; they are monodisperse (only one size population of iron oxides) and monocrystalline (= MION, i.e., each particle consists of only one crystal).
Used intravenously, iron-oxide particles should possess a particle size smaller than 50 nm in diameter so that they are not entrapped during their passage through the lungs.
Liposomes. Liposomes are another group of particulate contrast agents. Paramagnetic ions can either be encapsulated in the aqueous compartment of the liposomes or be linked to their lipid bilayers. Both manganese and gadolinium chelates have been attached to liposomes and studied preclinically. More sophisticated liposome compounds have been proposed, among them phospholipid spin- labelled and amphipathic chelate complexes.
13-04-01 Liver Agents
The liver has been selected as the primary organ for developing passive targeting compounds: vascular, hepatobiliary, and reticuloendothelial. Different possible enhancement patterns are depicted in Figure 13-11.
Enhancement patterns of different liver contrast agents (modified from ⇒ Leander).
Aside from the vascular structures, either the hepatocytes or the RES can be targeted. Vascular structures and highly vascularized lesions are commonly highlighted by dynamic examinations with the conventional low molecular weight contrast agents (Figure 13-12). Dynamic imaging is discussed in detail in Chapter 16.
Focal nodular hyperplasia (FNH) of the liver. Dynamic enhancement with Gd-DOTA; first highlighting of the arterial vessels, then strong enhancement of the tumor during the early phase of arterial enhancement; followed by the depiction of the veins. Timescale approximately 90 seconds.
Gd-EOB-DTPA and Gd-BOPTA (Figure 13-13) are two positive gadolinium based agents with lipophilic side groups. Gd-EOB-DTPA [⇒ Runge] is a targeted liver agent, whereas Gd-BOPTA is a multipurpose contrast agent, well suited for liver imaging [⇒ Spinazzi].
Mn-DPDP (mangafodipir; Figure 13-14) is a positive multipurpose agent taken up by, e.g., the hepatocytes [⇒ Rummeny]. The contrast enhancement seems to be connected to a limited release of manganese ion. The enhancement is long lasting and can be achieved with such low doses as 10 mmol/kg body weight. While on the market for liver applications, Mangafodipir was the preferred agent in patients with kidney problems. Oral or intravenous MnCl2 can have a similar effect.
Ferumoxides, or super-paramagnetic iron oxides, are negative enhancers taken up by the normal liver, which contains reticuloendothelial cells, but not by lesions that lack reticuloendothelial cells (Figure 13-15) [⇒ Paley; cf. iron oxides].
Gadolinium-BOPTA (MultiHance) in liver metastases of a pancreatic tumor. (a) plain T1-weighted GRE sequence; (b) plain T2-weighted GRE sequence; (c) enhanced T1-weighted GRE sequence 40 minutes after injection; (d) T1-weighted GRE sequence 90 minutes after injection.
Although the chemical composition of Gd-BOPTA appears similar to that of the extracellular gadolinium agents, it combines both extracellular and liver-targeted properties, because some 5% of it is excreted through the liver, as is shown in this case of multiple metastases (images courtesy of Drs. Caudana, Morana, and Pistolesi; Verona).
The uptake of Mn-DPDP (mangafodipir) in the liver relies on the ability of hepatocytes to excrete metal ions. Manganese separates from the DPDP-complex and is taken up by the hepatocytes.
T1-weighted GRE images. (a) The metastases are well delineated 15 minutes after the injection, and (b) even 24 hours after administration some of the contrast agent remains (images courtesy of Dr. Martí-Bonmatí; Valencia.)
Example of a negative liver contrast agent (ferumoxide). This particulate agent is taken up by endothelial and Kupffer's cells. They darken the liver tissue due to their effective shortening of the T2 relaxation time.
T2-weighted GRE: (a) precontrast; (b) postcontrast. The liver metastases are well delineated on the post-contrast image; with this agent, the normal liver tissue becomes black.