Reticuloendothelial MRI contrast agents

Last revised by Andrew Murphy on 2 Apr 2020

Reticuloendothelial MRI contrast agents can best be discussed in terms of those used for liver and spleen imaging and those for lymph node imaging.

Liver and spleen

The use of Gd-DTPA with routine imaging sequences of the liver is unsatisfactory. Particulate contrast agents targeted to the reticuloendothelial system (RES) of the liver and spleen, achieve the goals of improved detection and localization in the liver. This is analogous to the use of 99mTc-sulfur colloid in nuclear liver scans.

Two major cell types can be targeted for hepatic imaging. Hepatocytes comprise about 78% of the liver by volume, and Kupffer cells of the reticuloendothelial system comprise about 2% by volume. Originally, particulate contrast agents were targeted for the RES but recently ultrasmall particles have been used that bind to a specific receptor site on the hepatocyte cell membrane.

  • gadolinium oxide and magnetite
  • superparamagnetic iron oxide
  • liposomes
Gadolinium oxide

Gadolinium oxide is the prototype particulate contrast agent. This material accumulates in the liver and spleen of rabbits in both Kupffer cells and in the sinusoidal vascular spaces and effectively increases T1 and T2 relaxation as desired. The safety ratio (LD50/imaging dose) is only about 7:1 raising concerns of acute and chronic toxicity. It is therefore precluded from clinical use 1.

Magnetite (Fe3O4)

Magnetite is another prototype particulate contrast agent initially tested in dogs. It is a predecessor to coated particles used in clinical studies 2.

Superparamagnetic iron oxide

As with its use as an oral contrast agent, superparamagnetic iron oxide (SPIO) causes marked shortening T2 relaxation time resulting in a loss of signal in the liver and spleen with all commonly used pulse sequences. The most common form of iron oxide used is magnetite, which is a mixture of Fe2O3 and FeO. A mixture using Fe3O4 instead of FeO may also be used. Three mechanisms have been postulated to explain the relaxation enhancement of SPIO 3.

SPIO particles for parenteral use are coated with various substances to facilitate uptake by the reticuloendothelial system. These coatings have included albumin, a hydrophilic polymer, starch, and dextran.

The following problems that can arise with detecting small lesions in the liver using SPIO: 

  1. small lesions may be indistinguishable from the flow void in small blood vessels seen in cross-section
  2. aortic pulsation artifacts are more noticeable
  3. the one hour delay between injection and imaging make it impractical to decide at the last minute to give contrast.

A liposome is a spherical vesicle consisting of one or more bilayer phospholipid membranes or lamella. Liposomes for hepatic imaging range in size from about 20 nm to 400 nm diameter. Reasons to use liposomes as a carrier for paramagnetic contrast materials include: 

  1. changing the interaction between water molecules and the contrast agent
  2. changing the rate of removal of the contrast agent from the blood pool
  3. targeting specific organ systems, e.g., liver, spleen, and bone marrow. 

Paramagnetic materials can be incorporated into either the aqueous inner chamber or the bilayer membrane. Encapsulation of superparamagnetic iron oxide particles into liposomes (ferrosomes) has been reported. Both Gd-DTPA and manganese chloride (MnCl2) can be encapsulated into the aqueous inner chamber of liposomes 4.

Liposomes are taken up only by the Kupffer cells. Once in the Kupffer cells, Mn2+ ions or Gd-DTPA are slowly released and diffuse into adjacent hepatocytes, resulting in enhancement of normal liver but not malignancies.

Stable nitroxide free radicals have been attached to phosphatidylcholine, a common constituent of liposome lamellae. They may also be attached to derivatives of the fatty acid, stearic acid, as have the DTPA chelates of Mn and Gd. This results in a lipophilic side chain that allows incorporation into the liposome membrane.

Lymph nodes

Two clinical problems common to CT and MR imaging are:

  1. distinguishing unenlarged metastatic lymph nodes from normal lymph nodes
  2. differentiating enlarged metastatic nodes from benign hyperplastic nodes

Differentiation of metastases from fibrosis, lipomatosis and cysts is possible with resected lymph nodes in a 4.7 T magnet using voxels of size 0.1 by 0.1 by 1.0 mm; however, gradient strength and switching capabilities are not adequate in clinical scanners to obtain the necessary spatial resolution. This inadequacy of clinical MRI is circumvented by the use of USPIO.

USPIO particles with a mean diameter of 80 nm may be injected into the interstitium of the foot pad of rats. After a suitable delay, marked loss of signal of normal lymph nodes is seen. Metastatic nodes show less uptake resulting in less decrease in signal, allowing differentiation of normal-sized, metastatic nodes from uninvolved, normal nodes. From experience with conventional lymphangiography, this route of injection is unlikely to opacify all the abdominal lymph nodes 5.

USPIO particles, with a median diameter less than 10 nm, will localize in lymph nodes following an IV injection. This material does not undergo uptake by the RE system as rapidly as larger particles, resulting in a longer plasma half-life in rats (81 minutes vs 6 minutes). This factor and its small size allow transcapillary passage either into the interstitium and then to the lymph nodes or directly into the lymph nodes. In the rat model, IV injection of USPIO allows differentiation of normal lymph nodes from normal size metastatic nodes based on differences in signal characteristics. MR microscopy of excised lymph nodes, performed at 9.4 T shows the USPIO to be associated with macrophages in the medullary sinuses.

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