Magnetic Resonance Tracking of Stem Cells with Iron Oxide Particles - Intracellular Delivery: Fundamentals and Applications - page 464

3 MRI with Iron Oxide Particles

The most sensitive method of detecting cells by MRI currently is through the use of
iron oxide particles. Their development as MRI contrast agents took place more than
two decades ago. Then, gadolinium diethylenetriaminopentaacetic acid (Gd-DTPA)
was a commonly used contrast agent (Saini et al. 1987 ), but did not improve the
detection of liver carcinoma in clinical studies (Carr et al. 1984 ). In fact, metastases
were often obscured due to the extracellular distribution of Gd-DTPA into both
neoplastic and normal liver (Saini et al. 1986 ). This limitation was largely due to the
poor temporal resolution of the spin echo imaging sequences clinically available at
that time; multiphasic imaging sequences having not yet been developed. This
limitation has since been overcome by the development and implementation of fast
multi-echo breath-held spoiled gradient echo and motion-compensated fast spin echo
sequences. Today, gadolinium-based dynamic multiphasic contrast enhancement
remains the key method for the detection and characterisation of liver masses with
MRI in most centres. Because of the limitations of Gd-enhanced T1-weighted MRI
in the late 1980s and early 1990s, superparamagnetic iron oxide particles (SPIO)
attracted attention as an alternative for this application because of their large moment
in a magnetic field, absence of remnant magnetization when the field is removed
(superparamagnetism) and unique biodistribution (Mendonca and Lauterbur 1986 ;
Saini et al. 1987 ).
When injected intravenously, these particles home to the reticuloendothelial
system (Saini et al. 1987 ) and are taken up by macrophages in the liver, known as
Kupffer cells. The presence of SPIO causes darkening of normal hepatic tissue on
T2-weighted MR images, while liver carcinomas and metastases remain bright.
This application of SPIO led to the 1996 FDA approval of ferumoxide (US trade
name: Feridex®, Europe trade name: Endorem®, research name: AMI-25, generic
name: ferumoxide), which is administered by dilution in 5% dextrose and slow
infusion. Ferumoxide is a dextran-coated composite particle with a hydrated
diameter of 120-180 nm, comprising multiple 5 nm iron oxide nanoparticle cores
(Raynal et al. 2004 ). In 2001, European market approval was granted to a smaller
SPIO, ferucarbotran (trade name: Resovist®, research name: SHU 555A, generic
name: ferucarbotran), which is carboxydextran-coated, measures 62 nm in hydrated
diameter and comprises 5 nm iron oxide nanoparticle cores (Reimer et al. 1995 ;
Reimer and Balzer 2003 ). Compared to ferumoxide, ferucarbotran offers the advan-
tage of delivery by undiluted, bolus injection. It is also less likely to cause nausea
and other mild symptoms that are commonplace with ferumoxide.
Smaller than SPIO is a class of particles known as ultrasmall SPIO (USPIO),
with diameters less than 30 nm (Weissleder et al. 1990b ). Ultrasmall SPIO provides
a mixture of paramagnetic blood pool positive enhancement and reticuloendothe-
lial cell negative enhancement, and has been injected intravenously to differentiate
between darkened normal lymph nodes and metastatic ones that remain bright
(Weissleder et al. 1990a ). A USPIO undergoing clinical trials is ferumoxtran (trade
name: Sinerem/Combidex®, research name: AMI-227, generic name: ferumoxtran)
which has a 5 nm iron oxide core and 17-20 or 21-30 nm hydrated diameter as a