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Since first introduced in 1970s,164 MRI, a real-time, non-invasive imaging method with excellent spatial resolution, has become one of the most powerful diagnostics tool in clinical area. The basic principle of MRI is based on the mechanism of nuclear magnetic resonance (NMR) and hydrogen proton spin relaxation in an applied field.165 In a strong external magnetic field, the proton spins of water molecules will align with the direction of the field. If an electromagnetic pulse that match the Larmor frequency is applied, the proton spins will be excited by this energy and tipped away from z-axis (main magnetic field direction, B0) toward the transverse plane.

Immediately after the excitation, the transverse magnetization fades and the proton spins return to equilibrium state via two independent process: longitudinal relaxation (T1 relaxation) and

transverse relaxation (T2 relaxation), which give rise to the signal in receiver coil and generate

MR image.166 However, MRI is suffering from several drawbacks such as low contrast between lesions and surrounding healthy tissue in acquired images.165 Until now, many contrast agents have been developed to enhance the sensitivity of MRI so as to improve image quality. Generally, they are working under a principle of shortening the T1 or T2 relaxation time by altering local

magnetic field or the resonance properties in tissue. Substances with unpaired electrons such as Gd3+, Mn3+ and Fe3+ are able to withdraw the excess energy the nearby proton have absorbed from the electromagnetic pulse and are referred to as T1 contrast agents. Differently, SPIONs

Table 1.1. Iron oxide contrast agents which are commercialized or at different clinical stages3,8

such as magnetite (Fe3O4) or maghemite (Fe2O3) that can induce local magnetic field

inhomogeneities and accelerate dephasing due to spin-spin relaxation effect are T2 contrast

agents. Traditional gadolinium-based small molecular complexes that are applied for T1 contrast

enhancement usually have short circulation time and high toxicity. In contrast, SPIONs are easier to modify and more biocompatible in order to satisfy various imaging conditions. Table 1.1 presents the SPIONs agents that are commercial available or under clinical investigation.

Because contrast agents are administered either orally or via intravenous injection, several fundamental requirements should be applied to develop SPIONs contrast agents. First, nanoparticles should have low toxicity so as to be biocompatible. According to many studies, iron oxide nanoparticles usually exhibit acceptable safety for human use.167 Second, the nanoparticles should possess well stability in physiological environment, which means they should be able to sustain the internal ion strength and tolerate numerous biomolecules such as

Coupound Size (nm) Coating agent Target Development Tradename Company

Ferumoxides,

(AMI-25) 120-180 Dextran Liver Phase 1 Feridex

Guerbet, Advanced Magnetics Ferumoxtran- 10, AMI-227 15-30 Dextran Lymph node,

liver, blood pool Phase 3

Sinerem/ Combidex Guerbet, Advanced Magnetics Ferristene 3500 Sulfonated styrene- divinylbenzene copolymer

GI Commercial Abdoscan GE- Healthcare

Ferumoxsil,

AMI-121 300 Silicon GI Commercial

Lumirem/ Gastromark Guerbet, Advanced Magnetics Ferucarbotra

n 60 Dextran Liver Commercial Resovist Schering SHU-555C 21 Carboxydextran Blood pool Phase 1 Supravist Schering

antibodies and enzymes. Nanoparticles with poor colloidal stability would easily aggregate in biofluid and significantly increase their size, which will be eliminated rapidly. Third, specific MRI condition such as blood pool imaging or lymphatic imaging requires prolonged circulation time for data acquisition. Because as-prepared SPIONs are either insoluble in aqueous solution or only bear simple functionality that cannot be directly employed for imaging, appropriate surface modification is necessary for the applications. For example, Tong98 and co-workers demonstrate that, by fine-tuning the core size and PEG coating of SPIONs, the T2 relaxivity per

particle can be increased by >200-fold.

Another very important factor for SPIONs as MRI contrast agents is their hydrodynamic size rather than their actual size in dry state because human body is a water-rich system, and magnetic nanoparticles are working normally only when they are fully dispersed.3 Iron oxide nanoparticles with hydrodynamic size smaller than 40 nm are often classified as USPIO (ultra-small particles of iron oxide), whereas SPIO (small particles of iron oxide) is refer to as those with hydrodynamic size larger than 40 nm. According to their hydrodynamic size, different sized SPIONs have different biodistribution and elimination pathway that distinguished their types as contrast agents. Generally, larger particles are recognized as foreign particles and quickly taken up by reticuloendothelial system (RES) and eventually accumulated in liver or spleen after the administered into body. Therefore, SPIOs are widely designated as RES contrast agents to detect liver lesion or cancer. UPIOS, on the other hand, are able to pass through RES due to their small size and remain in the blood for 24-36 h.166 These particles will accumulate in lymph nodes or lymph vessels and reach a high concentration, producing pronounced T2

shortening effect. UPIOS can also be used as intravascular or blood pool contrast agents if they are coated with suitable materials such as PEG, so as to evade phagocytosis of RES cell and show long residence time in blood vessels.

Up to date, most SPIONs based contrast agents can be categorized into passive imaging mode. For example, in lymphatic imaging, SPIONs based contrast agents present their properties replying on the natural biodistribution of nanoparticles, where particles are predominantly

phagocytosed by macrophages in normal tissue while metastatic lymph node are lack of macrophages and do not take up contrast agents, resulting in different signal intensity.168 In other cancer detections or blood pool imaging, the distribution of contrast agents is mainly determined by the EPR effect.169,170 As we know, the tumor tissues are filled with abnormal, unsmooth vessels that are formed with poorly aligned cell with many leakages, which tend to accumulate more macromolecular drugs or nanoparticles than normal tissues. Thus, leakage of contrast medium into the extravascular space provides information on the permeability of a lesion or damage to capillary membranes.166 Conjugation of target specific molecules such as folic acid, vascular endothelial growth factor (VEGF) or transferrin whose receptors are over-expressed on cancer cell to the surface SPIONs can guide the contrast agents to favorite tissue and efficiently increase their residence time at target site.171,172 Thus, actively enhance the signal intensity and improve the image quality.

Iron oxide nanoparticles are mainly developed for T2 weighted image enhancement because

when high T1 relaxivity (r1) and low r1/r2 is preferred to maximize the T1 effect, the high

magnetic moment of iron oxide nanoparticles present much stronger effect on r2 than the 5

unpaired electron from ferric ions on r1. Hyeon173et al. solved this problem by simply adjusting

the synthesis condition and decreasing the size of as-prepared nanoparticle to around 1.5 nm, which maintains a large surface area of Fe3+ with unpaired electrons and effectively suppress the magnetic moment due to spin-canting effect and reduction of volume magnetic anisotropy.