Background

[PubMed]

Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used to create images because of their abundance in water molecules, which comprise >80% of most soft tissues. The contrast of proton MRI images depends mainly on the density of nuclear (proton spins), the relaxation times of the nuclear magnetization (T1, longitudinal; T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the use of contrast agents. Most contrast agents affect the T1 and T2 relaxation of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Cross-linked iron oxide (CLIO) and other iron oxide formulations affect T2 primarily and lead to a decreased signal. On the other hand, the paramagnetic T1 agents, such as gadolinium (Gd³⁺), and manganese (Mn²⁺), accelerate T1 relaxation and lead to brighter contrast images.

The superparamagnetic iron oxide (SPIO) structure is composed of ferric iron (Fe³⁺) and ferrous iron (Fe²⁺). The iron oxide particles are coated with a protective layer of dextran or other polysaccharide. These particles have large combined magnetic moments or spins, which are randomly rotated in the absence of an applied magnetic field. SPIO is used mainly as a T2 contrast agent in MRI, though it can shorten both T1 and T2/T2* relaxation processes. SPIO particle uptake into reticuloendothelial system (RES) is by endocytosis or phagocytosis. SPIO particles are also taken up by phagocytic cells such as monocytes, macrophages, and oligodendroglial cells. A variety of cells can also be labeled with these particles for cell trafficking and tumor-specific molecular imaging studies. SPIO agents are classified by their sizes with coating material (~20–3,500 nm in diameter) as large SPIO (LSPIO) nanoparticles, standard SPIO (SSPIO) nanoparticles, ultrasmall SPIO (USPIO) nanoparticles, and monocrystalline iron oxide nanoparticles (MION) (1).

Alzheimer’s disease (AD) is a major neurodegenerative disease associated with an irreversible decline of mental functions and with cognitive impairment (2). It is characterized pathologically by neuronal loss with the presence in the brain of senile plaques of β-amyloid (Aβ) peptides and intracellular neurofibrillary tangles of filaments that contain the hyperphosphorylated protein tau (3, 4). Accelerated deposition of Aβ deposits seems to be a key risk factor associated with AD. Early diagnosis of AD is important for treatment consideration and disease management (5). Several radioligands for positron emission tomography have been developed (6-8) and tested in humans as in vivo diagnostic tools for molecular imaging and measuring the formation of Aβ deposits (8). USPIO is composed of iron nanoparticles 4–6 nm in diameter, and the hydrodynamic diameter with polyethylene glycol or dextran coating is 20–50 nm. USPIO nanoparticles have a long plasma half-life because of their small size. The blood pool half-life of plasma relaxation times is calculated at ~24 h in humans (9) and 2 h in mice (10). Because of its long blood half-life, USPIO can be used as a blood pool agent during the early phase of intravenous administration (11). In the late phase, USPIO is suitable for the evaluation of RES in the body, particularly in lymph nodes (12). A cyclic peptide, Cys-Ile-Pro-Leu-Pro-Phe-Tyr-Asn-Cys, was identified with phage screening against Aβ₄₂ peptide (13). Ile-Pro-Leu-Pro-Phe-Tyr-Asn (PHO) was synthesized and conjugated to dextran-coated USPIO to form USPIO-PHO for MRI of Aβ₄₂ in the brain.

Synthesis

[PubMed]

PHO peptide was linked covalently to USPIO with the reactive alkyl halogen end of epichlohydrin binding to the hydroxyls of dextran coating of Fe₃O₄ particles (USPIO) to obtain a terminal glycidyl ether derivatives, which were then reacted with the amine group of the peptide (13). Longitudinal (r₁) and transverse (r₂) relaxivities (nuclear magnetic resonance (NMR) efficiency expressed in s−¹mM−¹) of USPIO-PHO were measured at 37°C and 20 MHz (r₁ = 32.26, r₂ = 85.32, and r₂/r₁ = 2.64) and 60 MHz (r₁ = 13.50, r₂ = 83.75, and r₂/r₁ = 6.20). The number of PHO peptides per USPIO was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Larbanoix et al. (13) performed in vitro binding of USPIO-PHO to mouse Aβ₄₂. USPIO-PHO had a binding affinity of 0.12 nM as determined with NMR relaxometry. USPIO did not bind to mouse Aβ₄₂.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

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