Characterization and Water-Proton Longitudinal Relaxivities of Liposome-Type Radical Nanoparticles Prepared via a Supramolecular Approach.

For the construction of metal-free magnetic resonance imaging (MRI) contrast agents, radical-based nanoparticles (RNPs) are promising materials because they allow the water-proton longitudinal relaxivity (r1) to be enhanced not only by paramagnetic resonance effects but also by prolonging the rotational correlation times (τR). However, the τR effect is limited because the radical units are often located within the central hydrophobic core of oil-in-water (o/w) emulsions, resulting in a lack of water molecules surrounding the radical units. In this study, to construct supramolecular RNPs that have high r1 values, we designed a liposome-type RNP in which the radical units are located at positions with sufficient surrounding water molecules. Using this strategy, PRO1 with a PROXYL framework was prepared by introducing hydrophilic groups on both sides of the radical unit. The RNP composed of PRO1 formed spherical nanoparticles approximately 100 nm in size and yielded a higher r1 value (0.26 mM-1 s-1) compared to those of small radical species and similar supramolecular o/w emulsion-type nanoparticles (0.17 mM-1 s-1 in PRO2).

Effects of Substituents on the Properties of Metal-Free MRI Contrast Agents.

Materials possessing electron spin can shorten the T 1 relaxation times in magnetic resonance imaging (MRI). For example, gadolinium (Gd) complexes with seven f-orbital electrons are widely used as contrast agents in clinical applications. However, Gd has severe potential side effects, and thus metal-free alternatives are needed. Toward this end, we synthesized seven NO radicals consisting of a dioxa-azaspiro[4.5]decane framework having various substituents, DAD-X (X = methyl, ethyl, n-propyl, c-propyl, vinyl, phenyl, and 2-pyridyl), that functioned as metal-free MRI contrast agents. The relationship between (i) water-proton relaxivity and log P and (ii) reactivity for ascorbic acid and the spin density of the NO oxygen atom were established, which provided a basis for the rational design of practical metal-free contrast agents.

Fluorescence Tumor-Imaging Using a Thermo-Responsive Molecule with an Emissive Aminoquinoline Derivative.

We synthesized (2,4-trifluoromethyl-7-N-bis(2,5,8,11-tetraoxatridecane-13-yl)-aminoquinoline) TFMAQ-diEg4, an emissive aminoquinoline derivative that incorporated two tetraethyleneglycol chains into an amino group. TFMAQ-diEg4 showed fluorescence and thermo-responsive properties accompanied by a lower critical solution temperature (LCST), due to the introduction of the oligoethylene glycol chain. This thermo-responsive LCST behavior occurred at the border of a cloud point. Below and above the cloud point, self-assemblies of 6-7-nm nanoparticles and ~2000-nm microparticles were observed, in vitro. In addition, TFMAQ-diEg4 showed a high solubility, over 20 mM for aqueous solution, in vivo, which not only prevented thrombosis but also allowed various examinations, such as single intravenous administration and intravenous drips. Intravenous administration of TFMAQ-diEg4, to tumor-bearing, mice led to the accumulation of the molecule in the tumor tissue, as observed by fluorescence imaging. A subset of mice was treated with local heat around their tumor tissue and an intravenous drip of TFMAQ-diEg4, which led to a high intensity of TFMAQ-diEg4 emission within the tumor tissue. Therefore, we revealed that TFMAQ-diEg4 was useful as a fluorescence probe with thermo-responsive properties.