Nanoparticles capable of accumulating in tumor tissues are promising materials for tumor imaging and therapy. In this study, two radical nanoparticles (RNPs), denoted as 1 and 2, composed of self-assembled ureabenzene derivatives possessing one or two amphiphilic side chains were demonstrated to be candidates for metal-free functional magnetic resonance imaging (MRI) contrast agents (CAs). Because of the self-assembly behavior of 1 and 2 in a saline solution, spherical RNPs of sizes ∼50-90 and ∼30-100 nm were detected. In a highly concentrated solution, RNP 1 showed considerably small water-proton relaxivity values (r and r), whereas RNP 2 showed an r value that was around 5 times larger than that of RNP 1. These distinct r values might be caused by differences in the self-assembly behavior by a hydration or dehydration process. In vivo studies with RNP 2 demonstrated a slightly enhanced T-weighted image in mice, suggesting that the RNPs can potentially be used as metal-free functional MRI CAs for T-weighted imaging.
For development of the metal-free MRI contrast agents, we prepared the supra-molecular organic radical, TEMPO-UBD, carrying TEMPO radical, as well as the urea, alkyl group, and phenyl ring, which demonstrate self-assembly behaviors using noncovalent bonds in an aqueous solution. In addition, TEMPO-UBD has the tertiary amine and the oligoethylene glycol chains (OEGs) for the function of pH and thermal responsiveness. By dynamic light scattering and transmission electron microscopy imaging, the resulting self-assembly was seen to form the spherical nanoparticles 10-150 nm in size. On heating, interestingly, the nanoparticles showed a lower critical solution temperature (LCST) behavior having two-step variation. This double-LCST behavior is the first such example among the supra-molecules. To evaluate of the ability as MRI contrast agents, the values of proton ((1)H) longitudinal relaxivity (r1) were determined using MRI apparatus. In conditions below and above CAC at pH 7.0, the distinguishable r1 values were estimated to be 0.17 and 0.21 mM(-1) s(1), indicating the suppression of fast tumbling motion of TEMPO moiety in a nanoparticle. Furthermore, r1 values became larger in the order of pH 7.0 > 9.0 > 5.0. Those thermal and pH dependencies indicated the possibility of metal-fee MRI functional contrast agents in the future.
As part of a series of investigations related to the construction of metal-free magnetic resonance imaging (MRI) contrast agents as alternatives to gadolinium agents, water-soluble biradicals, denoted as 1-AMP and 2-HEG, were prepared, in which two stable radicals were introduced to a ureabenzene framework. We found that 1-AMP possessed an amphiphilic side chain that consisted of an alkyl group and a hexaethylene glycol (HEG) chain, whereas 2-HEG possessed only an HEG chain. Accordingly, the biradicals showed self-assembly behavior due to multiple intermolecular interactions through which nanoparticles were formed in a water solution. Magnetic interaction took place in both biradicals, and the estimated interaction strength was J = 5.4 mT. Through MRI measurement, the water proton relaxivities, r 1, were estimated to be 0.12 and 0.41 mM–1 s–1 for 1-AMP and 2-HEG, respectively; in other words, the r 1 value for 2-HEG was approximately twice as high as that of monoradical-based contrast agents.
Materials possessing electron spin can shorten the T1 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.
Urea benzene derivatives (UBD) with amphiphilic side chains showed self-assembly behavior in aqueous solution to form nanoparticles~100 nm in size. Subsequent thermal treatment led to additional self-assembly of the nanoparticles due to dehydration of the amphiphilic side chains, producing microparticles. This self-assembly process was accompanied by a lower critical solution temperature (LCST) behavior, as revealed by the abrupt decrease in solution transmittance. In this study, three UBD (UBD-1-3) with different lengths of the alkyl segment in the amphiphilic side chain (namely, hexyl, heptyl, and octyl, respectively) were prepared to investigate the self-assembly behavior in aqueous solution. UBD-1-3 formed identical nanoparticles, with sizes in the 10~80 nm range but with different LCST values in the order 3 < 2 < 1. These results suggest a relationship between the hydrophobicity and the self-assembly behavior of UBD.
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