Self-Assembly Behavior of Emissive Urea Benzene Derivatives Enables Heat-Induced Accumulation in Tumor Tissue

Abstract

In this study we describe the construction of a system composed of thermally responsive molecules that can be induced to accumulate in tumor tissues by heating. EgX molecules consisting of an urea-benzene framework and oligoethylene glycol (OEG) functional groups with an emissive aminoquinoline formed nanoparticles (NPs) ∼10 nm in size at 23 °C with a fluorescence quantum yield of 7-10%. At higher temperatures, additional self-assembly occurred as a result of OEG dehydration, and the NPs grew to over 1000 nm in size; this was accompanied by low critical solution temperature behavior. EgXs accumulated in tumor tissues of mice at a body temperature of around 33-35 °C, an effect that was accelerated by external heating around the tumor to approximately 40 °C as a result of increased particle size and enhanced retention in tissue. These EgX NPs can serve as a tool for in vivo monitoring of tumor progression and response to treatment.

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

“…The solubility of TFMAQ-diEg4 in aqueous solutions was investigated, as the prevention of thrombosis is of significance for in vivo examinations. The solubility of TFMAQ-UBD, which has been previously reported as fluorescent probes [ 20 ], showed a limited solubility of below 20 mM. However, the resulting TFMAQ-diEg4 showed a high solubility of over 20 mM, in aqueous solutions, indicating that it could not only prevent thrombosis but could also allow for various in vivo examinations, such as single intravenous administration and intravenous drips, with or without local heating, around the tumor tissues.…”

“…The self-assembly of UBD is mediated by the response of OEG to heat, wherein, heat induces dehydration [ 18 , 19 ] and the molecule then self-assembles by hydrophobic interactions. Therefore, we prepared a thermo-responsive fluorescent molecule TFMAQ-UBD ( n = 3, 4, and 6, Scheme 1 ) [ 20 ], made up of UBD and an aminoqunoline derivative (TFMAQ) [ 21 , 22 , 23 , 24 ], which a fluorophore that possesses medium emission quantum yields. Accordingly, TFMAQ-UBD showed a self-assembly behavior at a low temperature, which led to the formation of nanoparticles, approximately ~10 nm in size.…”

Effect of Hydrophobicity on the Self-Assembly Behavior of Urea Benzene Derivatives in Aqueous Solution

“…The TEM images of UBD were obtained using uranyl acetate as a negative staining agent and the dried samples prepared according to previous reports [12,13,19]. As can be seen from the images shown in Figure 3, for all UBD, spherical nanoparticles with sizes in the 10-80 nm range were observed.…”

“…In contrast, the aromatic protons in the ortho position (H o in Scheme 1) were deshielded. These shielding [13,19,22] and deshielding shifts [13,19,23] typically derive from the formation of aggregates and the interaction via hydrogen bond between urea moiety and H o atoms in the phenyl ring, respectively. The chemical shift of the aromatic protons in the meta position (H m in Scheme 1) was plotted as a function of the concentration, and a breaking point was observed at 16 mM (Figure 1c), which corresponds to the CAC of UBD-1.…”

“…In addition, UBD have been used in our laboratory for the development of functional materials; namely, radical nanoparticles have been employed for metal-free magnetic resonance imaging contrast agents [13], and push-pull-type, aminoquinoline-based fluorescent probes have been constructed for bioimaging applications [14][15][16][17][18]. Among the latter, we have successfully developed a tumor-imaging probe activated by heat treatment [19].…”