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

Takeru Araki,Mariko Aso,Ryoma Shiraishi,Ichio Aoki,Shigeki Kobayashi,Satoru Karasawa,Ken-Ichi Yamada,Tokimi Oyama,Shuhei Murayama,Yasufumi Fuchi

doi:10.3390/nano8100782

Abstract

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.

Highlights

Tumor tissues are differentiated from healthy tissues on the basis of a number of different properties
The void spaces, which form when cancer cells undergo apoptosis, are approximately 10–500 nm in size; nanoparticles of this size have been shown to penetrate and remain within tumors. This is described as the enhanced permeability and retention (EPR) effect [7] and is very useful for drug delivery systems (DDS)
Taking advantage of the thermo-responsive properties of TFMAQ-diEg4, we showed that TFMAQ-diEg4 was useful as a fluorescent probe for tumor-imaging

Summary

Introduction

Tumor tissues are differentiated from healthy tissues on the basis of a number of different properties. Three of the most well-known features are, (1) the presence of a void space in the tumors [1,2], (2) acidic properties of tumors [3,4], and (3) higher temperature of tumor tissues [5,6]. The void spaces, which form when cancer cells undergo apoptosis, are approximately 10–500 nm in size; nanoparticles of this size have been shown to penetrate and remain within tumors. This is described as the enhanced permeability and retention (EPR) effect [7] and is very useful for drug delivery systems (DDS). Thetic route of TFMAQ-diEg4 is shown in Scheme S1. Synthetic route of TFMAQ-diEg4 is shown in Scheme S1. 1H NMR of TFMAQ-Eg4 and – diEg4 are shown in Figure S1 and S2

Solubility for Aqueous Solution

Materials and Methods

Single and Drip Administration via Tail Vein

Conclusions