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Biological and Medical Applications of Materials and Interfaces
Fluorine Meets Amine: Reducing Microenvironment-induced Aminoactivatable Nanoprobes for 19F Magnetic Resonance Imaging of Bio-thiols Pingsheng Huang, Weisheng Guo, Guang Yang, Huijuan Song, Yuqing Wang, Chun Wang, Deling Kong, and Weiwei Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b03764 • Publication Date (Web): 18 May 2018 Downloaded from http://pubs.acs.org on May 18, 2018
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ACS Applied Materials & Interfaces
Fluorine Meets Amine: Reducing Microenvironment-induced Amino-activatable Nanoprobes for 19F Magnetic Resonance Imaging of Bio-thiols Pingsheng Huang,a1 Weisheng Guo,b1 Guang Yang,c Huijuan Song,a Yuqing Wang,b Chun Wang,a,d Deling Kong,a* Weiwei Wang a* a
Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese
Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, P. R. China. b
Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center
for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing, 100190, P. R. China. c
Department of Polymer Science and Technology, School of Chemical Engineering and
Technology, Tianjin University, Tianjin 300072, P. R. China d
Department of Biomedical Engineering, University of Minnesota, Minneapolis MN 55455, USA
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ABSTRACT: 19F MRI is of great significance for non-invasive imaging and detection of various diseases. However, the main obstacle in the application of 19F MRI agents stems from the unmet signal sensitivity, due to the poor water-solubility and restricted mobility of segments with high numbers of fluorine atoms. Herein, we report a kind of intracellular reducing microenvironment-induced amino-activatable
19
F MRI
nanoprobe, which can be used for specific imaging of bio-thiols. In principle, the nanoprobe
has
an
initial
architecture
of
hydrophobic
core,
where
the
trifluoromethyl-containing segments are compactly packed and 19F NMR/MRI signals are
quenched
(“OFF”
state).
Upon
encountering
sulfydryl,
the
strong
electron-withdrawing 2, 4-dinitrobenzenesulfonyl groups are excised to recover secondary amino groups, whose pKa is proved to be 7.21. As a consequence, the molecular weight loss of the hydrophobic segment and the protonation of amino groups induce significant disturbance of hydrophilic/hydrophobic balance, leading to the disassembly of the nanoprobes, regain of spin-spin relaxation and 19F NMR/MRI signals (“ON” state, T2 up to 296 ± 5.3 ms). This nanoprobe shows high sensitivity and selectivity to bio-thiols, enabling intracellular and intratumoral imaging of glutathione. Our study not only provides a new nanoprobe candidate for bio-thiols imaging in vivo, but also a promising strategy for the molecular design of real water-soluble and highly sensitive 19F MRI nanoprobes. KEYWORDS:
19
F MRI, nanoprobe, reducing microenvironment, amino activation,
thiol imaging.
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ACS Applied Materials & Interfaces
1. INTRODUCTION Magnetic resonance imaging (MRI) is one of the most significant methods for non-invasive visualization of deep tissues, offering important information in analyzing living systems and providing theranostic guidance for multiple kinds of diseases.1-4 Currently, 1H MRI is often restricted by the undesirable contrast-to-noise ratio, which should attribute to the background signals caused by the abundant water and carbohydrate protons in biological systems. Apart from combination with contrast agents (CAs), the development of heteronuclear MRI atoms is proved to be one of the most promising strategies to circumvent this issue, such as
13
C,
23
Na,
31
P, or
19
F.5-6
Due to its favorable nuclear magnetic resonance (NMR) properties, such as high gyromagnetic ratio and NMR sensitivity, 100% natural abundance and spin 1/2, F atom attracts the most attention. Importantly, only trace amount (
