Hypoxia-Responsive Luminescent CEST MRI Agent for In Vitro and In Vivo Tumor Detection and Imaging

Abstract

Hypoxia is a feature of most solid tumors and a key determinant of cancer growth and propagation. Sensing hypoxia effectively could lead to more favorable clinical outcomes. Here, we report a molecular antenna-based bimodal probe designed to exploit the complementary advantages of magnetic resonance (MR)-and optical-based imaging. Specifically, we describe the synthesis and evaluation of a dual-action probe (NO 2 -Eu) that permits hypoxia-activated chemical exchange saturation transfer (CEST) MR and optical imaging. In CT26 cells, this NO 2 -Eu probe not only provides an enhanced CEST MRI signal but also turns "on" the optical signal under hypoxic conditions. Timedependent in vivo CEST imaging in a hypoxic CT26 tumor xenograft mouse model revealed probe-dependent tumor detection by CEST MRI contrast in the tumor area. We thus suggest that dual-action hypoxia probes, like that reported here, could have a role to play in solid tumor diagnosis and monitoring.

A novel CEST-contrast nanoagent for differentiating the malignant degree in breast cancer

“…2B ), and this attributed to the paramagnetic magnetic field of Eu 3+ and the electron transfer of hydrogen ions. 34 This was a great help to improve the sensitivity of CEST imaging. Then, the capability of pH detection was further investigated ( Fig.…”

“…More importantly, the paramagnetic magnetic field of Eu 3+ forms a strong electronic interaction with the amino hydrogen. 29,30,33,34 It induced the characteristic shift peak of arginine to low-field, which increased the chemical shift difference between amino and water molecules, further improving the CEST sensitivity (Scheme 1). Cells wound assays and the extracellular acidity ratio (ECAR) assays showed that 4T1 was more invasive and acid-producing than TUBO.…”

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

“…Besides, synergistic hypoxia-activated CEST magnetic resonance, and optical imaging of hypoxic tissues can take advantage of complementary strengths of modalities to enhance diagnostic capability. For example, Karan et al constructed a probe (NO 2 –Eu) to detect tumor hypoxia by the introduction of a 3-nitropthalimide group as an NTR-sensitive moiety (Figure a, b) . In the presence of NADH, NTR can convert the 3-nitropthalimide moiety of the NO 2 –Eu probe to the primary aromatic amino group.…”

“…(b) Time-dependent in vivo CEST imaging of probe NO 2 –Eu. Reproduced from ref with permission. Copyright (2022) American Chemical Society.…”

“…For example, Karan et al constructed a probe (NO 2 −Eu) to detect tumor hypoxia by the introduction of a 3-nitropthalimide group as an NTRsensitive moiety (Figure 12a, 12b). 370 In the presence of NADH, NTR can convert the 3-nitropthalimide moiety of the NO 2 −Eu probe to the primary aromatic amino group. The luminescent is activated by the intramolecular charge transfer (ICT) from the free NH 2 moiety to the Eu 3+ ion.…”