A Sophisticated Ratiometric Nuclear Medicine Imaging Strategy for Biological Microenvironment Abnormal Factor Detection

A novel ratiometric nuclear medicine strategy for noninvasively monitoring microenvironmental factors is developed, cleverly linking a ¹²⁵I-labeled targeting moiety (TM) to a ¹⁷⁷Lu-labeled clearable moiety (CM) through a disulfide bond. In hepatitis models, the probe is cleaved into two fragments with distinct metabolic fates, enabling the glutathione (GSH) detection via the ¹⁷⁷Lu /¹²⁵I signal ratio, as determined by energy discriminant single photon emission computed tomography (SPECT).

Abstract

Biological microenvironment detection is crucial for deciphering the mechanisms underlying malignant progression and predicting the treatment efficacy of diseases. Nevertheless, only very limited progress has been made toward non-invasive and quantitative detection of microenvironment abnormal factors, let alone with clinically compatible imaging modalities. Herein, a smart nuclear medicine probe is proposed, innovatively designed for quantitative visualization of glutathione (GSH) in vivo. This probe contains a disulfide bond that links two molecular segments labeled with ¹²⁵I and ¹⁷⁷Lu, respectively. Upon systemic delivery, the probe preferentially accumulates in the liver, where GSH cleaves it into two fragments with completely different metabolic fates: one retained at the response site and the other rapidly excreted. This unique feature provides an opportunity to use the ¹⁷⁷Lu/¹²⁵I signal ratio to non-invasively characterize the GSH concentration in vivo, enabling highly sensitive quantification of GSH that is strongly associated with many hepatic diseases. Moreover, the strategy also provides a reliable method for the quantitative visualization of GSH levels in tumors. It is thus believed the current study provides a groundbreaking method for non-invasively and quantitatively revealing disease-related microenvironment factors, not limited to GSH, in vivo.