Multimodality molecular imaging probes are essential to advancing biomedical and clinical research. Of them, bimodal molecular probes that integrate near infrared (NIR) fluorescence imaging and magnetic resonance imaging (MRI) modalities can provide accurate information in early diagnosis of malignant tumors and image-guided tumor surgery. Although several NIR fluorescence/MRI bimodal probes have been reported to offer high sensitivity and high spatial resolution for molecular imaging and surgical guidance, most of these probes display “always-on” signals regardless of interactions with targeted tumor cells, which can cause low tumor-to-background ratios (TBR) and make it difficult to effectively distinguish tumor tissues. Activatable NIR fluorescence/MRI bimodality imaging probes with “off-on” signals can reduce background and improve signal-to-noise ratio, which are advantageousfor tumor imaging. However, due to the lack of efficient approaches, such activatable bimodal probes are remaining rarely reported.
Ye’s group from the State Key Laboratory of Life Analytical Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, have focused on the development of stimuli-activatable molecular imaging probes for in vivo imaging in the past few years (J. Am. Chem. Soc. 2018, 140, 16340; Angew. Chem. Int. Ed. 2019, 58, 4886; Nano Lett. 2019, 19, 937; ACS Nano 2016, 10, 10075). Recently, they reported a strategy combining fluorogenic reaction with in situ self-assembly amenable to build activatable NIR fluorescence/MRI bimodal small molecule probes (called as fluorogenic MRI probes) for in vivo imaging (Figure 1). Using alkaline phosphatase (ALP) as a model enzyme, a probe, P-CyFF-Gd, was designed and synthesized to show “off” NIR fluorescence and low r1 relaxivity. Upon interaction with ALP overexpressed on the surface of tumor cells, rapid dephosphorylation of hydrophilic P-CyFF-Gd into fluorescent CyFF-Gd occurred, following by molecular self-assembly in situ to form magnetic nanoparticles. As such, both NIR fluorescence and r1 relaxivity were augmented. Besides, on-site assembling nanoparticles were also prone to anchoring on the cell membrane, which can facilitate cellular uptake and prolong retention in tumor cells. P-CyFF-Gd was successfully applied to detect and map orthotopic liver tumor margins in intraoperative mice, allowing for real-time image-guided resection of liver tumors. Such strategy can be adopted to design other stimuli-activatable bimodal probes useful in molecular imaging.
This work entitled with Activatable NIR Fluorescence/MRI Bimodal Probes for in Vivo Imaging by Enzyme-Mediated Fluorogenic Reaction and Self-Assembly was published in J. Am. Chem. Soc. 2019, DOI: 10.1021/jacs.9b03649. Runqi Yan and Yuxuan Hu are the co-first authors and Professor Deju Ye is the corresponding author. Academician Hong-Yuan Chen has given important suggestions to this work. Fei Liu, a technician from the State Key Laboratory of Analytical Chemistry for Life Science helped in the Cryo-SEM. This research is supported by the National Key R&D Program of China (2017YFA0701301), National NaturalScience Foundation of China (21775071 and 21632008), the Fundamental Research Funds for the Central Universities (020514380185), Excellent Research Program of Nanjing University (ZYJH004).
Figure 1 Schematic illustration shows an ALP-activatable NIR fluorescence (FL)/MR bimodal probe for in vivo imaging. (a) Chemical structure of P-CyFF-Gd and proposed ALP-mediated fluorogenic reaction and in situ self-assembly of P-CyFF-Gd into NPs. (b) Proposed mechanism of P-CyFF-Gd for NIR FL/MR bimodality imaging of ALP-positive tumor cells in vivo. (c) Fluorescence imaging of ALP activity in tumor cells by P-CyFF-Gd. (d) Cryo-SEM image of NPs formed on the membrane of a HeLa cell. (e) The NIR fluorescence imaging and (f) MR imaging of orthotopic liver tumor in mice.