JACS Cover Shanghai Institute of Materia Medica's cooperation in the development of a near-infrared secondary small molecule fluorescent probe that can cross the blood-brain barrier

Compared with visible light and NIR I fluorescence imaging, NIR-II fluorescence imaging has the advantages of lower tissue autofluorescence, deeper tissue penetration depth and higher imaging resolution, and is considered to be a promising imaging method
for the diagnosis and treatment of diseases and intraoperative real-time navigation.
In recent years, the research on NIR-II fluorescent probes and their application in the diagnosis and treatment of diseases has also received extensive attention and made great progress
.
However, due to the existence of the blood-brain barrier, there is currently a lack of NIR-II fluorescent probes, which can effectively image brain tissue and complex brain diseases
.
Therefore, the development of NIR-II fluorescent molecular probes that can cross the blood-brain barrier has important research and clinical translational significance
.

On December 13, 2022, Han Xiao's laboratory at Rice University and the team of Cheng Zhen of the Center for Molecular Imaging of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published a report entitled "Photostable Small-Molecule NIR-II Fluorescent Scaffolds that Cross the Blood" in the Journal of the American Chemical Society Brain Barrier for Noninvasive Brain Imaging", which was selected as the cover article
.

Based on BF2 formazan compounds, the study regulates the emission wavelength of the molecule and its amphiphilia by introducing different substituents, resulting in a near-infrared secondary fluorescent molecule
capable of crossing the BBB.
In vivo experiments on healthy mice and brain glioma model mice in situ, real-time non-invasive near-infrared II region development of brain tissue was successfully realized, and healthy brain tissue and glioma tissue
could be distinguished by the difference in the distribution of fluorescence signals in the brain.

Figure 1.
A novel near-infrared secondary fluorescent molecule with the ability to traverse the BBB was developed for mouse healthy brain and in situ glioma models
, respectively.

These molecules have emission wavelengths between 950-1004 nm and have moderate amphiphilicity (1.
3 < ClogP < 3.
2) and small molecular weights (< 488 g mol-1).

At the same time, they also have a large Stokes shift, high secondary fluorescence quantum yield and brightness
.
Under large laser density irradiation, the dye also exhibits very high photostability
.
In cellular-level simulated cross-BBB experiments, BF1 and BF6 molecules with molecular substituents morpholine and N,N-dimethylamine structures exhibited potential BBB traversal capabilities
.

Figure 2.
a.
Structure of BF1-BF8 series compounds; b.
Photostability of BF1 and ICG in cells; c.
Potential BBB crossing capability detection of BF1-BF8 series
compounds.

The researchers examined the distribution of compounds such as BF1-BF6 in healthy mice and found that BF1 and BF6 were able to cross the BBB very well and develop clearly on brain tissue (Figure 3a).

In order to better observe the process of its penetration into the BBB, the fluorescent dye ICG used clinically that cannot pass through the BBB was used as a reference to compare the differences
in their distribution in the brains of mice.
The results showed that within 20 s after administration, BF6 compounds were mainly distributed in blood vessels, and with the growth of time, the boundaries of blood vessels and tissues in the brain became more and more blurred, and the fluorescence signal in brain tissue continued to enhance until 120 s when the whole brain was lit up, and BF6 compounds were distributed in the entire brain tissue
of mice.
For mice in the ICG administration group, the brain fluorescence signal remained in the blood vessels until it was metabolized and disappeared (Figure 3b).

Subsequently, the researchers administered BF1 and BF6 to glioma model mice in situ through the tail vein and imaged them with zone II fluorescence
.
The results showed that normal tissue of the brain had a stronger fluorescence signal than the glioma-associated tissue area, which showed that dye molecules had a higher aggregation
in normal brain tissue than in glioma area.
By analyzing differentiated development of living and ex vivo brains, glioma regions and normal brain tissue
can be easily distinguished.

Figure 3.
a.
Distribution of BF1 and BF6 molecules in the brain and other tissues of healthy mice; b.
Different behavior of BF6 and ICG in cerebral blood vessels; Imaging
of BF1 and BF6 in mouse gliomas in situ.

This study is the first to report a near-infrared II fluorescent small molecule dye that can cross the blood-brain barrier, which provides a potential molecular framework
for the further design and development of near-infrared II fluorescent molecular probes for the diagnosis and treatment of brain diseases.

Shichao Wang, a postdoctoral fellow at Rice University, and Shi Hui, a postdoctoral fellow at the Shanghai Institute of Materia Medica, are co-first authors
of the study.
Professor Han Xiao of Rice University and researcher Cheng Zhen of the Molecular Imaging Center of Shanghai Institute of Materia Medica, are co-corresponding authors
.

Full text link: https://pubs.
acs.
org/doi/10.
1021/jacs.
2c11223?fig=abs1&ref=pdf

Magazine cover

(Contributing department: Cheng Zhen Research Group; Contributor: Shi Hui)