Xanthene‐Based Nitric Oxide‐Responsive Nanosensor for Photoacoustic Imaging in the SWIR Window

Abstract

Shortwave infrared (SWIR) dyes are characterized by their ability to absorb light from 900 to 1400 nm, which is ideal for deep tissue imaging owing to minimized light scattering and interference from endogenous pigments. An approach to access such molecules is to tune the photophysical properties of known near‐infrared dyes. Herein, we report the development of a series of easily accessible (three steps) SWIR xanthene dyes based on a dibenzazepine donor conjugated to thiophene (SCR‐1), thienothiophene (SCR‐2), or bithiophene (SCR‐3). We leverage the fact that SCR‐1 undergoes a bathochromic shift when aggregated for in vivo studies by developing a ratiometric nanoparticle for NO (rNP‐NO), which we employed to successfully visualize pathological levels of nitric oxide in a drug‐induced liver injury model via deep tissue SWIR photoacoustic (PA) imaging. Our work demonstrates how easily this dye series can be utilized as a component in nanosensor designs for imaging studies.

Two Key Descriptors for Designing Second Near-Infrared Dyes and Experimental Validation

“…Further validation of our proposed molecular descriptors was performed based on 50 non-MAP NIR-II dyes reported by other groups. − ,− These non-MAP NIR-II dyes could be classified into five types, including 14 BBT dyes, ,,,− ,,− 10 BODIPY dyes, ,− 12 xanthene dyes, ,− 12 polymethine dyes, ,,,, and 2 tetra-benzannulated xanthene dyes; , these basically covered most of the NIR-II dyes reported in previous works (Table S7). The absorption/emission wavelengths in the experiments and the corresponding values of the calculated Δ E gs and μ gs for these NIR-II dyes are summarized in Table S7.…”

Synthesis and Characterization of Novel Thienothiadiazole-Based D−π–A−π–D Fluorophores as Potential NIR Imaging Agents

“…NIR-I emissive fluorophores have been used for FI applications but suffer from issues such as low penetration depth and increased backscattering of emitted photons in vivo . , NIR-II emissive fluorophores have been shown to alleviate these issues; conversely, in this work, multiple concepts are utilized to design NIR-II emissive fluorophores . First is using the D−π–A−π–D molecular architecture, a well-known design strategy in the literature that has resulted in fluorophores with distinct optical properties . The second concept is to design the fluorophores with the goal of increasing their ICT properties .…”

Xanthene-based near-infrared chromophores for high-contrast fluorescence and photoacoustic imaging of dipeptidyl peptidase 4

“…An alternative approach is conjugating xanthene with varying p-conjugation systems at different positions. [15][16][17][18][19][20] For instance, p-conjugated expansion at position 3 afforded chromophores with NIR absorption wavelengths. 15,16 However, some of these chromophores always exist in a spirocyclic "closed" form or xanthene "open" form at physiological pH, preventing the design of analyte-activatable uorescence/PA imaging probes.…”

“…17,18 Recently, a type of xanthene-based NIR-II chromophore has been engineered by p-conjugated expansion at positions 3 and 6. 19,20 However, they intended to exist in the spirocyclic form and the carboxylic moiety needs to be esteried to inhibit the lactonization. Thus, the development of new xanthene-based NIR chromophores that exhibit analytemodulated photophysical properties is highly desirable.…”