Unsymmetrical pentamethine cyanines for visualizing physiological acidities from the whole-animal to the cellular scale with pH-responsive deep-red fluorescence

Wang, Yicheng; Lei, Zuhai; Cao, Chen; Hu, Jiayi; Du, Ling; Han, Limei; Liu, Cong

doi:10.1039/d1ra02217b

“…The acidic TME is a distinctive feature of various solid tumors, which can serve as an essential biomarker to develop tumor imaging agents. Usually, the pH of the normal cell microenvironment is carefully controlled between 7.2 and 7.4, while the pH declines to 6.5–6.8 in TME. − Boron-dipyrromethene fluorophores (BODIPY) ,− and heptamethine cyanines − -based NIR pH-sensitive probes were investigated for biosensing in vivo , since their long wavelength of absorption (λ abs ) and emission (λ em ) are advantageous for deep penetration. However, most of the studied NIR pH-sensitive probes exhibit p K a values between 4.5 and 7.5, indicating that they would be illuminated after reaching lysosomes (pH = 4.0–5.5).…”

Section: Introductionmentioning

confidence: 99%

Acidity-Triggered “Sticky Spotlight”: CCK2R-Targeted TME-Sensitive NIR Fluorescent Probes for Tumor Imaging In Vivo

Sun,

Wang,

Shi

et al. 2024

Bioconjugate Chem.

0

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Cancer which causes high mortality globally threatens public health seriously. There is an urgent need to develop tumor-specific near-infrared (NIR) imaging agents to achieve precise diagnosis and guide effective treatment. In recent years, imaging probes that respond to acidic environments such as endosomes, lysosomes, or acidic tumor microenvironments (TMEs) are being developed. However, because of their nonspecific internalization by both normal and tumor cells, resulting in a poor signal-to-noise ratio in diagnosis, these pH-sensitive probes fail to be applied to in vivo tumor imaging. To address this issue, a cholecystokinin-2 receptor (CCK2R)-targeted TME-sensitive NIR fluorescent probe R2SM was synthesized by coupling pH-sensitive heptamethine cyanine with a CCK2R ligand, minigastrin analogue 11 (MG11) for in vivo imaging, in which MG11 would target overexpressed CCK2Rs in gastrointestinal stromal tumors (GISTs). Cell uptake assay demonstrated that R2SM exhibited a high affinity for CCK2R, leading to receptormediated internalization and making probes finally accumulated in the lysosomes of tumor cells, which suggested in the tumor tissues, the probes were distributed in the extracellular acidic TME and intracellular lysosomes. With a pK a of 6.83, R2SM can be activated at the acidic TME (pH = 6.5−6.8) and lysosomes (pH = 4.5−5.0), exhibiting an apparent pH-dependent behavior and generating more intense fluorescence in these acidic environments. In vivo imaging showed that coupling of MG11 with a pHsensitive NIR probe facilitated the accumulation of probe and enhanced the fluorescence in CCK2R-overexpressed HT-29 tumor cells. A high signal was observed in the tumor region within 0.5 h postinjection, indicating its potential application in intraoperative imaging. Fluorescence imaging of R2SM exhibited higher tumor-to-liver and tumor-to-kidney ratios (2.1:1 and 2.3:1, respectively), compared separately with the probes that are lipophilic, pH-insensitive, or MG11-free. In vitro and in vivo studies demonstrated that the synergistic effect of tumor targeting with pH sensitivity plays a vital role in the high signal-to-noise ratio of the NIR imaging probe. Moreover, different kinds of tumor-targeting vectors could be conjugated simultaneously with the NIR dye, which would further improve the receptor affinity and targeting efficiency.

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“Dual‐Key‐and‐Lock” NIR‐II NSCyanines Enable High‐Contrast Activatable Phototheranostics in Extrahepatic Diseases

Tian

¹

,

Chen

²

,

Liu

³

et al. 2023

Angewandte Chemie

1

0

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Conventional cyanine dyes with a symmetric structure are "always‐on", which can easily accumulate in the liver and display high liver background fluorescence, inevitably interfering the accurate diagnosis and therapy in extrahepatic diseases. We herein report a platform of NIR‐II non‐symmetric cyanine (NSCyanine) dyes by harnessing a non‐symmetric strategy, which are extremely sensitive to pH/viscosity and can be activated via a“dual‐key‐and‐lock”strategy. These NSCyanine dyes with a low pKa (<4.0) only show weak fluorescence at lysosome pH (key1), however, the fluorescence can be completely switched on and significantly enhanced by intracellular viscosity (key2) in disease tissues, exhibiting high target‐to‐liver ratios up to 19.5/1. Notably, high‐contrast phototheranostics in extrahepatic diseases are achieved, including intestinal metastasis‐imaging, acute gastritis‐imaging, bacteria infected wound healing, and tumor ablation via targeted combined photothermal therapy and chemotherapy.

show abstract

“Dual‐Key‐and‐Lock” NIR‐II NSCyanines Enable High‐Contrast Activatable Phototheranostics in Extrahepatic Diseases

Tian

¹

,

Chen

²

,

Liu

³

et al. 2023

View full text Add to dashboard Cite

Conventional cyanine dyes with a symmetric structure are "always‐on", which can easily accumulate in the liver and display high liver background fluorescence, inevitably interfering the accurate diagnosis and therapy in extrahepatic diseases. We herein report a platform of NIR‐II non‐symmetric cyanine (NSCyanine) dyes by harnessing a non‐symmetric strategy, which are extremely sensitive to pH/viscosity and can be activated via a“dual‐key‐and‐lock”strategy. These NSCyanine dyes with a low pKa (<4.0) only show weak fluorescence at lysosome pH (key1), however, the fluorescence can be completely switched on and significantly enhanced by intracellular viscosity (key2) in disease tissues, exhibiting high target‐to‐liver ratios up to 19.5/1. Notably, high‐contrast phototheranostics in extrahepatic diseases are achieved, including intestinal metastasis‐imaging, acute gastritis‐imaging, bacteria infected wound healing, and tumor ablation via targeted combined photothermal therapy and chemotherapy.

show abstract

Unsymmetrical pentamethine cyanines for visualizing physiological acidities from the whole-animal to the cellular scale with pH-responsive deep-red fluorescence

Abstract: Unsymmetrical pentamethine cyanine fluorophores were developed and used to visualize physiological acidities from the whole-animal to the cellular scale with pH-responsive deep-red fluorescence.

Cited by 5 publications

References 30 publications

Acidity-Triggered “Sticky Spotlight”: CCK2R-Targeted TME-Sensitive NIR Fluorescent Probes for Tumor Imaging In Vivo

Acidity-Triggered “Sticky Spotlight”: CCK2R-Targeted TME-Sensitive NIR Fluorescent Probes for Tumor Imaging In Vivo

“Dual‐Key‐and‐Lock” NIR‐II NSCyanines Enable High‐Contrast Activatable Phototheranostics in Extrahepatic Diseases

“Dual‐Key‐and‐Lock” NIR‐II NSCyanines Enable High‐Contrast Activatable Phototheranostics in Extrahepatic Diseases

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