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

Area of Science:

• Biomedical Imaging
• Oncology
• Chemical Biology

Background:

• Cancer poses a significant global health challenge, necessitating advanced diagnostic tools.
• Current pH-sensitive probes lack specificity, leading to poor signal-to-noise ratios in vivo.
• Targeted imaging agents are crucial for precise cancer diagnosis and treatment guidance.

Purpose of the Study:

• To develop a tumor-specific, tumor microenvironment (TME)-sensitive near-infrared (NIR) fluorescent probe for enhanced in vivo cancer imaging.
• To evaluate the efficacy of a novel probe (R2SM) combining CCK2R targeting with pH sensitivity for gastrointestinal stromal tumor (GIST) imaging.

Main Methods:

• Synthesis of R2SM by conjugating a pH-sensitive heptamethine cyanine dye with a CCK2R-targeting ligand (MG11).
• In vitro cell uptake assays to assess R2SM affinity for CCK2R and lysosomal localization.
• In vivo fluorescence imaging in tumor-bearing models to evaluate probe accumulation, signal intensity, and tumor-to-background ratios.

Main Results:

• R2SM demonstrated high affinity for CCK2R, leading to receptor-mediated internalization and accumulation in tumor cell lysosomes.
• The probe exhibited pH-dependent fluorescence activation in acidic TMEs and lysosomes (pKa=6.83).
• In vivo imaging revealed rapid tumor accumulation and enhanced fluorescence in CCK2R-overexpressed tumors, with improved tumor-to-organ ratios compared to control probes.

Conclusions:

• The synergistic combination of CCK2R targeting and TME pH sensitivity significantly enhances the signal-to-noise ratio for NIR imaging probes.
• R2SM shows great potential for precise in vivo tumor imaging and intraoperative guidance.
• Further development could involve conjugating R2SM with other targeting vectors to improve receptor affinity and targeting efficiency.